Piezo1, the new actor in cell volume regulation.

All animal cells control their volume through a complex set of mechanisms, both to counteract osmotic perturbations of the environment and to enable numerous vital biological processes, such as proliferation, apoptosis, and migration. The ability of cells to adjust their volume depends on the activity of ion channels and transporters which, by moving K+, Na+, and Cl- ions across the plasma membrane, generate the osmotic gradient that drives water in and out of the cell. In 2010, Patapoutian's group identified a small family of evolutionarily conserved, Ca2+-permeable mechanosensitive channels, Piezo1 and Piezo2, as essential components of the mechanically activated current that mediates mechanotransduction in vertebrates. Piezo1 is expressed in several tissues and its opening is promoted by a wide range of mechanical stimuli, including membrane stretch/deformation and osmotic stress. Piezo1-mediated Ca2+ influx is used by the cell to convert mechanical forces into cytosolic Ca2+ signals that control diverse cellular functions such as migration and cell death, both dependent on changes in cell volume and shape. The crucial role of Piezo1 in the regulation of cell volume was first demonstrated in erythrocytes, which need to reduce their volume to pass through narrow capillaries. In HEK293 cells, increased expression of Piezo1 was found to enhance the regulatory volume decrease (RVD), the process whereby the cell re-establishes its original volume after osmotic shock-induced swelling, and it does so through Ca2+-dependent modulation of the volume-regulated anion channels. More recently we reported that Piezo1 controls the RVD in glioblastoma cells via the modulation of Ca2+-activated K+ channels. To date, however, the mechanisms through which this mechanosensitive channel controls cell volume and maintains its homeostasis have been poorly investigated and are still far from being understood. The present review aims to provide a broad overview of the literature discussing the recent advances on this topic.

Clinical and molecular characteristics of two Italian kindreds with hypoparathyroidism, deafness and renal dysplasia (HDR) syndrome.

PURPOSE: Hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome, also known as Barakat syndrome, is a rare autosomal dominant disease characterized by the triad of hypoparathyroidism, deafness, and renal abnormalities. The disorder is caused by the haploinsufficiency of the zinc finger transcription factor GATA3 and exhibits a great clinical variability with an age-dependent penetrance of each feature. We report two unrelated kindreds whose probands were referred to our outpatient clinic for further evaluation of hypoparathyroidism. METHODS: The proband of family 1, a 17-year-old boy, was referred for severe hypocalcemia (5.9 mg/dL) incidentally detected at routine blood tests. Abdomen ultrasound showed bilateral renal cysts. The audiometric evaluation revealed the presence of bilateral moderate hearing loss although the patient could communicate without any problem. Conversely, the proband of family 2, a 19-year-old man, had severe symptomatic hypocalcemia complicated by epileptic seizure at the age of 14 years; his past medical history was remarkable for right nephrectomy at the age of 4 months due to multicystic renal disease and bilateral hearing loss diagnosed at the age of 18 years. RESULTS: Based on clinical, biochemical, and radiologic data, HDR syndrome was suspected and genetic analysis of the GATA3 gene revealed the presence of two pathogenetic variants in exon 3, c.404dupC and c.431dupG, in the proband of family 1 and 2, respectively. CONCLUSION: HDR syndrome is a rare cause of hypoparathyroidism and must be excluded in all patients with apparently idiopathic hypoparathyroidism. A correct diagnosis is of great importance for early detection of other HDR-related features and genetic counseling.

Intact FGF23 concentration in healthy infants, children, and adolescents, and diagnostic usefulness in patients with X-linked hypophosphatemic rickets.

