Anton E. Tuinenburg

Chronic vagal stimulation for the treatment of low ejection fraction heart failure: results of the NEural Cardiac TherApy foR Heart Failure (NECTAR-HF) randomized controlled trial

Aim The neural cardiac therapy for heart failure (NECTAR-HF) was a randomized sham-controlled trial designed to evaluate whether a single dose of vagal nerve stimulation (VNS) would attenuate cardiac remodelling, improve cardiac function and increase exercise capacity in symptomatic heart failure patients with severe left ventricular (LV) systolic dysfunction despite guideline recommended medical therapy. Methods Patients were randomized in a 2 : 1 ratio to receive therapy (VNS ON) or control (VNS OFF) for a 6-month period. The primary endpoint was the change in LV end systolic diameter (LVESD) at 6 months for control vs. therapy, with secondary endpoints of other echocardiography measurements, exercise capacity, quality-of-life assessments, 24-h Holter, and circulating biomarkers. Results Of the 96 implanted patients, 87 had paired datasets for the primary endpoint. Change in LVESD from baseline to 6 months was −0.04 ± 0.25 cm in the therapy group compared with −0.08 ± 0.32 cm in the control group (P = 0.60). Additional echocardiographic parameters of LV end diastolic dimension, LV end systolic volume, left ventricular end diastolic volume, LV ejection fraction, peak V02, and N-terminal pro-hormone brain natriuretic peptide failed to show superiority compared to the control group. However, there were statistically significant improvements in quality of life for the Minnesota Living with Heart Failure Questionnaire (P = 0.049), New York Heart Association class (P = 0.032), and the SF-36 Physical Component (P = 0.016) in the therapy group. Conclusion Vagal nerve stimulation as delivered in the NECTAR-HF trial failed to demonstrate a significant effect on primary and secondary endpoint measures of cardiac remodelling and functional capacity in symptomatic heart failure patients, but quality-of-life measures showed significant improvement.

Rationale and study design of the NEuroCardiac TherApy foR Heart Failure Study: NECTAR-HF

Increased sympathetic activation and reduced parasympathetic tone are important pathophysiological contributors to the progression of heart failure, and are associated with poor outcome in patients. The aim of this study is to determine if vagal nerve stimulation (VNS) is a promising approach to modulate autonomic function and slow cardiac remodelling and the progression of heart failure.

Cardiac resynchronization therapy beyond nominal settings: who needs individual programming of the atrioventricular and interventricular delay?

AIMS This study aimed to determine the additional acute haemodynamic effect of atrioventricular (AV) and interventricular (VV) delay optimization compared with current nominal cardiac resynchronization therapy (CRT) device settings, and to explore whether clinical characteristics correlate to the effect of optimization. METHODS AND RESULTS Fifty CRT patients were prospectively enrolled. The optimal AV and VV delays were guided by relative improvement in maximum rate of left ventricular (LV) pressure rise (%dP/dt(max)). A significant improvement in %dP/dt(max) was obtained by optimization in 23-33% (sensed AV delay), 32-57% (paced AV delay), and 45% of patients (VV delay). Adjustment of the device nominal VV delay from 0 to 40 ms LV pre-activation would diminish the proportion of patients with additional effect of individual optimization from 45 to 15%. Heart failure aetiology [ischaemic 2 ± 2 vs. non-ischaemic 1 ± 1 percentage points (PP) %dP/dt(max), P= 0.013], gender (men 2 ± 2 vs. women 1 ± 1 PP %dP/dt(max), P= 0.012) and intrinsic PR interval (R= 0.49, P= 0.002) correlated to the degree of effect of AV delay optimization. Women yielded more effect of VV delay optimization (4 ± 3 vs. 2 ± 1 PP %dP/dt(max), P= 0.026). CONCLUSION Compared with the best of the currently available device nominal AV and VV delays, 23-45% of CRT patients can yield additional acute haemodynamic effect by individual optimization of the delays. A new nominal VV delay of 40 ms LV pre-activation is recommended. Male gender, ischaemic aetiology, and longer PR interval are associated with a larger effect of individual optimization.

