[History of surgical treatment of cardiac arrhythmias in Germany : Surgical treatment of ventricular tachycardia and supraventricular tachycardia, especially pre-excitation syndromes (WPW)]. / Geschichte der chirurgischen Behandlung von Herzrhythmusstörungen in Deutschland : Chirurgische Therapie ventrikulärer Tachykardien sowie supraventrikulärer Tachykardien, insbesondere Präexzitationssyndromen (WPW).

The history of surgical treatment of ventricular tachycardias (VT) is short, lasting from 1978 until 1993. "Indirect procedures" with infarct scar resection were performed without electrophysiologic studies, whereas "direct procedures" consisted of either complete endocardial incisions ("encircling endocardial ventriculotomy") or large endocardial resections ("endocardial peel-off" technique) after precise epicardial and endocardial mapping procedures. In Germany, the first to report on intra-operative electrophysiologic mapping for VT treatment were Ostermeyer, Breithardt and Seipel in 1979. In 1981, the Hannover group (Frank, Klein) published their first results of surgical treatment of VT. In 1984, Ostermeyer et al. demonstrated that a partial endocardial incision resulted in more beneficial results with less myocardial damage (8% versus 46%) than applying a complete encircling incision. In 1987, the Düsseldorf group reported treatment results of 93 patients. After 5 years, 77% had no VT recurrence, while total mortality after 1 year was 11% and after 5 years 30%. In 1992, the Hannover group reported results of 147 patients after endocardial resection for VT. Total mortality after 3 years was 27%; recurrence of VT events occurred in 18% of the surviving cohort.The history of surgical procedures for supraventricular tachycardia (SVT), in particular Wolff-Parkinson-White (WPW) syndrome, is even shorter than that of surgery for VT. As early as 1969, Sealy, Gallagher and Cox reported the first cases of surgical intervention for WPW syndrome via endocardial access in cardioplegic arrest. In 1984, Guiraudon and Klein reported on a new procedure with epicardial access to the accessory bundle without cardioplegia in laterally localised conduction pathways. In Germany, too, the groups in Düsseldorf (Ostermeyer, Seipel, Breithardt, Borggrefe) from 1980 and the Hannover group (Frank, Klein and Kallfelz) from 1981 performed surgical procedures for WPW syndrome. In 1987, Borggrefe reported on 18 patients with WPW syndrome and atrial fibrillation who had undergone surgery. After 2 years, 14 of 18 patients had no recurrences of tachycardia; in 1989, Frank, Klein and Kallfelz (Hannover) reported on 10 children (2-14 years) operated on using the cryoablation technique. Between 1984 and 1992, a total of 120 patients with SVT, mostly WPW syndrome, were operated on in Hannover; after 42 months, 12 patients had a recurrence of SVT. Two patients died during the reoperation.

[Short history of the DC-Catheter-Ablation]. / Kurze Geschichte der Katheterablation mit DC-Schocks.

Direct current (DC) catheter ablation in 5 patients aiming to interrupt rapid atrioventricular (AV) conduction with atrial fibrillation and subsequent pacemaker implantation was first published by M. M. Scheinman et al. (San Francisco, CA, USA) in 1982. In Germany, L. Seipel, G. Breithardt, and M. Borggrefe reported their first experience with DC catheter ablation in 1984, followed by the group in Bonn (M. Manz and B. Lüderitz) in 1985. The first international DC catheter ablation registry, which also included four German centers, reported DC catheter ablation results of 127 patients in 24 centers in 1984. Complete AV block was achieved in 71% patients. In 1992, the Hannover group (H­J. Trappe, H. Klein and J. Huang) reported results of DC catheter ablation of AV conduction performed between 1983 and 1990 in 100 patients (86% with rapid atrial fibrillation, 14% with AV-node reentry tachycardias). The first successful DC catheter ablation in a patient with Wolff-Parkinson-White (WPW) syndrome was reported in 1985 by F. Morady et al. (San Francisco, CA, USA). In 1987, M. Borggrefe et al. were the first to report a switch from DC catheter ablation to a high-frequency (HF) catheter ablation procedure in a patient with WPW syndrome. The use of DC catheter ablation to treat ventricular tachycardia (VT) was described by G. O. Hartzler (Kansas City, MO, USA) in 3 patients in 1983. M. Borggrefe et al. (1989) reported on 24 patients who underwent DC catheter ablation for VT. Of those, 17 patients did not have VT recurrence within the following 14 months. In 1994, the Hannover group (H-J Trappe, H. Klein) published their 5­year long-term results of DC catheter ablation of VT in 51 patients. VT recurrence occurred in 57% patients and overall mortality was also high (16%). A comparison of DC catheter ablation with HF catheter ablation for recurrent VT was reported in 1994 by G. Gonska et al. (Göttingen, Germany). After 2 years follow-up, success rates were not found to be significantly different.

