Event rates and risk factors in patients with Brugada syndrome and no prior cardiac arrest: a cumulative analysis of the largest available studies distinguishing ICD-recorded fast ventricular arrhythmias and sudden death.

BACKGROUND: All available studies that have addressed the issue of risk stratification in patients with type 1 Brugada electrocardiographic (ECG) pattern have considered a combined end point constituted by implantable cardioverter-defibrillator-recorded fast ventricular arrhythmias (ICD-FVA) and sudden death (SD) in patients without ICD. OBJECTIVE: As ICD-FVA are only a surrogate of SD, we tried to focus on the prognostic value of classical risk factors by separating patients with ICD-FVA from those without ICD who suffered SD. METHODS: We made a cumulative analysis of the largest available studies. Studies were selected in which the incidence of FVA and SD could be determined in patients with and without ICD separately. In addition, we tried to analyze the prognostic value of risk factors in patients with and without ICD separately. RESULTS: A total of 2176 patients were recruited from 5 studies, about one-third of whom had an ICD and two-thirds did not. Event rates per 1000 patient-years of follow-up were 31.3 (25­39) and 6.5 (4-10) in patients with and without ICD, respectively (P < .001). When considering FVA in patients with ICD, each single risk factor (spontaneous type 1 ECG pattern, familial juvenile SD, and +EPS) displayed limited clinical value, mainly owing to its low specificity (21%-61%) and low positive predictive value (9%-15%). CONCLUSIONS: In patients with type 1 Brugada ECG pattern, most arrhythmic events occur in patients with an ICD while SD is rare in patients without an ICD. While we have an acceptable ability to predict ICD-FVA, we have insufficient data to predict SD.

Incidence and clinical relevance of uncontrolled ventricular rate during atrial fibrillation in heart failure patients treated with cardiac resynchronization therapy.

AIMS: Uncontrolled ventricular rate (VR) during atrial fibrillation (AF) may cause clinical deterioration in heart failure (HF) patients who need continuous biventricular pacing to achieve cardiac resynchronization therapy (CRT). We aimed at evaluating the association between AF, uncontrolled VR, and sub-optimal CRT, defined as low biventricular pacing percentage (BIVP%). METHODS AND RESULTS: All 1404 patients had HF, New York Heart Association (NYHA) ≥II, left ventricular ejection fraction (LVEF) ≤35%, and QRS ≥120 ms, and received an implantable CRT defibrillator (CRT-D). Occurrence of AF, VR during AF and lifetime BIVP% were estimated from device data. Ventricular rate during AF was defined as uncontrolled in patients with mean VR>80 bpm and maximum VR>110 bpm. Over a median follow-up of 18 months, AF was detected in 443 of 1404 patients (32%). In this sub-group of AF patients, VR during AF was uncontrolled in 150 of 443 patients (34%). Multivariate Cox regression analysis showed that age [hazard ratio (HR) = 1.03, 95% confidence interval (CI) = 1.00-1.06, P= 0.028], and uncontrolled VR [HR = 1.69 (CI = 1.01-2.83), P= 0.046] were the only independent predictors of clinical outcome, assessed by HF hospitalizations and death. The median lifetime BIVP% was 95% (25-75 percentile range 91-99%). Biventricular pacing percentage was significantly and inversely correlated to VR, decreasing by 7% for each 10 bpm increase in VR. Sub-optimal CRT, defined as BIVP% <95%, was predicted by the occurrence of persistent or permanent AF [odds ratio (OR) = 3.77, CI = 2.44-5.82, P< 0.001], and uncontrolled VR [OR = 2.25, CI = 1.35-3.73, P= 0.002]. CONCLUSION: Uncontrolled VR occurs in one-third of CRT-D patients, who experience AF, and is associated with HF hospitalizations and death and with sub-optimal CRT (lifetime BIVP%<95%).

Convergence of integrins and EGF receptor signaling via PI3K/Akt/FoxO pathway in early gene Egr-1 expression.

