Multiscale quantification of morphological heterogeneity with creation of a predictor of longer survival in glioblastoma

Intratumor heterogeneity is a main cause of the dismal prognosis of glioblastoma (GBM). Yet, there remains a lack of a uniform assessment of the degree of heterogeneity. With a multiscale approach, we addressed the hypothesis that intratumor heterogeneity exists on different levels comprising traditional regional analyses, but also innovative methods including computer-assisted analysis of tumor morphology combined with epigenomic data. With this aim, 157 biopsies of 37 patients with therapy-naive IDH-wildtype GBM were analyzed regarding the intratumor variance of protein expression of glial marker GFAP, microglia marker Iba1 and proliferation marker Mib1. Hematoxylin and eosin stained slides were evaluated for tumor vascularization. For the estimation of pixel intensity and nuclear profiling, automated analysis was used. Additionally, DNA methylation profiling was conducted separately for the single biopsies. Scoring systems were established to integrate several parameters into one score for the four examined modalities of heterogeneity (regional, cellular, pixel-level and epigenomic). As a result, we could show that heterogeneity was detected in all four modalities. Furthermore, for the regional, cellular and epigenomic level, we confirmed the results of earlier studies stating that a higher degree of heterogeneity is associated with poorer overall survival. To integrate all modalities into one score, we designed a predictor of longer survival, which showed a highly significant separation regarding the OS. In conclusion, multiscale intratumor heterogeneity exists in glioblastoma and its degree has an impact on overall survival. In future studies, the implementation of a broadly feasible heterogeneity index should be considered.     

Conduction characteristics at the crista terminalis during onset of pulmonary vein atrial fibrillation

INTRODUCTION: Focal atrial fibrillation (AF) may initiate with an irregular rapid burst of atrial ectopic (AE) activity from a pulmonary vein (PV) focus, but how AF is maintained it is not known. The crista terminalis (CT) is an important line of block in atrial flutter (AFL), but its role in AF has not been determined. The aim of this study was to examine the conduction properties of the CT during onset of AF. METHODS AND RESULTS: In 10 patients (mean age 38 +/- 8 years), we analyzed conduction across the CT during onset of focal AF from an arrhythmogenic PV and during pacing from the same PV at cycle lengths of 700 and 300 ms. A 20-pole catheter was positioned on the CT using intracardiac echocardiography. In 10 control patients with no history of AF, we analyzed conduction across the CT during pacing from the distal coronary sinus at 700 and 300 ms. In all 10 AF patients, AF was initiated with 1 to 9 AE beats (median 5) from a PV. During sinus rhythm, there were no split components (SC) recorded on the CT. During PV AE activity, discrete SC were recorded on the CT in all patients over 6.3 +/- 0.9 bipoles (3.7 +/- 0.3 cm). Maximal splitting of SC was 66 +/- 31 ms (37-139). There was an inverse relationship between AE coupling intervals and the degree of splitting between SC in all patients. Degeneration to AF was preceded by progressive decrement across the CT. SC were recorded during PV pacing at 700 and 300 ms (maximal distance between SC of 24 +/- 3 ms and 43 +/- 5 ms, respectively, P < 0.001). Maximum SC at CT in controls was 13 +/- 8 ms at 700 ms (P = 0.06 vs AF patients) and 16 +/- 9 ms at 300 ms (P < 0.01 vs AF patients). CONCLUSION: (1) These observations provide evidence of anisotropic, decremental conduction across the CT during onset of focal AF and during pacing from the same PV. A line of functional conduction block develops along this anatomic structure (CT). Whether this line of block acts as an initiator of AF or simply contributes passively to nonuniform fibrillatory conduction is unknown. (2) In some patients with focal AF, development of conduction block along the CT may provide a substrate for typical AFL.     

Clinical evaluation of a policy of early repeated internal cardioversion for recurrence of atrial fibrillation

INTRODUCTION: The clinical value of cardioversion (CV) of persistent atrial fibrillation (AF) is limited by the high rate of early AF recurrence, which may be related to the persistence of atrial electrical remodeling. We examined the hypothesis that the likelihood of maintaining sinus rhythm after CV of persistent AF is significantly enhanced by a policy of early repeated CV. METHODS AND RESULTS: Fifty-nine patients with persistent AF underwent internal CV (CV 1). Those patients cardioverted were monitored with daily transtelephonic ECG. In the event of AF recurrence, these patients were admitted rapidly for repeat CV (CV 2) and, if further recurrence occurred, a third CV (CV 3) was performed. Daily ECG monitoring was continued until 1 month of sinus rhythm was maintained or a total of three CVs were performed. Of the 59 patients undergoing CV 1, 43 were discharged in sinus rhythm and 29 subsequently had AF recurrence during monitoring. Twenty-three of these underwent CV 2 and 11 of these underwent CV 3. Of those having repeated CVs, only 4 patients maintained sinus rhythm for 1 month (3 after CV 2 and 1 after CV 3). The remaining patients had repeated AF recurrence during the monitoring period. Mean time from AF recurrence to CV 2 was 20+/-13 hours and from AF recurrence to CV 3 was 13+/-7.2 hours. Atrial effective refractory periods increased from 189+/-16 msec at CV 1 to 215+/-18 msec at CV 3 (P < 0.05), indicating reversal of atrial electrical remodeling during this period. CONCLUSION: A policy of early repeated CVs for AF recurrence has very limited clinical value despite evidence of reversal of atrial electrical remodeling. The time between AF recurrence and repeat CV may need to be reduced further if such a policy is to succeed.     