[History of the implantable cardioverter-defibrillator in Germany]. / Die Geschichte des implantierbaren Kardioverter-Defibrillators in Deutschland.

The implantable cardioverter-defibrillator (ICD) was a breakthrough in the prevention of sudden cardiac death. After years of technical development in the USA, Michel Mirowski succeeded in proving reliable automatic defibrillation of ventricular tachyarrhythmias through initial human implantations in 1980, despite many obstacles. Nearly 4 years later, the first patients received ICDs at multiple centers in Germany. Subsequently, outside the USA, Germany became the country with highest implantation rates. The absolute number of implantations remained small as long as implantations required epicardial defibrillation electrodes and therefore thoracotomy by cardiac surgeons. Pacemaker-like implantation using a transvenous defibrillation electrode with a pectoral ICD became feasible in the early 1990s pushing implantation rates to the next level. Technical advancements were accompanied by clinical research in Germany, and often, the first-in-human studies were conducted in Germany. In 1991, the first guidelines for indications were established in the USA and Germany. Several randomized studies on indications were published between 1996 and 2009, mostly led by American teams with German participation, but also under German leadership (CASH, CAT, DINAMIT, IRIS). The DANISH study in 2016 questioned the results of these long-standing studies. Instead of providing ICDs to patients using a broad indication, future efforts aim to identify patients who, despite optimal medical therapy, cardiac resynchronization therapy (CRT), and/or catheter ablation, need protection against sudden cardiac death. Risk scores incorporating myocardial scars in magnetic resonance imaging (MRI) and genetic information are expected to contribute to more individualized and effective indications.

Advances in Our Clinical Understanding of Autonomic Regulation Therapy Using Vagal Nerve Stimulation in Patients Living With Heart Failure.

The ANTHEM-HF, INOVATE-HF, and NECTAR-HF clinical studies of autonomic regulation therapy (ART) using vagus nerve stimulation (VNS) systems have collectively provided dose-ranging information enabling the development of several working hypotheses on how stimulation frequency can be utilized during VNS for tolerability and improving cardiovascular outcomes in patients living with heart failure (HF) and reduced ejection fraction (HFrEF). Changes in heart rate dynamics, comprising reduced heart rate (HR) and increased HR variability, are a biomarker of autonomic nerve system engagement and cardiac control, and appear to be sensitive to VNS that is delivered using a stimulation frequency that is similar to the natural operating frequency of the vagus nerve. Among prior studies, the ANTHEM-HF Pilot Study has provided the clearest evidence of autonomic engagement with VNS that was delivered using a stimulation frequency that was within the operating range of the vagus nerve. Achieving autonomic engagement was accompanied by improvement from baseline in six-minute walk duration (6MWD), health-related quality of life, and left ventricular EF (LVEF), over and above those achieved by concomitant guideline-directed medical therapy (GDMT) administered to counteract harmful neurohormonal activation, with relative freedom from deleterious effects. Autonomic engagement and positive directional changes have persisted over time, and an exploratory analysis suggests that improvement in autonomic tone, symptoms, and physical capacity may be independent of baseline NT-proBNP values. Based upon these encouraging observations, prospective, randomized controlled trials examining the effects on symptoms and cardiac function as well as natural history have been warranted. A multi-national, large-scale, randomized, controlled trial is well underway to determine the outcomes associated with ART using autonomic nervous system engagement as a guide for VNS delivery.