Rationale, objectives, and design of the EUTrigTreat clinical study: a prospective observational study for arrhythmia risk stratification and assessment of interrelationships among repolarization markers and genotype

Aims The EUTrigTreat clinical study has been designed as a prospective multicentre observational study and aims to (i) risk stratify patients with an implantable cardioverter defibrillator (ICD) for mortality and shock risk using multiple novel and established risk markers, (ii) explore a link between repolarization biomarkers and genetics of ion (Ca2+, Na+, K+) metabolism, (iii) compare the results of invasive and non-invasive electrophysiological (EP) testing, (iv) assess changes of non-invasive risk stratification tests over time, and (v) associate arrythmogenomic risk through 19 candidate genes. Methods and results Patients with clinical ICD indication are eligible for the trial. Upon inclusion, patients will undergo non-invasive risk stratification, including beat-to-beat variability of repolarization (BVR), T-wave alternans, T-wave morphology variables, ambient arrhythmias from Holter, heart rate variability, and heart rate turbulence. Non-invasive or invasive programmed electrical stimulation will assess inducibility of ventricular arrhythmias, with the latter including recordings of monophasic action potentials and assessment of restitution properties. Established candidate genes are screened for variants. The primary endpoint is all-cause mortality, while one of the secondary endpoints is ICD shock risk. A mean follow-up of 3.3 years is anticipated. Non-invasive testing will be repeated annually during follow-up. It has been calculated that 700 patients are required to identify risk predictors of the primary endpoint, with a possible increase to 1000 patients based on interim risk analysis. Conclusion The EUTrigTreat clinical study aims to overcome current shortcomings in sudden cardiac death risk stratification and to answer several related research questions. The initial patient recruitment is expected to be completed in July 2012, and follow-up is expected to end in September 2014. Clinicaltrials.gov identifier: NCT01209494.

The ECG in Cardiac Resynchronization Therapy: Influence of Left and Right Ventricular Preactivation and Relation to Acute Response

Influence of Preactivation on the ECG in CRT. Introduction: The aims of this study were to compare ECG signs of biventricular electrical resynchronization during cardiac resynchronization therapy (CRT) with various interventricular (VV) delays and to correlate these and other ECG characteristics with the acute hemodynamic benefit of CRT.

Are CRT upgrade procedures more complex and associated with more complications than de novo CRT implantations? A single centre experience

ObjectiveThe objective of the study was to examine whether cardiac resynchronisation therapy upgrade procedures are more complex and associated with more complications than de novo implantations.MethodWe retrospectively compared 134 upgrade procedures performed between 2006–2012 with a random, equally sized, sample of de novo CRT device implantations in the same period. Procedural data and the occurrence of periprocedural (≤ 30 days) and long-term device-related (≤ 1 year) complications were analysed. Complications with consequences were defined as those in need of adjustment of standard care.ResultsMedian time to upgrade was 57 (31–115) months. There were no significant differences in procedure duration, radiation time or total hospitalisation between upgrades and de novo implantations. Perioperative complications occurred in 6.7 % of upgrade patients and in 9.0 % of de novo patients. The most frequently seen complications were phrenic nerve stimulation, coronary sinus dissection and pocket haematoma. Procedure success was comparable (upgrade: 98.5 % versus de novo: 96.3 %). A total of 236 patients completed 1 year of follow-up. Ten (4.2 %) patients had a long-term device-related complication with consequences including phrenic nerve stimulation, lead dislodgement/dysfunction, and infection (upgrade: 3.5 % versus de novo: 4.9 %).ConclusionUpgrade procedures are not more complex nor associated with more complications than de novo CRT implantations.

The concept of triple wavefront fusion during biventricular pacing : Using the EGM to produce the best acute hemodynamic improvement in CRT

Previous reports suggest that biventricular pacing (BiVp) fused with intrinsic conduction (BiVp‐fusion, triple wavefront fusion) is associated with improved resynchronization compared to pure‐BiVp in cardiac resynchronization therapy (CRT). This study aimed to assess the association between acute hemodynamic benefit of CRT and signs of BiVp‐fusion by using a novel electrogram (EGM)‐based method.

