Everolimus for epilepsy and autism spectrum disorder in tuberous sclerosis complex: EXIST-3 substudy in Japan.

BACKGROUND: Epilepsy and autism spectrum disorder (ASD) are the common neurological manifestations of tuberous sclerosis complex (TSC). EXIST-3 study has recently demonstrated that everolimus reduces seizures in patients with TSC and refractory epilepsy. Here we report the efficacy and safety of everolimus for treatment-refractory seizures in Japanese patients of EXIST-3, along with the exploratory analysis evaluating the everolimus effect on comorbid ASD symptoms in these patients. METHODS: Primary endpoint was change in seizure frequency from baseline defined as response rate (≥50% reduction) and median percentage reduction in the seizure frequency. Pervasive Developmental Disorders Autism Society Japan Rating Scale (PARS) scores were assessed at baseline and at week-18 for ASD symptoms. RESULTS: Overall, 35 Japanese patients were randomized to everolimus low-exposure (LE; n = 10), everolimus high-exposure (HE; n = 14), or placebo (n = 11). The response rate was 30.0% and 28.6% versus 0% with the everolimus LE and HE versus placebo arm, respectively. Similarly, the median percentage reduction in seizure frequency was 6.88% and 38.06% versus -6.67%. Stomatitis was the most frequently reported adverse event (everolimus LE, 100%; HE, 78.6%; placebo, 9.1%). Four of 11 patients with ASD in the everolimus arms and 1 of 8 patients with ASD in the placebo arm showed ≥5 point decrease in PARS scores. CONCLUSIONS: Adjunctive everolimus treatment improved seizure frequency with a tolerable safety relative to placebo among 35 Japanese patients with TSC-associated refractory seizures, consistent with the results of overall EXIST-3 study involving 366 patients. A favorable trend towards the improvement of ASD symptoms was observed.

Incremental value of B-type natriuretic peptide for detection and risk reclassification of obstructive coronary artery disease on computed tomography angiography.

BACKGROUND: B-type natriuretic peptide (BNP) is well known to increase as a result of left ventricular systolic dysfunction and is a useful diagnostic marker for heart failure. The purpose of this study was to assess the incremental value of BNP for predicting obstructive coronary artery disease (CAD) on computed tomography angiography (CTA) in patients with suspected CAD. METHODS: This was an observational analysis of patients with stable CAD undergoing CTA in our institution between April 2008 and June 2014. Consecutive 947 patients with suspected CAD who underwent 64-slice CTA were enrolled. Obstructive CAD was defined as more than 50% luminal narrowing. We divided the patients into 2 groups according to median BNP value (20.3pg/ml). Duke clinical score for obstructive CAD was calculated for each patient. RESULTS: Obstructive CAD was found in 273 (28.0%) patients. Median follow-up period was 37 months (interquartile range 21-55 months). Kaplan-Meier curves showed that BNP above median was significantly associated with major adverse cardiac events (p=0.001). In multivariable logistic analysis, patients with BNP above median were associated with the presence of obstructive CAD, as compared with BNP below median [odds ratio, 2.55; 95% confidence interval (CI), 1.79-3.63; p<0.001]. Analyzing the incremental value of the Duke clinical score and BNP, the predictive value of the Duke clinical score [area under the curve (AUC), 0.714] could be increased by BNP (AUC 0.745 for the combined model; p<0.001). Addition of BNP to a model containing the Duke clinical score resulted in net reclassification improvement index of 0.14 (95% CI: 0.053-0.205, p<0.001). CONCLUSIONS: BNP might provide an incremental improvement in the detection of obstructive CAD on CTA when combined with a conventional cardiovascular risk score.

Prediction of chronic renal insufficiency after coronary angiography by an early increase in oxidative stress and decrease in glomerular filtration rate.

BACKGROUND: Oxidative stress caused by contrast medium is thought to be one of the main mechanisms of contrast-induced acute kidney injury. A prospective study was conducted to evaluate the relationship between oxidative stress caused by contrast agent administration and long-term renal function. METHODS AND RESULTS: Thirty-six consecutive patients who underwent coronary angiography were enrolled. Urinary F2-isoprostane, a marker of oxidative stress, was measured at baseline and 24h after angiography, and serum creatinine was measured at baseline, 24h and 1 year after the procedure. The change in estimated glomerular filtration rate (eGFR) at 1 year after angiography correlated significantly with the change in eGFR at 24h after angiography (r=0.729, P<0.001). We also found a significant correlation between the increase in urinary F2-isoprostane at 24h and the decrease in eGFR at 1 year (r=0.439, P=0.022). In multivariate analysis, the decrease in eGFR at 1 year after coronary angiography correlated with the increase in F2-isoprostane at 24h after angiography as well as the decrease in eGFR at 24h after angiography (P=0.039 and P<0.001, respectively). CONCLUSIONS: Contrast-induced nephrotoxicity might be transient; however, an early decrease in eGFR and increase in oxidative stress are associated with chronic renal insufficiency. Careful long-term follow-up and adequate medical intervention are necessary for these patients.