Protected risk stratification with the wearable cardioverter-defibrillator: results from the WEARIT-II-EUROPE registry.

BACKGROUND: The prospective WEARIT-II-EUROPE registry aimed to assess the value of the wearable cardioverter-defibrillator (WCD) prior to potential ICD implantation in patients with heart failure and reduced ejection fraction considered at risk of sudden arrhythmic death. METHODS AND RESULTS: 781 patients (77% men; mean age 59.3 ± 13.4 years) with heart failure and reduced left ventricular ejection fraction (LVEF) were consecutively enrolled. All patients received a WCD. Follow-up time for all patients was 12 months. Mean baseline LVEF was 26.9%. Mean WCD wearing time was 75 ± 47.7 days, mean daily WCD use 20.3 ± 4.6 h. WCD shocks terminated 13 VT/VF events in ten patients (1.3%). Two patients died during WCD prescription of non-arrhythmic cause. Mean LVEF increased from 26.9 to 36.3% at the end of WCD prescription (p < 0.01). After WCD use, ICDs were implanted in only 289 patients (37%). Forty patients (5.1%) died during follow-up. Five patients (1.7%) died with ICDs implanted, 33 patients (7%) had no ICD (no information on ICD in two patients). The majority of patients (75%) with the follow-up of 12 months after WCD prescription died from heart failure (15 patients) and non-cardiac death (15 patients). Only three patients (7%) died suddenly. In seven patients, the cause of death remained unknown. CONCLUSIONS: Mortality after WCD prescription was mainly driven by heart failure and non-cardiovascular death. In patients with HFrEF and a potential risk of sudden arrhythmic death, WCD protected observation of LVEF progression and appraisal of competing risks of potential non-arrhythmic death may enable improved selection for beneficial ICD implantation.

Comparison of symptomatic and functional responses to vagus nerve stimulation in ANTHEM-HF, INOVATE-HF, and NECTAR-HF.

AIMS: Clinical studies of vagal nerve stimulation (VNS) for heart failure with reduced ejection fraction have had mixed results to date. We sought to compare VNS delivery and associated changes in symptoms and function in autonomic regulation therapy via left or right cervical vagus nerve stimulation in patients with chronic heart failure (ANTHEM-HF), increase of vagal tone in heart failure (INOVATE-HF), and neural cardiac therapy for heart failure (NECTAR-HF) for hypothesis generation. METHODS AND RESULTS: Descriptive statistics were used to analyse data from the public domain for differences in proportions using Pearson's chi-square test, differences in mean values using Student's unpaired t-test, and differences in changes of mean values using two-sample t-tests. Guideline-directed medical therapy recommendations were similar across studies. Fewer patients were in New York Heart Association 3, and baseline heart rate (HR) was higher in ANTHEM-HF. In INOVATE-HF, VNS was aimed at peripheral neural targets, using closed-loop delivery that required synchronization of VNS to R-wave sensing by an intracardiac lead. Pulse frequency was low (1-2 Hz) because of a timing schedule allowing ≤3 pulses of VNS following at most 25% of detected R waves. NECTAR-HF and ANTHEM-HF used open-loop VNS delivery (i.e. independent of any external signal) aimed at both central and peripheral targets. In NECTAR-HF, VNS delivery at 20 Hz caused off-target effects that limited VNS up-titration in a majority of patients. In ANTHEM-HF, VNS delivery at 10 Hz allowed up-titration until changes in HR dynamics were confirmed. Six months after VNS titration, significant improvements in both HR and HR variability occurred only in ANTHEM-HF. When ANTHEM-HF and NECTAR-HF were compared, greater improvements from baseline were observed in ANTHEM-HF in standard deviation in normal-to-normal R-R intervals (94 ± 26 to 111 ± 50 vs. 146 ± 48 to 130 ± 52 ms; P < 0.001), left ventricular ejection fraction (32 ± 7 to 37 ± 0.4 vs. 31 ± 6 to 33 ± 6; P < 0.05), and Minnesota Living with Heart Failure mean score (40 ± 14 to 21 ± 10 vs. 44 ± 22 to 36 ± 21; P < 0.002). When compared with INOVATE-HF, greater improvement in 6-min walk distance was observed in ANTHEM-HF (287 ± 66 to 346 ± 78 vs. 304 ± 111 to 334 ± 111 m; P < 0.04). CONCLUSIONS: In this post-hoc analysis, differences in patient demographics were seen and may have caused the differential responses in symptoms and function observed in association with VNS. Major differences in technology platforms, neural targets, VNS delivery, and HR and HR variability responses could have also potentially played a very important role. Further study is underway in a randomized controlled trial with these considerations in mind.

