Rationale and design of the BUDAPEST-CRT Upgrade Study: a prospective, randomized, multicentre clinical trial.

AIMS: There is lack of conclusive evidence from randomized clinical trials on the efficacy and safety of upgrade to cardiac resynchronization therapy (CRT) in patients with implanted pacemakers (PM) or defibrillators (ICD) with reduced left ventricular ejection fraction (LVEF) and chronic heart failure (HF). The BUDAPEST-CRT Upgrade Study was designed to compare the efficacy and safety of CRT upgrade from conventional PM or ICD therapy in patients with intermittent or permanent right ventricular (RV) septal/apical pacing, reduced LVEF, and symptomatic HF. METHODS AND RESULTS: The BUDAPEST-CRT study is a prospective, randomized, multicentre, investigator-sponsored clinical trial. A total of 360 subjects will be enrolled with LVEF ≤ 35%, NYHA functional classes II-IVa, paced QRS ≥ 150 ms, and a RV pacing ≥ 20%. Patients will be followed for 12 months. Randomization is performed in a 3:2 ratio (CRT-D vs. ICD). The primary composite endpoint is all-cause mortality, a first HF event, or less than 15% reduction in left ventricular (LV) end-systolic volume at 12 months. Secondary endpoints are all-cause mortality, all-cause mortality or HF event, and LV volume reduction at 12 months. Tertiary endpoints include changes in quality of life, NYHA functional class, 6 min walk test, natriuretic peptides, and safety outcomes. CONCLUSION: The results of our prospective, randomized, multicentre clinical trial will provide important information on the role of cardiac resynchronization therapy with defibrillator (CRT-D) upgrade in patients with symptomatic HF, reduced LVEF, and wide-paced QRS with intermittent or permanent RV pacing. CLINICAL TRIALS.GOV IDENTIFIER: NCT02270840.

Catheter Ablation of Ventricular Tachycardia as the First-Line Therapy in Patients With Coronary Artery Disease and Preserved Left Ventricular Systolic Function: Long-Term Results.

INTRODUCTION: Patients with coronary artery disease (CAD), relatively preserved left ventricular ejection fraction (LVEF), and hemodynamically tolerated ventricular tachycardia (VT) may benefit from catheter ablation as the first-line treatment. Our aim was to analyze the long-term results of VT ablation in this population. METHODS AND RESULTS: Thirty-one patients (1 woman, mean age 67 ± 10 years) with CAD, tolerated VT, and LVEF ≥40% underwent catheter ablation as the first-line treatment of the arrhythmia. Catheter ablation was performed in order to abolish all inducible VTs. An ICD was implanted if sustained VT of any morphology remained inducible after the procedure. The mean LVEF was 48 ± 6% and the mean VT cycle length reached 348 ± 70 milliseconds in the study cohort. Clinical and all inducible VTs were abolished in 90% (28/31) and 58% (18/31) of the patients, respectively. An ICD was subsequently implanted in 42% of cases. Over a mean follow-up of 3.8 ± 2.9 years, 42% (13/31) patients died. Survival of the patients with or without the ICD was not significantly different (P = 0.47). VT recurrence was observed in 11% (2/18) of patients who had complete elimination of all inducible VTs. No sudden death occurred in patients without the ICD. CONCLUSIONS: Catheter ablation of VT as the first-line treatment in patients with CAD and relatively preserved LVEF is a viable strategy. It may prevent implantation of the ICD in a considerable proportion of patients. Abolition of all inducible VTs confers low VT recurrence rate over a long-term follow-up.

The Seattle Heart Failure Model predicts survival in patients with cardiac resynchronization therapy: a validation study.

BACKGROUND: The Seattle Heart Failure Model (SHFM) predicts mortality in patients with heart failure, but no study has investigated model performance in subjects with cardiac resynchronization therapy (CRT). METHODS AND RESULTS: Prospectively collected registry data of 427 patients with CRT were used for the evaluation of the discrimination and calibration performance of the SHFM. The primary end point was all-cause mortality. Calibration profile was assessed with the use of Hosmer-Lemeshow tests, and discrimination was assessed by calculating areas under receiver operating characteristic curves (AUCs) derived from the model. Mean (SD) age of the study population was 61.2 (11.1) years (72.6% male). During a median follow-up of 24.7 months, 16.9% (72/427) of the patients reached the primary end point, with observed outcomes of 34/303, 54/234, and 72/97 at years 1, 2, and 5, respectively. No evidence of insufficient fit was found in any calibration tests. AUC estimates in all subjects were 0.7377 (95% CI 0.6575-0.8179) at year 1, 0.7936 (95% CI 0.7317-0.8556) at year 2, and 0.7572 (95% CI 0.6455-0.8689) at year 5. CONCLUSIONS: SHFM offers an accurate prediction of survival in patients with CRT, with good observed calibration and AUC estimates indicating discrimination performance similar to those found by earlier validation studies.