Feasibility of targeting catheter ablation to the markedly low-voltage area surrounding infarct scars in patients with post-infarction ventricular tachycardia.

BACKGROUND: In routine substrate mapping of the left ventricle, an abnormal area is defined as having an amplitude <1.5 mV. However, that is usually too large for catheter ablation in post-infarction ventricular tachycardia (VT) and the use of strict voltage criteria may produce better outcomes. METHODS AND RESULTS: Twenty patients with post-infarction VT underwent substrate mapping using an electroanatomic mapping system. Strict voltage criteria were defined as: non-arrhythmogenic area, >0.6 mV; low-voltage area (LVA), >0.1 to or=150 ms) was significantly higher in the LVAs than in the border areas with an amplitude of >0.6 to

Effects of linear ablation at the isthmus between the tricuspid annulus and inferior vena cava for atrial flutter on autonomic nervous activity: analysis of heart rate variability.

Heart rate is largely affected by the autonomic nervous system. However, little is known about the anatomic pathway of autonomic nerve fibers innervating the sinus node. The present study: (1) evaluates the effects of cavotricuspid isthmus ablation for common atrial flutter (AFL) on autonomic nervous function by using heart rate variability analysis, and (2) investigates the distribution of autonomic nerve pathways innervating the sinus node. Twelve patients with paroxysmal common atrial flutter who maintained sinus rhythm both before and after radiofrequency ablation were selected for the study. Holter ambulatory recordings were performed before and after (2.3 +/- 1.0 days) radiofrequency ablation of cavotricuspid isthmus. Heart rate and time domain (SDANN, rMSSD, pNN50) and frequency domain (low frequency (LF), high frequency (HF), LF/HF) analysis of heart rate variability were compared before and after ablation. Mean heart rate did not change significantly after ablation (59 +/- 6 vs 61 +/- 9 beats/min); parasympathetic indices of heart rate variability (SDANN, rMSSD, pNN50, HF) did not change significantly (110 +/- 37 vs 117 +/- 20 ms; 32 +/- 21 vs 28 +/- 9 ms; 4.8 +/- 0.9 vs 4.7 +/- 0.71n(ms2)); and sympathetic indices of heart rate variability (LF/HF) did not change significantly (1.1 +/- 0.2 vs 1.2 +/- 0.1). Cavotricuspid isthmus ablation for atrial flutter did not significantly change heart rate and heart rate variability because parasympathetic and sympathetic fibers innervating the sinus node are scarce in this region.

Atrial components contributing to pseudo r' deflection in lead V1 in slow/fast atrioventricular nodal reentrant tachycardia: analysis of the atrial activation sequence by basket catheter isochronal mapping.

Electrocardiographic recognition of the P' wave during tachycardia is very useful in the diagnosis of supraventricular tachycardias. In slow/fast (S/F) atrioventricular nodal reentrant tachycardia (AVNRT), no discrete P' waves are observed on ECG and pseudo r' deflection in lead V1 (pseudo r') is commonly recognized. However, the atrial components that contribute to the genesis of pseudo r' in lead V1 have not been described and this study aimed to clarify them by analysis of the whole activation sequence of the right atrium using Basket catheter isochronal mapping. The study group comprised 48 patients with AVNRT. Pseudo r' was defined as an upward deflection in the terminal portion of the QRS complex during tachycardia that was not recognized during sinus rhythm and it occurred in 45 patients (94%). During S/F AVNRT, the retrograde atrial activation was earliest on His bundle electrogram, followed by the coronary sinus ostium, distal coronary sinus and high right atrium. Only the high lateral aspect of the right atrium was activated after the end of the QRS complex. The interval between the onset of QRS in multiple surface ECG leads and the atrial activities on high right atrium was similar to the V-r' interval in lead V1 (111+/-20ms, 117+/-11 ms) and correlated with the V-r' interval (r=0.56). Pseudo r' deflection in lead V1 is a highly sensitive indicator of S/F AVNRT, and appears to result from the activation of the superolateral aspect of the right atrium.