Impact of Autonomic Regulation Therapy in Patients with Heart Failure: ANTHEM-HFrEF Pivotal Study Design.

BACKGROUND: The ANTHEM-HFrEF (Autonomic Regulation Therapy to Enhance Myocardial Function and Reduce Progression of Heart Failure with Reduced Ejection Fraction) pivotal study is an adaptive, open-label, randomized, controlled study evaluating whether autonomic regulation therapy will benefit patients with advanced HFrEF. While early-phase studies have supported potential use of vagus nerve stimulation to deliver autonomic regulation therapy for HFrEF, results of larger clinical trials have been inconsistent. The ANTHEM-HFrEF study uses a novel design, with adaptive sample size selection, evaluating effects on morbidity and mortality as well as symptoms and function. METHODS: The ANTHEM-HFrEF study will randomize patients (2:1) to autonomic regulation therapy plus guideline-directed medical therapy, or guideline-directed medical therapy alone. The morbidity and mortality trial utilizes a conventional frequentist approach for analysis of the primary outcome end point-reduction in the composite of cardiovascular death or first HF hospitalization-and a Bayesian adaptive approach toward sample size selection. Embedded within the ANTHEM-HFrEF study is a second trial evaluating improvement in symptoms and function. Symptom/function success will require meeting 2 risk-related conditions (trend for reduced cardiovascular death/HF hospitalization and sufficient freedom from device-related serious adverse events) and 3 efficacy end point components (changes in left ventricular EF, 6-minute walk distance, and Kansas City Cardiomyopathy Questionnaire overall score). CONCLUSIONS: Vagus nerve stimulation remains a promising, yet unproven treatment in HFrEF. A successful ANTHEM-HFrEF pivotal study would provide an important advance in HFrEF treatment and offer a model for expediting evaluation of new therapies. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT03425422.

Death with an implantable cardioverter-defibrillator: a MADIT-II substudy.

AIMS: There are limited data regarding factors that identify implantable cardioverter-defibrillator (ICD) patients who will experience either ventricular tachyarrhythmic (VTA) or non-arrhythmic (NA) mortality, and the commonly used clinical classification of sudden cardiac death (SCD) vs. non-sudden cardiac death (NSCD) may not be accurate enough. We aimed to correlate clinical adjudication of mortality events to device interrogation data and to identify risk factors for VTA mortality in Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II). METHODS AND RESULTS: Of the 746 patients who received an ICD in MADIT-II, 44 died from cardiac causes and had available interrogation data at the time of death. Sudden cardiac death vs. NSCD was defined by an adjudication committee. Ventricular tachyarrhythmic and NA arrhythmic deaths were categorized by the presence or absence of ventricular tachycardia or fibrillation (VT/VF) during the terminal event. Mode of death was found to be inaccurate when validated by device interrogation for VTA events: 50% patients adjudicated as SCD did not have a VTA event at the time of death; and 25% of adjudicated NSCD were found to have VT/VF during the mortality event. Multivariate analysis showed that factors independently associated with VTA mortality included: VT/VF >72 h prior to the mortality event [hazard ratio (HR) 8.0; P < 0.001], hospitalization for heart failure (HR 6.7; P = 0.001), and a history of hypertension (HR 4; P = 0.04). CONCLUSION: Current classification of SCD vs. NSCD fails to identify VTA events at the time of death in a significant proportion of patients, and simple clinical parameters can be used to identify ICD recipients with increased risk for VTA mortality.

Left Ventricular Lead Location and Long-Term Outcomes in Cardiac Resynchronization Therapy Patients.

