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Loss-of-function mutations in the CYP24A1 gene, which encodes the vitamin D-24 hydroxylase, have been recognized as a cause of elevated 1,25-dihydroxyvitamin D concentrations, hypercalcemia, hypercalciuria, nephrocalcinosis and nephrolithiasis in infants and adults. As only a case report describing 2 adult patients has been reported in Italian population, we report here the mutation analysis of CYP24A1 gene in an Italian cohort of 12 pediatric and adult patients with idiopathic infantile hypercalcemia (IIH).We performed mutational screening of CYP24A1 gene in a cohort of 12 Italian patients: 8 children with nephrocalcinosis, hypercalcemia and PTH levels10 pg/ml and 4 adult patients with nephrolithiasis, mild hypercalcemia and PTH levels10 pg/ml from 11 unrelated Italian families. Clinical and biochemical data were collected. Genomic DNA was extracted from peripheral blood leucocytes using standard methods, and whole coding sequence of CYP24A1 gene was analysed in all patients and family members by polymerase chain reaction and direct sequencing. The potential pathogenicity of the newly identified missense mutations was evaluated by 3 different in silico approaches (Sorting Intolerant from Tolerant, Polyphen and Mutation Taster) and by comparative analysis in 14 different species using ClustalW software.CYP24A1 bi-allelic mutations were found in 8 individuals from 7 Italian families (7/11; 64%). Overall, 6 different CYP24A1 mutations, including one small deletion (p.Glu143del), 4 missense mutations (p.Leu148Pro; p.Arg396Trp; p.Pro503Leu; p.Glu383Gln) and one nonsense mutation (p.Tyr220*) were identified. Two out of 6 mutations (p.Tyr220* and p.Pro503Leu) were not previously described. Moreover, a new CYP24A1 variant was identified by genetic screening of asymptomatic controls.To the best of our knowledge, this is the first report of a CYP24A1 molecular analysis performed in an Italian cohort of adult and pediatric Italian patients. This study (1) confirms that CYP24A1 plays a causal role in some but not all cases of IIH (64%); (2) expands the spectrum of known CYP24A1 pathogenic mutations; (3) describes 2 hotspots detected in 50% of all Italian cases; and (4) emphasizes the importance of recognition and genetic diagnosis of CYP24A1 defects in infantile as well as adult hypercalcemia.

Dabigatran is a novel target specific oral anticoagulant for stroke prevention in non valvular atrial fibrillation. Little is still known about its real-world effectiveness and safety in the italian population. Aim of our study was to evaluate the efficacy and safety of dabigatran in a large single-center cohort of "real-life" italian population with non-valvular AF and to compare the results with those obtained from the RE-LY trial and the Medicare study.We studied a prospective cohort of 2108 patients (1119 male; mean age 69.4 ± 9.4 years) who started the oral anticoagulant treatment with dabigatran 110 mg twice-daily (DAB 110; N = 1075; 51%) or 150 mg twice-daily (DAB 150; N = 1033; 49%). Follow-up data were obtained trough outpatients visits each 3-6 months for assessing the clinical status, adherence to treatment, occurrence of side effects and major cardiovascular complications.In DAB 150 group the mean age was 64.9 ± 8.8 years, 56.8% of patients was male. CHA2DS2Vasc Score was ≥ 3 in 94.3% and HAS-BLED was ≥ 3 in 59.7%. In DAB 110 group (N = 1075) the mean age was 73.9 ± 7.5 years; 49.5% of patients was male. CHA2DS2Vasc Score was ≥ 3 in 73.4% and HAS-BLED was ≥ 3 in 87.4% of DAB 110 patients. One patient taking Dabigatran 110 mg bid had ischemic stroke without significantly neurological sequelae. In both groups, no patient experienced hemorrhagic stroke during the follow-up period. 147 patients (6.9%) of MonaldiCare population reported adverse effects from treatment with dabigatran, of whom 121 patients (5.7%) discontinued therapy. We reported one case of subarachnoid hemorrhage (0.05%) in a patient with high thrombo-embolic and high hemorrhagic risk score who was taking dabigatran 150 mg bid and one case (0.05%) of bladder bleeding in a patient who was taking dabigatran 110 mg bid. No major gastrointestinal bleeding was observed in the MonaldiCare population.MonaldiCare registry showed a safety profile of both dosages of dabigatran regarding major of fatal bleeding in a "real life" single center italian population at high thromboembolic and hemorrhagic risk. The majority of MonaldiCare patients tolerated dabigatran treatment without significant side effects. The efficacy of dabigatran was demonstrated by very low prevalence of ictus/TIA, also when patients underwent electrical AF cardioversion independently of the transesophageal examination.