OBJECTIVE: FGF23 measurement may have a diagnostic role to investigate patients with phosphate disorders. However, normal values for infants, children, and adolescents have not been defined. METHODS: In a total of 282 (males 145, females 137) healthy infants (n = 30), prepubertal (n = 147), pubertal (n = 59), and postpubertal (n = 46), and in twenty patients with X-linked hypophosphatemic rickets (XLH, age 10.2 ± 5.6 years) serum phosphate (automated analyzer), and plasma intact FGF23 (immunochemiluminescent sandwich assay, DiaSorin) concentrations were measured. RESULTS: Intact FGF23 concentrations were higher in healthy infants than in prepubertal (P < 0.01) and postpubertal subjects (P < 0.05); pubertal subjects showed higher values (P < 0.05) than postpubertal subjects. Serum phosphate concentrations were higher (P < 0.001) in healthy infants than in prepubertal, pubertal, and postpubertal subjects. Pubertal subjects had higher (P < 0.001) serum phosphate concentrations than postpubertal subjects. Intact FGF23 and serum phosphate concentrations did not differ (P = NS) by sex, age of menarche, and time after menarche. In healthy subjects, there was no correlation between intact FGF23 and serum phosphate concentrations. Intact FGF23 concentrations were higher (P < 0.0001) in patients with XLH than in healthy subjects according to chronological age and pubertal development. In all patients, intact FGF23 concentrations were above 40 pg/mL; intact FGF23 concentrations were inversely correlated with serum phosphate concentrations (r = -0.65; P < 0.01). CONCLUSION: In healthy subjects, chronological age and puberty were main determinants of intact FGF23 concentrations. Intact FGF23 concentrations may be a useful marker for the early diagnosis of XLH in pediatric patients.

Citraconate inhibits ACOD1 (IRG1) catalysis, reduces interferon responses and oxidative stress, and modulates inflammation and cell metabolism.

Although the immunomodulatory and cytoprotective properties of itaconate have been studied extensively, it is not known whether its naturally occurring isomers mesaconate and citraconate have similar properties. Here, we show that itaconate is partially converted to mesaconate intracellularly and that mesaconate accumulation in macrophage activation depends on prior itaconate synthesis. When added to human cells in supraphysiological concentrations, all three isomers reduce lactate levels, whereas itaconate is the strongest succinate dehydrogenase (SDH) inhibitor. In cells infected with influenza A virus (IAV), all three isomers profoundly alter amino acid metabolism, modulate cytokine/chemokine release and reduce interferon signalling, oxidative stress and the release of viral particles. Of the three isomers, citraconate is the strongest electrophile and nuclear factor-erythroid 2-related factor 2 (NRF2) agonist. Only citraconate inhibits catalysis of itaconate by cis-aconitate decarboxylase (ACOD1), probably by competitive binding to the substrate-binding site. These results reveal mesaconate and citraconate as immunomodulatory, anti-oxidative and antiviral compounds, and citraconate as the first naturally occurring ACOD1 inhibitor.

Loss of DJ-1 impairs antioxidant response by altered glutamine and serine metabolism.

The oncogene DJ-1 has been originally identified as a suppressor of PTEN. Further on, loss-of-function mutations have been described as a causative factor in Parkinson's disease (PD). DJ-1 has an important function in cellular antioxidant responses, but its role in central metabolism of neurons is still elusive. We applied stable isotope assisted metabolic profiling to investigate the effect of a functional loss of DJ-1 and show that DJ-1 deficient neuronal cells exhibit decreased glutamine influx and reduced serine biosynthesis. By providing precursors for GSH synthesis, these two metabolic pathways are important contributors to cellular antioxidant response. Down-regulation of these pathways, as a result of loss of DJ-1 leads to an impaired antioxidant response. Furthermore, DJ-1 deficient mouse microglia showed a weak but constitutive pro-inflammatory activation. The combined effects of altered central metabolism and constitutive activation of glia cells raise the susceptibility of dopaminergic neurons towards degeneration in patients harboring mutated DJ-1. Our work reveals metabolic alterations leading to increased cellular instability and identifies potential new intervention points that can further be studied in the light of novel translational medicine approaches.

Which factors predict the behavior of ventricular extrasystoles in athletes over time?

Spontaneous behavior of ventricular extrasystoles (VE) was analysed. From a database containing 578 athletes with VE, 84 males and 11 females (29.9 ± 18.1 years) having ≥ 100 VE or repetitive VE [ventricular couplets (VC) or ventricular tachycardias (VT)] at first 24-hour Holter electrocardiographic monitoring (24-h-HM) (baseline) and at least 1-year of follow-up (3.1 ± 2.2 years) over the past 10 years were selected. The baseline was compared with the last 24-h-HM to establish DVE (VE reduction of at least 98%/24 h in the absence of VC or VT). SDVE was calculated as standard deviation of the number of VE on serial 24-h-HMs. DVE and SDVE were considered as dependent variables. Independent variables were: age, sex, type of sport, symptoms, baseline VE rate (BVE), baseline VC and VT, VE morphology, VE behavior during the baseline training session, disqualification from competitive sports, echocardiographic abnormalities. DVE occurred in 32 athletes (34%). SDVE varied from 0 to 12,658 VE/24 h (1916 ± 2649.9). Disappearance of VE during the baseline training session (DVET) correlated to DVE (P = 0.0319). BVE directly correlated to SDVE (P = 0.0008). Athletes' VE are highly variable over time, their variability depending on BVE, and they not infrequently tend to disappear. The only useful variable for predicting DVE is DVET.