Rapid decline in acute stimulation thresholds with steroid-eluting active-fixation pacing leads

BACKGROUND AND AIM: There is an increasing use of active-fixation leads for cardiac pacing, yet concerns remain regarding initial high stimulation thresholds. The aim was to perform a detailed analysis of pacing parameters at the time of implantation to determine when lead repositioning should be considered. METHODS: We performed a prospective observational study of consecutive new pacemaker implants. Detailed analysis of pacing parameters was collected at 2-minute intervals for 10 minutes, and at day 1 and week 8 following implant. RESULTS: Ninety-four patients underwent implantation of 79 dual-chamber and 15 single-chamber pacemakers using active-fixation leads in both chambers. An initial threshold of >1 V was demonstrated in 45/94 (48%) ventricular leads (mean threshold 1.5 +/- 0.3 V). This declined rapidly to 0.9 +/- 0.3 V at 4 minutes (P < 0.01), 0.7 +/- 0.3 V at 10 minutes (P < 0.01), and 0.6 +/- 0.3 V at day 1 (P < 0.01). At day 1, 43/45 leads were <1 V. There were 79 atrial leads. An initial threshold of >1 V (mean 1.7 +/- 0.6 V) was demonstrated in 41/79 (52%) leads falling significantly to 1.1 +/- 0.5 V at 4 minutes (P < 0.01), 0.9 +/- 0.4 V at 10 minutes (P < 0.01), and 0.6 +/- 0.2 V at day 1 (P < 0.01). At 10 minutes, 32 of 41 leads demonstrated a threshold of <1 V with all leads <1 V at day 1. Thresholds were maintained medium term. CONCLUSIONS: Active-fixation leads are commonly associated with initially high thresholds that fall rapidly. An initial threshold of 2 V should be provisionally accepted and retested at 4 minutes. The majority will have a threshold of <1 V the following day. A failure of a high threshold to decline at 4 minutes requires lead repositioning.     

Effect of amiodarone on dispersion of atrial refractoriness and cycle length in patients with atrial fibrillation

INTRODUCTION: Amiodarone is effective in preventing the recurrence of atrial fibrillation (AF) after cardioversion (CV). Dispersion of atrial refractoriness may be relevant to the generation of AF. We designed a study to determine the electrophysiologic effects of amiodarone in patients with previous early recurrence of AF after CV. METHODS AND RESULTS: Fifteen patients with previous AF recurrence (without antiarrhythmic drugs) after CV (CV1) were selected for amiodarone therapy and repeat CV (CVamio). Prior to CV1, mean AF cycle length (AFCL) had been recorded at four atrial sites (right atrial appendage [RAA], distal coronary sinus [DCS], right atrial lateral wall [LAT], and interatrial septum [IAS]) and dispersion of AFCL had been calculated. These patients were treated with amiodarone and, prior to CVamio, AFCL was recorded at the four atrial sites as for CV1. Between CV1 and CVamio, AFCL increased at all atrial sites: 153 +/- 13 msec to 179 +/- 14 msec at RAA, 144 +/- 12 msec to 174 +/- 18 msec at DCS, 158 +/- 13 msec to 182 +/- 16 msec at LAT, and 161 +/- 18 msec to 181 +/- 17 msec at IAS. Dispersion of AFCL decreased from 24 +/- 10 msec at CV1 to 15 +/- 11 msec at CVamio (P = 0.01). The median time in sinus rhythm increased from 3.12 hours post CV1 to 28 days post CVamio, (P < 0.02). CONCLUSION: Amiodarone causes a reduction in the dispersion of AFCL. This action may be relevant to the beneficial effects of amiodarone in patients with AF.     

Focal atrial tachycardia from the ostium of the coronary sinus: electrocardiographic and electrophysiological characterization and radiofrequency ablation

OBJECTIVES: The goal of this study was to characterize the electrocardiographic and electrophysiologic features and frequency of focal atrial tachycardia (AT) originating from the coronary sinus ostium (CS). BACKGROUND: The ostium of the coronary sinus has been described as a site of origin of AT, but detailed characterization of these tachycardias is limited. METHODS: Thirteen patients (6.7%) of 193 undergoing radiofrequency ablation (RFA) for focal AT are reported. Endocardial activation maps (EAM) were recorded from catheters at the CS (10 pole), crista terminalis (20 pole), and His positions. The P waves were classified negative, positive, isoelectric, or biphasic. RESULTS: The mean age was 41 +/- 6 years, seven female patients, with symptoms for 8 +/- 3 years. Tachycardia was induced by programmed extra-stimuli in eight patients, was spontaneous in three patients, and in response to isoproterenol in two patients. These foci had a characteristic P-wave morphology. At the CS ostium, the P-wave was deeply negative in all inferior leads, negative or isoelectric becoming positive in lead V(1), then progressively negative across the precordium. Lead aVL was positive in all patients. Earliest EAM activity occurred at the proximal CS at 20 +/- 3 ms ahead of P-wave. Mean activation time at the successful RFA site = -36 +/- 8 ms; RFA was acutely successful in 11 of 13 patients. Long-term success was achieved in 11 of 11 over a median follow-up of 25 +/- 4 months. CONCLUSIONS: The CS ostium is an uncommon site of origin for focal AT (6.7%). It can be suspected as a potential anatomic site of AT origin from the characteristic P-wave and activation timing. Long-term success was achieved with focal ablation in the majority of patients.     

Bundle Branch Reentrant Tachycardia in a Patient with Normal Ventricular Function

We report an unusual case of bundle branch reentrant tachycardia, in a patient with normal left ventricular function, cured by radiofrequency catheter ablation. However, the long-term prognosis of these patients is uncertain. We discuss the indications for an implantable defibrillator in this group.