The reproducibility of electrocardiographic (ECG) recordings in syncopal recurrences and the diagnostic role of nonsyncopal arrhythmias are not well known. The objective of this study was to analyse the reproducibility of the ECG findings recorded with implantable loop recorders in 41 patients with suspected neurally-mediated syncope who were included in the International Study on Syncope of Uncertain Origin-2 study and that had > or =2 events recorded by implantable loop recorders. In these patients, the electrocardiogram obtained with the first documented syncope (index syncope) was compared with other recorded events. Twenty-two patients had > or =2 syncopes, and their electrocardiograms were reproducible in 21 (95%): 15 with sinus rhythm, 5 with asystole, and 1 with ventricular tachycardia; 1 had asystole at first syncope and sinus rhythm at recurrent syncope. In 32 patients with nonsyncopal episodes, an arrhythmia was documented in 9, and all of them had the same arrhythmia during the index syncope (100% reproducibility); conversely, when sinus rhythm was documented (23 patients) during nonsyncopal episodes, an arrhythmia was still documented in 6 during the index syncope (70% reproducibility; p = 0.0004). In conclusion, the ECG findings during the first syncope are highly reproducible in subsequent syncopes. The presence of an arrhythmia during nonsyncopal episodes is also highly predictive of the mechanism of syncope, but the presence of sinus rhythm does not rule out the possibility of arrhythmia during syncope. Therefore the finding of an arrhythmia during a nonsyncopal episode allows the etiologic diagnosis of syncope, and eventually to anticipate treatment, without waiting for syncope

Nifedipine, diltiazem and verapamil are three effective calcium-antagonists in the treatment of angina pectoris. We compared their effects on effort angina to evaluate whether one of them is more efficacious. The data were collected from 42 patients (37 males, 5 females; mean age 51 +/- 4) entering one of 3 different trials; the beginning of all trials comprised a two-week, single blind, placebo run-in phase. An exercise stress test was performed at the end of this period and it was considered as basal test for the statistical analysis. Then the 42 patients were divided in 3 groups of 14 and entered a double-blind, randomized phase of drug treatment. The 3 groups started 3 parallel trials: 1) placebo/nifedipine 60 mg/day; 2) placebo/verapamil 360 mg/day; 3) placebo/diltiazem 240 mg/day. The duration of each trial was of 6 weeks (3 weeks of treatment with placebo and 3 weeks with active substance). Exercise stress tests were performed at the end of each phase of the trials, and the resulting data were compared with the data of the test performed at the end of run-in period. Parameters evaluated were: heart rate, blood pressure and rate pressure product at basal conditions, at submaximal and peak exercise; moreover we considered workload, maximal ST segment depression, total exercise duration and frequency of exercise-induced angina. Verapamil reduced rate pressure product at basal condition; all three drugs reduced rate pressure product at submaximal exercise, but a significant statistical difference was found only for verapamil and diltiazem.(ABSTRACT TRUNCATED AT 250 WORDS)