FOLFOXIRI plus bevacizumab as first-line treatment in BRAF mutant metastatic colorectal cancer.

BACKGROUND: BRAF V600E mutation plays a negative prognostic role in metastatic colorectal cancer (mCRC), leading to a median Progression Free Survival (PFS) of 4-6months with first-line conventional treatments. Our group recently reported in a retrospective exploratory analysis of a phase II trial that FOLFOXIRI (5-FU/LV+Oxaliplatin+Irinotecan) plus bevacizumab might allow to achieve remarkable results in terms of PFS and Overall Survival (OS) also in this poor-prognosis subgroup. The aim of this work was to prospectively validate our retrospective finding. PATIENTS AND METHODS: This phase II trial was designed to detect an increase in 6month-Progression Free Rate (6m-PFR) from 45% to 80% in a population of BRAF mutant mCRC patients treated with first-line FOLFOXIRI plus bevacizumab. Secondary end-points were PFS, OS, response rate (RR) and the analysis of outcome parameters in the pooled population consisting of both retrospectively and prospectively included patients. This trial is registered with ClinicalTrials.gov, number NCT01437618. RESULTS: Two-hundred-fourteen potentially eligible mCRC patients were screened for BRAF mutational status. Fifteen BRAF mutant patients (7%) were included in the validation cohort. At a median follow up of 25.7months, 6m-PFR was 73%. Median PFS and OS were 9.2 and 24.1months, respectively. In the pooled population, at a median follow up of 40.4months, 6m-PFR was 84%. Median PFS and OS were 11.8 and 24.1months, respectively. Overall RR and disease control rate were 72% and 88%, respectively. CONCLUSION: Lacking randomised trials in this specific molecular subgroup, FOLFOXIRI plus bevacizumab might be a reasonable option for the first-line treatment of BRAF mutant mCRC patients.

Nasal nitric oxide and nitric oxide synthase expression in primary ciliary dyskinesia.

No study has evaluated the correlation between different expression of nitric oxide synthase (NOS) isoforms in nasal epithelial cells and nasal NO (nNO) level in primary ciliary dyskinesia (PCD). Gene expression of endothelial (NOS3) and inducible NOS (NOS2) and their correlation with nNO level, ciliary function and morphology were studied in patients with PCD or secondary ciliary dyskinesia (SCD). NOS3 gene polymorphisms were studied in blood leukocytes. A total of 212 subjects were studied (48 with PCD, 161 with SCD and three normal subjects). nNO level correlated with mean ciliary beat frequency (p = 0.044; r = 0.174). The lower the nNO level the higher was the percentage of immotile cilia (p<0.001; r = -0.375). A significant positive correlation between NOS2 gene expression and nNO levels was demonstrated in all children (p = 0.001; r = 0.428), and this correlation was confirmed in patients with PCD (p = 0.019; r = 0.484). NOS2 gene expression was lower in PCD than in SCD (p = 0.04). The NOS3 isoform correlated with missing central microtubules (p = 0.048; r = 0.447). nNO levels were higher in PCD subjects with the NOS3 thymidine 894 mutation, and this was associated with a higher ciliary beat frequency (p = 0.045). These results demonstrate a relationship between nNO level, NOS mRNA expression and ciliary beat frequency.

Clinical and genetic findings in a series of Italian children with pure hereditary spastic paraplegia.

BACKGROUND: hereditary spastic paraplegias (HSP) are a group of neurodegenerative disorders characterized by progressive lower extremity spastic weakness. SPG7, SPG4 and SPG3A are some of the autosomal genes recently found as mutated in recessive or dominant forms of HSP in childhood. SPG31 is more often associated with a pure spastic paraplegia phenotype, but genotype-phenotype correlation is still unclear. The aims of the current study was: (i) to verify the mutational frequency of SPG4, SPG3A, SPG31 and SPG7 genes in our very-well-selected childhood sample, and (ii) to improve our knowledge about the clinical and electrophysiological HSP phenotypes and their possible correlation with a specific mutation. METHODS: a sample of 14 Italian children affected by pure HSP (mean age at diagnosis 5.9 years) was extensively investigated with electrophysiological, neuroradiological and genetic tests. RESULTS: three SPG4 mutations were identified in three patients: two novel missense mutations, both sporadic, and one multiexonic deletion already reported. A novel large deletion in SPG31 gene involving exons 2-5 was also detected in one young patient. No mutations in the SPG7 and in the SPG3A genes were found. CONCLUSIONS: our data confirm that HSP represent a heterogeneous group of genetic neurodegenerative disorders, also in sporadic or autosomal recessive early onset forms. Multiplex Ligation-dependent Probe Amplification-based mutation screening for SPG4 and SPG31 genes would be added to sequencing-based screening of SPG4, SPG31 and SPG3A genes in the routine diagnosis of HSP children.

