Objective. Newborns of mothers positive for antiRo/SSA autoantibodies may develop a series of electrocardiographic (EKG) disturbances. Prolongation of the corrected QT (QTc) interval was recently reported in a significant proportion of children with maternally acquired anti-Ro/SSA antibodies, with a concomitant disappearance of EKG abnormalities and acquired maternal autoantibodies during the first year, suggesting a direct, reversible electrophysiologic effect of anti-Ro/ SSA antibodies on the ventricular repolarization. On this basis, we investigated whether these antibodies may also affect cardiac repolarization in anti-Ro/SSApositive adult patients with connective tissue diseases.Methods. Fifty-seven patients with connective tissue diseases were selected: 31 had anti-Ro/SSA antibodies and 26 did not (controls). In all subjects, we analyzed the QTc interval, heart rate variability, and signalaveraged high-resolution EKG recording.Results. Anti-Ro/SSA-positive patients showed a significant prolongation of the mean QTc interval compared with the controls (mean ؎ SD 445 ؎ 21 versus 419 ؎ 17 msec; P ‫؍‬ 0.000005). Eighteen of the 31 anti-Ro/SSA-positive patients (58%) and none of the 26 anti-Ro/SSA-negative patients had QTc values above the upper limit of normal (440 msec). Both groups had a reduction in heart rate variability, with a prevalence for the sympathetic nervous system and a high incidence of ventricular late potentials; these values were not significantly different between the 2 groups.Conclusion. Adult patients with anti-Ro/SSApositive connective tissue diseases showed a high prevalence of QTc interval prolongation. This feature, with the concomitant abnormalities in the autonomic tone and ventricular late excitability observed in all patients studied, suggests that anti-Ro/SSA-positive patients may have a particularly high risk of developing lifethreatening arrhythmias.Neonatal lupus is a rare syndrome related to the transplacental passage of autoantibodies from mothers positive for anti-Ro/SSA (and anti-La/SSB) to their newborns. These mothers frequently have autoimmune disorders, especially connective tissue diseases; however, they are sometimes entirely asymptomatic. The main feature of neonatal lupus is congenital heart block (CHB), an irreversible disturbance in cardiac conduction. Many recent studies have investigated the possible electrophysiologic and molecular mechanisms of CHB, and the findings suggest a direct arrhythmogenic activity of anti-Ro/SSA antibodies. In particular, it has been demonstrated that affinity-purified anti-Ro/SSA antibodies from mothers of children with CHB are able to induce a complete atrioventricular block in the human fetal heart as well as in a rat model of the heart, which inhibits L-type calcium currents (1).CHB is the main, but not the only, electrocardiographic abnormality associated with the transplacental passage of anti-Ro/SSA antibodies. Mazel and colleagues (2) reported sinus bradycardia in a murine model injected with IgG obtained from mothers of childr...

Raynaud?s phenomenon (RP) and cutaneous fibrosis are the distinctive manifestations of scleroderma, in which Endothelin-1 plays a fundamental pathogenetic role. Bosentan, an Endothelin-1 receptor antagonist used for the treatment of pulmonary arterial hypertension, retards the beginning of new sclerodermic digital ulcers (DU). This open-label, observational, retrospective study verified the effect of Bosentan on RP and skin fibrosis in sclerodermic outpatients affected by pulmonary arterial hypertension without DU. Fourteen subjects (13 women, 1 man; mean age 60 ± 7.5 years; ten with limited and four with diffuse scleroderma) were observed at baseline (T0) and after four (T1), twelve (T2), twenty-four (T3) and forty-eight (T4) weeks during treatment with Bosentan. They were evaluated for daily quantity and duration of RP attacks and skin thickness (using modified Rodnan total skin score, MRSS). Videocapillaroscopic evaluation was performed at T0 and T4. Bosentan decreased significantly the number and duration of RP attacks, beginning at T2 (p<0.05). Videocapillaroscopy showed significant improvement of microcirculatory patterns at T4 (p<0.05). MRSS decreased throughout the study, reaching the statistical significance at T3 and T4 (p<0.01) in the whole cohort. The present data suggest that Bosentan is effective in stabilizing the microcirculation involvement and in improving skin fibrosis irrespective of scleroderma patterns.