Long-term arrhythmia variability after monomorphic ventricular tachycardia in patients with an implantable cardioverter defibrillator.

BACKGROUND: Arrhythmia burden in patients receiving an implantable cardioverter defibrillator (ICD) after monomorphic ventricular tachycardia (mVT) is higher than in patients with other indications. We investigated the long-term arrhythmia profile in this subset of patients. METHODS: Fifty-two patients with an ICD implanted after mVT were followed up for at least 3 months. The cycle lengths (CLs) of the tachycardias recovered from the device memory were compared with the CL of the index arrhythmia. Morphological analysis of the intracardiac electrograms was performed and the response to antitachycardia pacing (ATP) was also assessed. RESULTS: A total of 833 mVT episodes with intracardiac electrograms occurred during the follow-up (3-58 months; mean: 30.3 months) in 41 of the 52 patients analyzed. mVTs with different CLs as compared with the index mVT were found in 26 (50.0%), and at least two different mVT morphologies were observed in 28 (53.8%) patients. Multiple mVT morphologies were predictive of lower ATP efficacy (95.6%, 85.0%, and 70.3% in the patients with 1, 2, and 3 or more mVT morphologies, respectively; P < 0.0001) and a higher shock burden (4.2%, 19.3%, and 24.7% in the patients with 1, 2, and 3 or more mVT morphologies, respectively; P < 0.0001). CONCLUSION: A high mVT burden was demonstrated with marked variability of the arrhythmias as concerns both CL and morphology in patients with an ICD implanted for mVT. Multiple mVT morphologies during the follow-up were predictive of lower ATP efficacy and a higher shock burden.

[Cryoballon isolation of the pulmonary veins in atrial fibrillation: mid-term results after the first 55 patients]. / Pitvarfibrilláció kezelése a pulmonalis vénák krioballon-izolációjával: Középtávú eredmények az elsô 55 beteg alapján.

UNLABELLED: Several transcatheter techniques based on radiofrequency energy were elaborated for the treatment of atrial fibrillation through the last decade. Recently, similar success rates with a better safety profile concerning life threatening complications were reported with the novel methode of cryoballon isolation of the pulmonary veins. This paper summarizes our initial experience with cryoballon ablation after the first 55 patients. METHOD: [corrected] Symptomatic patients refractory to aniarrhythmic medication mostly with paroxysmal atrial fibrillation without significant structural heart disease were enrolled. Cannulation and isolation of all pulmonary veins were attempted using a 28 mm double-wall cryoballon inflated at the ostium of the vein and abolishing eletrical activity of atrial tissue around its perimeter by freezing to -70 C. Intravenous heparin during and oral anticoagulant after the procedure was administered. Conventional ECGs, Holter ECGs and transtelephonic ECG recordings were used through 6 months follow-up for rhythm monitoring. RESULTS: In 55 patients enrolled (18 female; age: 56 + or - 33,64 years) 165 out ot 192 (86%) pulmonary veins were successfully isolated. All pulmonary veins were isolated in 37 patients (67%). Procedure time was 155.67 + or - 100.66 min, while fluoroscopy time was 34.04 + or - 31.89 min. In 34 patients with 6 months follow-up 24 (70%) either remained free of arrhythmia (17 patients) or had a significant decrease in arrhythmia burden (7 patients). CONCLUSION: Based on our initial experience, cryoballon isolation of pulmonary veins appears to be a more simple procedure with similar efficacy to radiofrequency ablation in the treatment of atrial fibrillation.

Intracardiac Fibrinolysis and Endothelium Activation Related to Atrial Fibrillation Ablation with Different Techniques.