Post automatic implantable cardioverter defibrillator implant therapies: drugs and ablative techniques.

The aim of this article is to report the evidences about the use of drugs and ablation after implantation of a cardioverter defibrillator. Drugs can be utilized to prevent appropriate and inappropriate shocks, can influence positively or negatively defibrillation threshold, can be useful for the treatment of electrical storm. Ablation can be performed for direct cure of coexisting atrial and ventricular tachyarrhythmias or for AV node modulation. In particular, previous data demonstrate that rescue ventricular tachycardia ablation of drug-refractory electrical storm is possible by a substrate-orientated ablation approach even in patients with complex chronic infarction and various ventricular tachycardias. At the end of this article it is described how remote monitoring, a new very promising technical improvement, can be utilized for deciding, almost in real time, the use of both these therapies or for controlling their efficacy.

Is implantable defibrillator indicated in all patients on cardiac resynchronization therapy?

Implantable cardioverter defibrillator (ICD) and cardiac resynchronization therapy (CRT) have been introduced during the recent years to improve survival, decrease hospital readmissions and mortality, and to improve functional status and quality of life for patients with heart failure and left ventricular systolic dysfunction (LVSD). Studies which evaluated the use of CRT or ICD alone or compared CRT with CRT-ICD in patients with heart failure and LVSD are listed in this article. The results obtained are already influencing clinical practice in the US, where it has been estimated that 90% of patients receiving a CRT device now are being implanted with an ICD component. However, it is still today debated whether patients with LVSD and heart failure should be routinely offered a CRT-ICD. In fact, there are some issues that still should be solved before to establish indication for CRT-D in all heart failure patients with an indication for CRT: 1) a non complete agreement among the different societies which wrote recommendations for guidelines (a comparative table is reported); 2) a better identification of implantable patients and an amelioration of utilized devices; 3) economic and ethical ramifications of this therapy. Anyway still now the crucial question is: ''Can resynchronization be done in isolation or must be accompanied by an ICD device?''. To answer to this question we can only express which is, in our opinion, the actual position of many physicians who work in the field of pacing and electrophysiology: ''The lesson to be learned is that we still can not predict surely which patient will die of sudden death. Until a method of identifying the high risk patients can be developed, the safest strategy should be to advise a combined ICD-CRT device for patients with indication for CRT''.

Role of natriuretic peptides in heart failure patients with special reference to those on cardiac resynchronization therapy.

In recent years natriuretic peptides (NPs) have emerged as important tools for evaluation of heart failure patients. Since its approval by the Food and Drug Administration (FDA) in November 2000, recent surveys suggest that approximately 83% of hospitals in the US use some type of NP testing. Although NP testing was originally focused on rapid diagnosis of patients presenting to the emergency department with shortness of breath, clinicians regularly look to NPs for diagnosing minimally symptomatic or asymptomatic left ventricular dysfunction, and using NPs levels in clinic to help ascertain when decompensation is present. NP testing is now included in the guidelines for the diagnosis and treatment of chronic heart failure and in the Italian Consensus Document for the clinical use of NPs. Recommendations indicate that assessment of NPs can be considered a reliable rule-out test of heart failure in primary care and in the emergency room even if they stated that the role for treatment monitoring or for prognostic evaluation needs to be determined. In recent years, cardiac resynchronization therapy (CRT) was introduced as a new treatment modality for patients with systolic heart failure and several studies suggest that plasma concentration of NPs ensues as a very useful parameter for evaluating and monitoring patients who undergo CRT. Thus this article aims not only to summarise data concerning NPs measurement in patients with heart failure, but also to indicate how these markers could be utilized in the future to objectively assess effects of CRT (identification of responders). In conclusion, if further studies will confirm above mentioned remarks, it would be possible that NPs evaluation can help to tailor the more suitable therapy for each heart failure patient and, therefore, to reduce the number of failures.