Background: Men normally have shorter heart rate-corrected QT interval (QTc) than women, at least in part due to accelerating effects of testosterone on ventricular repolarization. Accumulating data suggest that androgen-deprivation therapy (ADT) used for the treatment of prostatic cancer, may increase Torsades de Pointes (TdP) risk by prolonging QTc. However, the evidence for such an association is currently limited to few case reports, in most cases deriving from the analysis of uncontrolled sources such as pharmacovigilance databases.Objective: To better determine the clinical impact of ADT on TdP development, we examined the prevalence of this therapy in a consecutive cohort of 66 TdP patients, prospectively collected over a ~10 years period.Methods and Results: We found and described four patients who were under ADT for prostatic cancer when TdP occurred, and in two cases degenerated to cardiac arrest. Notably, in this unselected population, ADTs unexpectedly represented the second most frequently administered QT-prolonging medication in males (4/24, 17%), after amiodarone. Moreover, in the ADT patients, a blood withdrawal was performed within 24 h from TdP/marked QTc prolongation occurrence and circulating concentration of androgens and gonadothropins were measured. As expected, all cases showed markedly reduced testosterone levels (total, free, and available). Conclusion:We provide evidence that a significant proportion of patients developing TdP were under treatment with ADT for prostatic cancer, thus confirming the clinical relevance of previous pharmacovigilance signals. An accurate assessment of the arrhythmic risk profile should be included in the standard of care of prostatic cancer patients before starting ADT.

Background: Cryptogenic stroke (CS) represents 25% of ischemic strokes. Especially after CS, the detection of atrial fibrillation (AF) is important because it provides clues to the mechanism of stroke. However, the relationship between AF and stroke appears more complex than a simple cause-effect mechanism, suggesting that the association between AF and stroke may be due to other systemic and atrial factors including systemic inflammation that may lead to atrial remodeling and subsequent atrial cardiopathy. Objective: The aim of this study was to evaluate the relationship among different electrocardiographic parameters, inflammatory markers and in-hospital AF occurrence after acute CS. Methods: 222 patients with CS underwent 12-lead resting ECG at admission and 7-day in-hospital ECG monitoring. The following indices were evaluated: P-wave dispersion (PWD), P-wave index, P-wave axis, atrial size and high-sensitivity-C reactive protein (CRP). Results: AF was detected in 44 patients. AF-group had significantly higher PWD, P-wave index, PR interval, CRP and greater frequency of abnormal P-wave axis in comparison with no-AF group. There was a significant correlation between CRP and PWD (r=0.28). By using the mediation analysis, performed according to the “bootstrapping” method, we found that PWD is a significant mediator variable of the relationship between CRP and AF occurrence, accounting for 40% of the association. Conclusions: In cryptogenic stroke, high PWD is partly due to systemic inflammation that increases AF risk possibly via atrial electric remodeling. These findings could also suggest inflammation as a possible therapeutic target in order to prevent atrial electrical alterations and finally AF occurrence in CS.

Background: The “1-3-6-12-day rule” for starting direct oral anticoagulants (DOACs) in patients with nonvalvular atrial fibrillation after acute ischemic stroke or transient ischemic attack recommends timings that may be later than used in clinical practice. We investigated more practical optimal timing of DOAC initiation according to stroke severity. Methods: The combined data of prospective registries in Japan, Stroke Acute Management with Urgent Risk-factor Assessment and Improvement-nonvalvular atrial fibrillation (September 2011 to March 2014) and RELAXED (February 2014 to April 2016) were used. Patients were divided into transient ischemic attack and 3 stroke subgroups by the National Institutes of Health Stroke Scale score: mild (0–7), moderate (8–15), and severe (≥16). The early treatment group was defined as patients starting DOACs earlier than the median initiation day in each subgroup. Outcomes included a composite of recurrent stroke or systemic embolism, ischemic stroke, and severe bleeding within 90 days. Six European prospective registries were used for validation. Results: In the 1797 derivation cohort patients, DOACs were started at median 2 days after transient ischemic attack and 3, 4, and 5 days after mild, moderate, and severe strokes, respectively. Stroke or systemic embolism was less common in Early Group (n=785)—initiating DOACS within 1, 2, 3, and 4 days, respectively—than Late Group (n=1012) (1.9% versus 3.9%; adjusted hazard ratio, 0.50 [95% CI, 0.27–0.89]), as was ischemic stroke (1.7% versus 3.2%, 0.54 [0.27–0.999]). Major bleeding was similarly common in the 2 groups (0.8% versus 1.0%). On validation, both ischemic stroke (2.4% versus 2.2%) and intracranial hemorrhage (0.2% versus 0.6%) were similarly common in Early (n=547) and Late (n=1483) Groups defined using derivation data. Conclusions: In Japanese and European populations, early DOAC initiation within 1, 2, 3, or 4 days according to stroke severity seemed to be feasible to decrease the risk of recurrent stroke or systemic embolism and no increase in major bleeding. These findings support ongoing randomized trials to better establish the optimal timing of DOAC initiation.