OBJECTIVE: The effect of pulmonary vein isolation (PVI) on fibrinolytic and endothelial activation with currently applied periprocedural anticoagulation has not been explored. We measured markers of fibrinolysis and endothelium activation before and after PVI with the second-generation cryoballoon (Cryo), pulmonary vein ablation catheter (PVAC-Gold), and irrigated radiofrequency (IRF). METHODS: Markers of fibrinolysis and endothelium activation in left atrial (LA) blood samples were measured in 31 patients before and after PVI (Cryo:10, PVAC-Gold: 7, IRF: 14). Periprocedural anticoagulation included uninterrupted vitamin K antagonist and iv heparin (ACT≥300 sec) during LA dwelling. RESULTS: Levels of D-dimer (median; interquartile range, mgFEU/L) increased with all techniques (PVAC: 0.34; 0.24-0.50 versus 0.70; 0.61-1.31; p=0.0313, Cryo: 0.33; 0.28-0.49 versus 0.79; 0.65-0.93; p=0.0313, Cryo: 0.33; 0.28-0.49 versus 0.79; 0.65-0.93; p=0.0313, Cryo: 0.33; 0.28-0.49 versus 0.79; 0.65-0.93; PAP complex level (ng/ml) increased after Cryo (247.3, 199.9-331.6 versus 270.9, 227.9-346.7; p=0.0313, Cryo: 0.33; 0.28-0.49 versus 0.79; 0.65-0.93; p=0.0313, Cryo: 0.33; 0.28-0.49 versus 0.79; 0.65-0.93; p=0.0313, Cryo: 0.33; 0.28-0.49 versus 0.79; 0.65-0.93; PAI-1 activity (%) decreased with the PVAC (1.931; 0.508-3.859 versus 0.735, 0.240-2.707; p=0.0313, Cryo: 0.33; 0.28-0.49 versus 0.79; 0.65-0.93; p=0.0313, Cryo: 0.33; 0.28-0.49 versus 0.79; 0.65-0.93; p=0.0313, Cryo: 0.33; 0.28-0.49 versus 0.79; 0.65-0.93; VWF antigen levels and FVIII activity increased after PVI with all the 3 techniques. The levels of soluble VCAM-1 (ng/ml) did not change after PVAC procedures, but increased after Cryo (542, 6; 428.5-753.1 versus 619.2; 499.8-799.0; p=0.0313, Cryo: 0.33; 0.28-0.49 versus 0.79; 0.65-0.93; p=0.0313, Cryo: 0.33; 0.28-0.49 versus 0.79; 0.65-0.93. CONCLUSION: PVI with contemporary ablation techniques and periprocedural antithrombotic treatment induces coagulation and endothelium activation of similar magnitude with different ablation methods.

Independent effect of atrial fibrillation on natriuretic peptide release.

BACKGROUND: We investigated whether the increase of plasma natriuretic peptides (NPs) in atrial fibrillation (AF) is independent of the effect of AF on the left atrial (LA) hemodynamics. METHODS: Hemodynamically stable patients scheduled for AF ablation underwent assessment of B-type natriuretic peptide (BNP) and mid-regional pro-atrial natriuretic peptide (MR-proANP), echocardiography, and direct measurement of left atrial (LA) pressure. Concentrations of the NPs were compared between patients in AF (n = 31) and controls in sinus rhythm (SR; n = 31) who were matched for age, gender, heart rate, left ventricular ejection fraction, LA volume index, and directly measured mean LA pressure. Eighteen patients underwent serial measurement of NPs and LA pressure during native SR and after 20 min of pacing-induced AF. RESULTS: Compared to the patients in SR, the patients in AF had 2.6 times higher unadjusted BNP [median (inter-quartile range), 101 (63, 129) vs. 38 (26, 79) ng/L] and two times higher unadjusted MR-proANP [183 (140, 230) vs. 91 (67, 135) pmol/L; both p < 0.001]. Concentrations of both NPs correlated with mean LA pressure in the patients in SR (r = 0.75 for BNP and 0.62 for MR-proANP, both p < 0.001) but not in the patients in AF (r = 0.18 and 0.04, respectively, both p > 0.3). Both NPs increased significantly during induced AF [adjusted median (IQR) relative change, BNP: 27 (22; 40)%, MR-proANP: 75 (64; 99)%, both p < 0.001] without a significant change in the LA pressure. CONCLUSIONS: The increase of NPs in AF was independent of its effect on the LA hemodynamics.

Resting and Exercise-Induced Left Atrial Hypertension in Patients With Atrial Fibrillation: The Causes and Implications for Catheter Ablation.

OBJECTIVES: The aim of this paper was to investigate the prevalence of resting and exercise-induced left atrial hypertension (LAH) in patients with nonvalvular atrial fibrillation (AF), association of the LAH with other cardiac abnormalities, and its implications for AF catheter ablation. BACKGROUND: The clinical role of LAH in patients with established AF is largely unknown. METHODS: Patients scheduled for catheter ablation of AF (n = 240; age 60 ± 10 years; 67% men, 62% paroxysmal AF) underwent detailed echocardiography, assessment of quality of life (QoL), left atrial (LA) voltage mapping, and measurement of the LA pressure at rest and during isometric handgrip exercise. After ablation they were followed for AF recurrence for 16 ± 6 months. RESULTS: Resting and exercise-induced LAH (mean LA pressure >15 mm Hg) occurred in 15% and 34% of the patients, respectively. Both the patients with resting and exercise-induced LAH had typical features of latent heart failure with preserved ejection fraction associated with advanced LA structural and functional remodeling. AF recurred after ablation in 45% of the patients. LAH was an independent risk factor for arrhythmia recurrence (hazard ratio: 1.7, 95% confidence interval: 1.2 to 2.2). The patients with LAH had worse baseline QoL, but they benefited significantly more from a successful ablation than the patients without LAH. CONCLUSIONS: Presence of either resting or exercise-induced LAH identified AF patients with a distinct clinical profile, extensive LA substrate, and different clinical response to catheter ablation. Stratification of AF patients based on the LA exercise hemodynamics could help in the future to tailor the ablation strategy.