Resynchronization of mitral valve annular segments reduces functional mitral regurgitation in cardiac resynchronization therapy.

AIM: Cardiac resynchronization therapy (CRT) reduces the severity of functional mitral regurgitation (FMR) in patients with heart failure and left bundle branch block. Our hypothesis was that the induction of a more synchronous mitral valve anulus contraction can be a mechanism of FMR reduction in CRT patients. METHODS: An echo tissue Doppler imaging (TDI) examination was performed at baseline and 6 months after biventricular pacing system implant in 30 patients (4 females and 26 males, 74.1+/-6.1 years) with dilatative or ischemic chronic heart failure, NYHA class = or >III, ejection fraction (EF) = or <35% and QRS = or >140 ms. EF, Myocardial Performance Index (MPI), left end-diastolic and systolic volumes (LVEDV, LVESV), mitral regurgitation jet area/left atrial area (JA/LAA), effective regurgitant orifice area (EROA), mitral anulus contraction (MAC) were evaluated. Using TDI, at the 6 left ventricle (LV) basal segments the time to the peak myocardial sustained systolic velocity (Ts) and the standard deviation (SD) of TS were evaluated. RESULTS: At 6 months follow-up NYHA class, EF, MPI were significantly improved, LV volumes were reduced. FMR degree, evaluated both as JA/LAA and EROA, was significantly reduced. This effect was associated with the 6 basal segments resynchronization and with a more effective annular contraction. CONCLUSIONS: Our data show that CRT by resynchronizing left ventricular basal segments produces a more effective mitral valve annulus contraction and contributes to FMR improvement. Further studies need to evaluate if this could be taken into account as new therapeutic perspective of functional mitral valve regurgitation.

Effects of subthreshold shocks on wavelet propagation during atrial fibrillation in humans.

OBJECTIVES: Our objectives are: first to investigate the effects of internal cardioversion energies on the wave fronts propagation in the right atrium immediately after the energy delivery; second, to track the time course of these effects. METHODS: The study is based on a measure of organization of the endoatrial electrograms obtained by a multipolar basket catheter inserted in the right atrium. We estimated the level of organization by computing the percentage of points laying on the signal baseline (i.e., number of occurrences, NO). NO values were computed on two-second long windows. Six non-overlapped windows were selected, one just before and five just after the last unsuccessful shock. RESULTS: Immediately after the shock most of the patients exhibited an increase in the organization patterns. This increase was more evident in those patients with rather disorganized patterns and higher energy threshold. This effect fades within a few seconds after the shock delivery. CONCLUSIONS: Our data confirm the idea that the electrical shock causes a widespread extinction of electrical wavefronts, which regenerates after the shock. Since an increase of organization may lead to a reduction of energy threshold, a potential application of these findings might consist in the delivery of multiple subthreshold shocks instead of a single one.

Measure of synchronisation of right atrial depolarisation wavefronts during atrial fibrillation.

A new index of synchronisation (IS) between the electrical activity of pairs of close atrial sites during atrial fibrillation (AF) is introduced. The index assesses the probability of finding synchronous activations in intra-atrial bipolar electrograms and is based on the assumption that two activations closely spaced in time are likely to belong to the same depolarisation wavefront. A dedicated statistical treatment to test this hypothesis is also illustrated. Experimental data were obtained using a multipolar basket catheter in the right atrium in 20 patients during normal sinus rhythm (NSR), atrial flutter (AFL, one patient), high-frequency pacing (HFP, two patients) and chronic AF (17 patients), and 30 segments were obtained from each. From the 24 pairs of bipoles, a single averaged IS and its standard deviation were extracted. The IS was 1 in NSR and HFP and 0.95 +/- 0.02 during AFL. During AF, the IS provided a quantitative measure of the degree of coupling of various atrial sites. The IS varied significantly among the recording sites (range 0.38-0.96), showing a patient-dependent pattern, and decreased as the arrhythmia complexity increases. No temporal trends were observed for the IS values in any chronic AF patient. On average, in each site, the dispersion of the IS over time was lower than 32% of the mean, for all patients. Additional relevant features of the proposed index are its high temporal resolution (2s) and robustness to activation time estimation error, to missing or false detections and to the ever-changing pattern of propagation. The index of synchronisation is a descriptor of the electrophysiological properties of atrial tissues.