The early gene early growth response (Egr-1), a broadly expressed member of the zing-finger family of transcription factors, is induced in many cell types by a variety of growth and differentiation stimuli, including epidermal growth factor (EGF). Here we demonstrate that Egr-1 expression is mainly regulated by integrin-mediated adhesion. Integrin-dependent adhesion plays a dual role in Egr-1 regulation, either being sufficient "per se" to induce Egr-1, or required for EGF-dependent expression of Egr-1, which occurs only in adherent cells and not in cells in suspension. To dissect the molecular basis of integrin-dependent Egr-1 regulation, we show by FLIM-based FRET that in living cells beta1-integrin associates with the EGF receptor (EGFR) and that EGF further increases the extent complex formation. Interestingly, Egr-1 induction depends on integrin-dependent PI3K/Akt activation, as indicated by the decrease in Egr-1 levels in presence of the pharmacological inhibitor LY294002, the kinase-defective Akt mutant and Akt1/2 shRNAs. Indeed, upon adhesion activated Akt translocates into the nucleus and phosphorylates FoxO1, a Forkhead transcription factors. Consistently, FoxO1silencing results in Egr-1-increased levels, indicating that FoxO1 behaves as a negative regulator of Egr-1 expression. These data demonstrate that integrin/EGFR cross-talk is required for expression of Egr-1 through a novel regulatory cascade involving the activation of the PI3K/Akt/Forkhead pathway.

Rate control in patients with pacemaker affected by brady-tachy form of sick sinus syndrome.

BACKGROUND: In sinus node disease (SND) atrial tachyarrhythmias (ATs) may frequently occur, after implant of a pacemaker for bradycardia, and are to be managed by rate or rhythm control. METHODS: We evaluated ventricular heart rate (HR) during AT, AT-related symptoms and hospitalizations in 333 patients who received DDDRP pacemakers for SND. RESULTS: In days with 24 hours of AT, mean daily HR during AT was > 80, 90, 100, 110, and 120 beats per minute (bpm) in 191 (57%), 114 (34%), 55 (16%), 23 (7%), and 11 (3%) patients, respectively. The proportion of patients with a mean daily HR > 80 bpm during AT despite the use of rate control agents was 28% among patients treated with calcium-channel blockers, 43% with digoxin, 49% with a combination of agents, 54% with amiodarone, 64% with sotalol, and 69% with beta blockers. Patients with HR > 100 bpm experienced a higher prevalence of both AT-related hospitalizations and cardiovascular hospitalizations than those with HR < or = 100 bpm (36% vs 21%, P = .013; 42% vs 28%, P = .003) and a significantly higher number of AT-related symptoms (1.8 +/- 0.9 vs 1.4 +/- 1.0, P = .008). CONCLUSIONS: Limited attention has been dedicated to rate control in patients with pacemaker. This is the first study to evaluate the prevalence and implications of inappropriate rate control in patients with pacemaker. We found that in a substantial proportion of patients with SND who have recurrent ATs despite pacing, mean daily HR during AT is high and that these patients present increased hospitalizations and more symptoms, thus suggesting the need to improve rate control.

Clustering of ventricular tachyarrhythmias in heart failure patients implanted with a biventricular cardioverter defibrillator.

BACKGROUND: Temporal patterns of ventricular tachyarrhythmia (VT/VF) have been studied only in patients who have received implantable cardioverter defibrillators (ICD) for secondary prevention of sudden death, and mainly in ischemic patients. The aim of this study was to evaluate VT/VF recurrence patterns in heart failure (HF) patients with biventricular ICD and to stratify results according to HF etiology and ICD indication. METHODS AND RESULTS: We studied 421 patients (91% male, 66 +/- 9 years). HF etiology was ischemic in 292 patients and nonischemic in 129. ICD indication was for primary prevention in 227 patients and secondary prevention in 194. Baseline left ventricular ejection fraction (LVEF) was 26 +/- 7%, QRS duration 168 +/- 32 msec, and NYHA class 2.9 +/- 0.6. In a follow-up of 19 +/- 11 months, 1,838 VT/VF in 110 patients were appropriately detected. In 59 patients who had > or = 4 episodes, we tried to determine whether VT/VF occurred randomly or rather tended to cluster by fitting the frequency distribution of tachycardia interdetection intervals with exponential functions: VT/VF clusters were observed in 46 patients (78% of the subgroup of patients with > or = 4 episodes and 11% of the overall population). On multivariate logistic analysis, VT/VF clusters were significantly (P < 0.01) associated with ICD indication for secondary prevention (odds ratio [OR] = 3.12; confidence interval [CI] = 1.56-6.92), nonischemic HF etiology (OR = 4.34; CI = 2.02-9.32), monomorphic VT (OR = 4.96; CI = 2.28-10.8), and LVEF < 25% (OR = 3.34; CI = 1.54-7.23). Cardiovascular hospitalizations and deaths occurred more frequently in cluster (21/46 [46%]) than in noncluster patients (63/375 (17%), P < 0.0001). CONCLUSIONS: In HF patients with biventricular ICDs, VT/VF clusters may be regarded as the epiphenomenon of HF deterioration or as a marker of suboptimal response to cardiac resynchronization therapy.