New perspectives in the renin-angiotensin-aldosterone system (RAAS) IV: circulating ACE2 as a biomarker of systolic dysfunction in human hypertension and heart failure.

BACKGROUND: Growing evidence exists for soluble Angiotensin Converting Enzyme-2 (sACE2) as a biomarker in definitive heart failure (HF), but there is little information about changes in sACE2 activity in hypertension with imminent heart failure and in reverse remodeling. METHODS, FINDINGS: Patients with systolic HF (NYHAII-IV, enrolled for cardiac resynchronisation therapy, CRT, n = 100) were compared to hypertensive patients (n = 239) and to a healthy cohort (n = 45) with preserved ejection fraction (EF>50%) in a single center prospective clinical study. The status of the heart failure patients were checked before and after CRT. Biochemical (ACE and sACE2 activity, ACE concentration) and echocardiographic parameters (EF, left ventricular end-diastolic (EDD) and end-systolic diameter (ESD) and dP/dt) were measured. sACE2 activity negatively correlated with EF and positively with ESD and EDD in all patient's populations, while it was independent in the healthy cohort. sACE2 activity was already increased in the hypertensive group, where signs for imminent heart failure (slightly decreased EF and barely increased NT-proBNP levels) were detected. sACE2 activities further increased in patients with definitive heart failure (EF<50%), while sACE2 activities decreased with the improvement of the heart failure after CRT (reverse remodeling). Serum angiotensin converting enzyme (ACE) concentrations were lower in the diseased populations, but did not show a strong correlation with the echocardiographic parameters. CONCLUSIONS: Soluble ACE2 activity appears to be biomarker in heart failure, and in hypertension, where heart failure may be imminent. Our data suggest that sACE2 is involved in the pathomechanism of hypertension and HF.

Transcranial measurement of cerebral microembolic signals during pulmonary vein isolation: a comparison of two ablation techniques.

BACKGROUND: Pulmonary vein isolation has increasingly been used to cure atrial fibrillation, but concerns have recently been raised that subclinical brain damage may occur because of microembolization during these procedures. We compared the occurrence of bubble formation seen on intracardiac echocardiography and the microembolic signals (MESs) detected by transcranial Doppler on the use of different ablation techniques and anticoagulation strategies. METHODS AND RESULTS: This prospective study included 35 procedures in 34 consecutive patients (age, 52; SD, 12.8 years; female:male 9:25). Pulmonary vein isolation was performed with a cryoballoon and the conventional anticoagulation protocol (activated clotting time >250 s) in 10 procedures (group 1), with a multipolar duty-cycled radiofrequency pulmonary group 2), and with regime a pulmonary vein ablation catheter with an aggressive anticoagulation (activated clotting time >320 s) in 13 procedures (group 3). The mean total numbers of MESs detected during the procedures were 833.7 (SD, 727.4) in group 1, 3142.6 (SD, 1736.4) in group 2, and 2204.6 (SD, 1078.1) in group 3 (P=0.0005). MESs were detected mostly during energy delivery in the pulmonary vein ablation catheter groups, whereas a relatively even distribution of emboli formation was seen during cryoballoon ablations. A significant correlation was found in all groups between the degree of bubble formation on intracardiac echocardiography and the number of MESs (P=0.0000). CONCLUSIONS: Duty-cycled radiofrequency ablation is associated with significantly more MESs, even when more aggressive anticoagulation is applied. With both techniques most of these microemboli are gaseous in nature.

The prevalence of obesity is increased in patients with late compared with early onset psoriasis.

PURPOSE: We compared the clinical and epidemiologic characteristics of early and late onset psoriasis with an emphasis on potential differences in the comorbidities associated with each subtype. METHODS: An observational, multicenter study was performed, and associations between the age at the time of diagnosis and binary comorbidity outcomes were evaluated using multiple logistic regression analysis adjusted for age and other relevant confounders. RESULTS: An increased prevalence of positive family history, psoriatic arthritis, and depression was observed in patients with early onset psoriasis. On the other hand, late onset psoriasis was more frequently associated with obesity and elevated waist circumference compared with early onset form. Elderly psoriatic patients (at the age of 75 years) with late onset psoriasis are at an especially high risk for obesity compared with individuals at the same age with an early onset disease. CONCLUSIONS: The increased frequency of psoriasis in the family of early onset patients may suggest that manifestation of psoriasis at younger age is driven by strong genetic influence. However, such a remarkable association of abdominal obesity with late onset psoriasis may suggest that obesity can be one of the acquired factors that may predispose for the development of psoriasis in the elderly.