Increased cardiac sympathetic activity and insulin-like growth factor-I formation are associated with physiological hypertrophy in athletes.

Physiological hypertrophy represents the adaptive changes of the heart required for supporting the increased hemodynamic load in regularly trained healthy subjects. Mechanisms responsible for the athlete's hypertrophy still remain unknown. In 15 trained competitive soccer players and in 15 healthy men not engaged in sporting activities (sedentary control subjects) of equivalent age, we investigated the relationship among cardiac growth factor formation, cardiac sympathetic activity, and left ventricular morphology and function. Cardiac formation of insulin-like growth factor (IGF)-I, endothelin (ET)-1, big ET-1, and angiotensin (Ang) II was investigated at rest by measuring artery-coronary sinus concentration gradients. Cardiac sympathetic activity was studied by [(3)H]norepinephrine (NE) kinetics. Cardiac IGF-I, but not ET-1, big ET-1, and Ang II, formation was higher in athletes than in control subjects (P<0.01). NE levels in arterial and peripheral venous blood did not differ between groups. In contrast, coronary sinus NE concentration was higher in athletes than in control subjects (P<0.01). Cardiac, but not total systemic, NE spillover was also increased in athletes (P<0.01), whereas cardiac [(3)H]NE reuptake and clearance were not different. Echocardiographic modifications indicated a volume overload-induced hypertrophy associated with increased myocardial contractility. Multivariate stepwise analysis selected left ventricular mass index as the most predictive independent variable for cardiac IGF-I formation and velocity of circumferential fiber shortening for cardiac NE spillover. In conclusion, increased cardiac IGF-I formation and enhanced sympathetic activity selectively confined to the heart appear to be responsible for the physiological hypertrophy in athletes performing predominantly isotonic exercise.

Non-linear coupling of atrial activation processes during atrial fibrillation in humans.

The activation patterns underlying the electrical activity of the heart during atrial fibrillation (AF) are not entirely random. The aim of this study was to assess the local organization of the activation processes during AF by estimating the non-linear coupling between activation sequences (ASs) in two atrial sites. To quantitatively estimate the degree of non-linear coupling we extracted two indices based on a multivariate embedding procedure and on the estimation of the correlation dimension (CD) and correlation entropy (CE), termed independence of complexity and of independence of predictability, respectively. We analysed AS in two atrial sites in 30 informed subjects during chronic AF of type I, II and III (Wells' classification), ten 6-s-long episodes of each type. Surrogates were used to reject the hypothesis that the time series were generated by linear stochastic dynamics. We estimated CD and CE according to the coarse-grained approach, which leads to a fixed high value for the embedding dimension in all the analysed ASs, and a typical value for the distance between the two ASs in the phase space. Various degrees of organization, ranging from completely synchronized to fully de-coupled signals, were observed: significant degrees of non-linear coupling were found in segments belonging in types I and II AF, whereas type III electrograms always turned out to be weakly coupled. This finding links the morphology of single electrograms to the synchronization between pairs of closely spaced electrograms. Our bivariate approach suggests that the measurement of organization during AF should be based on the estimation of the non-linear coupling between two sites. This approach appears to be more reliable and sensitive than non-linear analysis of single electrograms or linear analysis of their coupling.

Altered values of heart rate variability in patients with relapse of atrial fibrillation during the first week after electrical cardioversion: preliminary data.

BACKGROUND: It has not so far been elucidated whether the autonomic nervous system plays a role in the pathogenesis of atrial fibrillation relapse after electrical cardioversion. METHODS: In 40 consecutive patients with atrial fibrillation (22 males, 18 females, mean age 60 +/- 2 years) submitted to successful electrical cardioversion (external in 26 and low-energy internal in 14) we evaluated the heart rate variability (24-hour Holter recording) immediately after restoration of sinus rhythm in order to assess the cardiac sympatho-vagal drive. RESULTS: Patients with atrial fibrillation relapse within the first week of electrical cardioversion were characterized by a significantly higher low/high frequency ratio. CONCLUSIONS: Despite the heterogeneity of the studied population (concerning both the therapy and etiology of atrial fibrillation), our data strongly suggest that the evaluation of the low/high frequency ratio by means of power spectral analysis immediately after electrical cardioversion is a useful tool for the identification of those patients who are prone to atrial fibrillation recurrence. Our conclusions are supported by the finding of high positive and negative predictive values for the low/high frequency ratio both in the 24-hour period and during daytime.