Differential multivariable risk prediction of appropriate shock versus competing mortality - A prospective cohort study to estimate benefits from ICD therapy

BACKGROUND AND OBJECTIVE We prospectively investigated combinations of risk stratifiers including multiple EP diagnostics in a cohort study of ICD patients. METHODS For 672 enrolled patients, we collected history, LVEF, EP study and T-wave alternans testing, 24-h Holter, NT-proBNP, and the eGFR. All-cause mortality and first appropriate ICD shock were predefined endpoints. RESULTS The 635 patients included in the final analyses were 63 ± 13 years old, 81% were male, LVEF averaged 40 ± 14%, 20% were inducible at EP study, 63% had a primary prophylactic ICD. During follow-up over 4.3 ± 1.5 years, 108 patients died (4.0% per year), and appropriate shock therapy occurred in n = 96 (3.9% per year). In multivariate regression, age (p < 0.001), LVEF (p < 0.001), NYHA functional class (p = 0.007), eGFR (p = 0.024), a history of atrial fibrillation (p = 0.011), and NT-pro-BNP (p = 0.002) were predictors of mortality. LVEF (p = 0.002), inducibility at EP study (p = 0.007), and secondary prophylaxis (p = 0.002) were identified as independent predictors of appropriate shocks. A high annualized risk of shocks of about 10% per year was prevalent in the upper quintile of the shock score. In contrast, a low annual risk of shocks (1.8% per year) was found in the lower two quintiles of the shock score. The lower two quintiles of the mortality score featured an annual mortality <0.6%. CONCLUSIONS In a prospective ICD patient cohort, a very good approximation of mortality versus arrhythmic risk was possible using a multivariable diagnostic strategy. EP stimulation is the best test to assess risk of arrhythmias resulting in ICD shocks.

Sex differences in outcomes of primary prevention implantable cardioverter-defibrillator therapy: combined registry data from eleven European countries

Abstract Aims Therapy with an implantable cardioverter defibrillator (ICD) is established for the prevention of sudden cardiac death (SCD) in high risk patients. We aimed to determine the effectiveness of primary prevention ICD therapy by analysing registry data from 14 centres in 11 European countries compiled between 2002 and 2014, with emphasis on outcomes in women who have been underrepresented in all trials. Methods and results Retrospective data of 14 local registries of primary prevention ICD implantations between 2002 and 2014 were compiled in a central database. Predefined primary outcome measures were overall mortality and first appropriate and first inappropriate shocks. A multivariable model enforcing a common hazard ratio for sex category across the centres, but allowing for centre-specific baseline hazards and centre specific effects of other covariates, was adjusted for age, the presence of ischaemic cardiomyopathy or a CRT-D, and left ventricular ejection fraction ≤25%. Of the 5033 patients, 957 (19%) were women. During a median follow-up of 33 months (IQR 16–55 months) 129 women (13%) and 807 men (20%) died (HR 0.65; 95% CI: [0.53, 0.79], P-value < 0.0001). An appropriate ICD shock occurred in 66 women (8%) and 514 men (14%; HR 0.61; 95% CI: 0.47–0.79; P = 0.0002). Conclusion Our retrospective analysis of 14 local registries in 11 European countries demonstrates that fewer women than men undergo ICD implantation for primary prevention. After multivariate adjustment, women have a significantly lower mortality and receive fewer appropriate ICD shocks.

Circadian pattern of short-term variability of the QT-interval in primary prevention ICD patients - EU-CERT-ICD methodological pilot study

Objective Short-term variability of the QT-interval (STV-QT) was shown to be associated with an increased risk of ventricular arrhythmias. We aimed at investigating (a) whether STV-QT exhibits circadian pattern, and (b) whether such pattern differs between patients with high and low arrhythmia risk. Methods As part of the ongoing EU-CERT-ICD study, 24h high resolution digital ambulatory 12-lead Holter recordings are collected prior to ICD implantation for primary prophylactic indication. Presently available patients were categorized based on their arrhythmia score (AS), a custom-made weighted score of the number of arrhythmic events on the recording. STV-QT was calculated every hour in 30 patients of which 15 and 15 patients had a high and a low AS, respectively. Results The overall dynamicity of STV-QT showed high intra- and inter-individual variability with different circadian patterns associated with low and high AS. High AS patients showed a prominent peak both at 08:00 and 18:00. At these times, STV-QT was significantly higher in the high AS patients compared to the low AS patients (1.22ms±0.55ms vs 0.60ms±0.24ms at 08:00 and 1.12ms±0.39ms vs 0.64ms±0.29ms at 18:00, both p < 0.01). Conclusion In patients with high AS, STV-QT peaks in the early morning and late afternoon. This potentially reflects increased arrhythmia risk at these times. Prospective STV-QT determination at these times might thus be more sensitive to identify patients at high risk of ventricular arrhythmias.