Twenty patients without laboratory evidence of cardiac disease who underwent electrophysiological study because of recurrent ventricular tachyarrhythmias.The study population was divided into two groups: group A (20 patients [six males and 14 females] mean age 42.2 +/- 13 years), with idiopathic ventricular tachycardia (VT), and group B (30 controls [10 males and 20 females] mean age 43.6 +/- 16 years). Noninvasive multiparametric analysis of the ventricular repolarization phase was performed on the standard 12-lead electrocardiogram by using a digitizer connected with a computerized system. The intervals JT, heart rate-corrected JT (JTc), JT apex (JTa), heart rate-corrected JTa (JTac), T apex T end (TaTe) and heart rate-corrected TaTe (TaTec) were measured and considered to be representative of the whole depolarization process. QT dispersions (QTeD) and QTc dispersions (QTecD) were calculated to assess the degree of spatial inhomogeneity of action potential duration.Patients in group A had higher JT (272 +/- 36 ms versus 265 +/- 25 ms, P = 0.01), JTc (336 +/- 28 ms versus 318 +/- 18 ms, P = 0.01), JTa (210 +/- 28 ms versus 185 +/- 28 ms, P = 0.001) and JTac (240 +/- 20 ms versus 215 +/- 13 ms, P0.001) values than those of patients in group B, despite shorter TaTe (71 +/- 10 ms versus 90 +/- 18 ms, P0.001) and TaTec (88 +/- 12 ms versus 110 +/- 12 ms, P0.001). Moreover, QTeD and QTecD were significantly longer in group A than in group B (55 +/- 18 ms versus 42 +/- 19 ms [P = 0.01] and 80 +/- 18 ms versus 55 +/- 28 ms [P = 0.001], respectively).Patients with idiopathic VT exhibit inhomogeneous prolongation of ventricular repolarization, due to a considerable increase in the initial part in association with a shorter terminal phase, as well as a greater dispersion of ventricular repolarization.

Cardiotrophin-1 (CT-1) is a member of the interleukin (IL-6) family of cytokines. Plasma CT-1 levels correlate with the left ventricle mass index in patients with dilatated cardiomyopathy and congestive heart failure (CHF). The aim of this paper was to evaluate CT-1 plasma levels, before and after cardiac resynchronization therapy CRT, and to characterizeits prognostic role in patients with CHF. Fifty-two consecutive patients (M/F = 39/13; 56 ± 11 years old) underwent clinical and echocardiographic evaluation, and blood sample collection at baseline. The same evaluation was repeated 6.4 ± 0.79 months after CRT. Patients with a decreased LV end-systolic volume by at least 15% (reverse remodeling) were considered echo responders to CRT. Twenty-nine patients (56%) were responders to CRT. After CRT, only 15 patients (29%) showed increased CT-1 after CRT. They were all non responders to CRT. A multivariate, logistic model showed CT-1 as an independent predictor of CRT echo response (p = 0.005; OR 0.97). During follow-up (18 ± 7 months), 21 cardiac events in 18 patients occurred. A Cox multivariable model showed plasma BNP pre-CRT (p = 0.02; CI 1.2-5.6; OR 3.1) and CT1 post-CRT (p = 0.01; CI 1.4-4.3; OR 2.7) as independent predictors of cardiac events. Analysis of CT-1 plasma levels deserves future consideration for larger, longitudinal studies in patients with CHF.

We examined the effect of left ventricular filling on different combinations of programmable heart rate and atrioventricular delay in patients with dual-chamber pacemakers. Pacing mode with heart rates of 60 beats/min and 156 ms of atrioventricular delay induced a diastolic pattern that resembles more than others the one observed in healthy subjects in sinus rhythm.

Cardiac arrhythmias are common in patients with chronic obstructive pulmonary disease. Several factors may contribute to the development of arrhythmias in these patients including hypoxemia, hypercapnia, acid-base disturbances. The aim of the study was to assess QTc dispersion in patients with chronic obstructive pulmonary disease, who are at high risk of arrhythmias. Interlead QT variability as measured on the 12-lead electrocardiogram is not a technical artifact but probably reflects regional differences in ventricular repolarization. Increased dispersion of ventricular recovery time is believed to provide a substrate which supports serious ventricular arrhythmias. We showed that in patients with chronic obstructive pulmonary disease, free of underlying structural heart disease, the QTc dispersion is significant greater (p = 0.036) than in a control group, despite a similar value in mean QTc value. The data of the present study suggest that the determination of dispersion of repolarization times may be affected by metabolic changes occurring in patients with chronic obstructive pulmonary disease.