OBJECTIVES: The authors aimed to evaluate the association of left ventricular (LV) lead location and long-term outcomes in MADIT-CRT (Multicenter Automatic Defibrillator Implantation With Cardiac Resynchronization Therapy). BACKGROUND: There is limited data on the association of lead location with long-term clinical outcomes in patients with cardiac resynchronization therapy with defibrillator (CRT-D). METHODS: The LV lead location was classified in 797 patients with CRT-D, in 569 patients with left bundle branch block (LBBB), in 228 patients with non-LBBB, and in 505 patients with an implantable cardioverter-defibrillator (ICD) only. Leads were classified into apical (n = 83) and non-apical (n = 486); with the non-apical LV leads further categorized into anterior (n = 99) and posterior/lateral (n = 387) within LBBB. All-cause mortality and heart failure (HF) events were assessed using Kaplan-Meier and Cox analyses. RESULTS: In CRT-D patients with LBBB and posterior/lateral LV lead location, there was an association with a significant reduction in long-term all-cause mortality (hazard ratio [HR]: 0.54, 95% confidence interval [CI]: 0.37 to 0.79; p = 0.001), and HF events (HR: 0.44, 95% CI: 0.33 to 0.60; p < 0.001) compared to an ICD only, accompanied with better LV reverse remodeling. CRT-D patients with LBBB and an anterior LV lead location were shown to be associated with a significant reduction in HF events compared to an ICD only (anterior HR: 0.50, 95% CI: 0.30 to 0.82; p = 0.006); however, no association with mortality reduction was observed from CRT-D versus an ICD only. CRT-D was not associated with improved outcomes in non-LBBB patients, regardless of LV lead location. CONCLUSIONS: In mild HF patients with LBBB and an implanted CRT-D, lateral/posterior, and anterior LV lead locations are similarly associated with reduction in the risk of HF or death events compared to ICD alone. Mortality benefit derived from CRT-D is associated only with patients with lateral/posterior LV lead location. An apical LV lead location should be avoided due to the early risk of death whenever possible. (Multicenter Automatic Defibrillator Implantation With Cardiac Resynchronization Therapy [MADIT-CRT], NCT00180271; Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy Post Approval Registry [MADIT-CRT-PAR], NCT01294449; and MADIT-CRT Long-Term International Follow-Up Registry - Europe, NCT02060110).

One-year follow-up of the prospective registry of patients using the wearable defibrillator (WEARIT-II Registry).

BACKGROUND: The WEARIT-II Registry demonstrated efficacy and safety of the wearable cardioverter defibrillator (WCD) for at-risk cardiac patients. However, 1-year outcomes in this population have not been reported. METHODS: The WEARIT-II Registry enrolled 2,000 U.S. patients prescribed the WCD. One-year mortality data from start of WCD use were prospectively collected for 1,846 patients (93%). Outcome data were analyzed by disease etiology and implantable cardioverter defibrillator (ICD) implantation following WCD use. RESULTS: During 12 months of follow-up, 73 patients died (4%). Kaplan-Meier survival analysis showed differences in all-cause mortality from WCD prescription between patients with ischemic versus nonischemic cardiomyopathy versus congenital/inherited heart disease (4% vs 3% vs 7%, P = 0.013). Patients with ventricular arrhythmia events during WCD use had a higher 1-year mortality (10% vs 3%, P = 0.042). Renal disease, increasing age, prior syncope, and nonbeta-blocker use predicted mortality. One-year mortality was similar in patients who did versus did not receive an ICD following WCD use in ischemic (3% vs 4%, P = 0.470) and nonischemic cardiomyopathy (3% vs 3%, P = 0.892). Patients with congenital/inherited heart disease with no implanted ICD had a trend toward a higher rate of mortality than those who received an ICD (8% vs 3%, P = 0.082). Multivariate models confirmed these findings. CONCLUSION: One-year follow-up from the WEARIT-II Registry shows an overall good survival in patients prescribed the WCD. Short-term use of WCD allows appropriate risk stratification for decision on an ICD implantation in at-risk ischemic and nonischemic cardiomyopathy patients. Congenital/inherited heart disease patients had a higher risk of 1-year mortality even without an implanted ICD post-WCD.