Long-term outcome of targeted therapy of underlying conditions in patients with early persistent atrial fibrillation and heart failure: data of the RACE 3 trial.

AIMS: The Routine vs. Aggressive risk factor driven upstream rhythm Control for prevention of Early persistent atrial fibrillation (AF) in heart failure (HF) (RACE 3) trial demonstrated that targeted therapy of underlying conditions improved sinus rhythm maintenance at 1 year. We now explored the effects of targeted therapy on the additional co-primary endpoints; sinus rhythm maintenance and cardiovascular outcome at 5 years. METHODS AND RESULTS: Patients with early persistent AF and mild-to-moderate stable HF were randomized to targeted or conventional therapy. Both groups received rhythm control therapy according to guidelines. The targeted group additionally received four therapies: angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers (ARBs), statins, mineralocorticoid receptor antagonists (MRAs), and cardiac rehabilitation. The presence of sinus rhythm and cardiovascular morbidity and mortality at 5-year follow-up were assessed. Two hundred and sixteen patients consented for long-term follow-up, 107 were randomized to targeted and 109 to conventional therapy. At 5 years, MRAs [76 (74%) vs. 10 (9%) patients, P < 0.001] and statins [81 (79%) vs. 59 (55%), P < 0.001] were used more in the targeted than conventional group. Angiotensin-converting enzyme inhibitors/ARBs and physical activity were not different between groups. Sinus rhythm was present in 49 (46%) targeted vs. 43 (39%) conventional group patients at 5 years (odds ratio 1.297, lower limit of 95% confidence interval 0.756, P = 0.346). Cardiovascular mortality and morbidity occurred in 20 (19%) in the targeted and 15 (14%) conventional group patients, P = 0.353. CONCLUSION: In patients with early persistent AF and HF superiority of targeted therapy in sinus rhythm maintenance could not be preserved at 5-year follow-up. Cardiovascular outcome was not different between groups. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov NCT00877643.

Rate control drugs differ in the prevention of progression of atrial fibrillation.

AIMS: We hypothesize that in patients with paroxysmal atrial fibrillation (AF), verapamil is associated with lower AF progression compared to beta blockers or no rate control. METHODS AND RESULTS: In this pre-specified post hoc analysis of the RACE 4 randomized trial, the effect of rate control medication on AF progression in paroxysmal AF was analysed. Patients using Vaughan-Williams Class I or III antiarrhythmic drugs were excluded. The primary outcome was a composite of first electrical cardioversion (ECV), chemical cardioversion (CCV), or atrial ablation. Event rates are displayed using Kaplan-Meier curves and multivariable Cox regression analyses are used to adjust for baseline differences. Out of 666 patients with paroxysmal AF, 47 used verapamil, 383 used beta blockers, and 236 did not use rate control drugs. The verapamil group was significantly younger than the beta blocker group and contained more men than the no rate control group. Over a mean follow-up of 37 months, the primary outcome occurred in 17% in the verapamil group, 33% in the beta blocker group, and 33% in the no rate control group (P = 0.038). After adjusting for baseline characteristics, patients using verapamil have a significantly lower chance of receiving ECV, CCV, or atrial ablation compared to patients using beta blockers [hazard ratio (HR) 0.40, 95% confidence interval (CI) 0.19-0.83] and no rate control (HR 0.64, 95% CI 0.44-0.93). CONCLUSION: In patients with newly diagnosed paroxysmal AF, verapamil was associated with less AF progression, as compared to beta blockers and no rate control.

Development and external validation of prediction models to predict implantable cardioverter-defibrillator efficacy in primary prevention of sudden cardiac death.

AIMS: This study was performed to develop and externally validate prediction models for appropriate implantable cardioverter-defibrillator (ICD) shock and mortality to identify subgroups with insufficient benefit from ICD implantation. METHODS AND RESULTS: We recruited patients scheduled for primary prevention ICD implantation and reduced left ventricular function. Bootstrapping-based Cox proportional hazards and Fine and Gray competing risk models with likely candidate predictors were developed for all-cause mortality and appropriate ICD shock, respectively. Between 2014 and 2018, we included 1441 consecutive patients in the development and 1450 patients in the validation cohort. During a median follow-up of 2.4 (IQR 2.1-2.8) years, 109 (7.6%) patients received appropriate ICD shock and 193 (13.4%) died in the development cohort. During a median follow-up of 2.7 (IQR 2.0-3.4) years, 105 (7.2%) received appropriate ICD shock and 223 (15.4%) died in the validation cohort. Selected predictors of appropriate ICD shock were gender, NSVT, ACE/ARB use, atrial fibrillation history, Aldosterone-antagonist use, Digoxin use, eGFR, (N)OAC use, and peripheral vascular disease. Selected predictors of all-cause mortality were age, diuretic use, sodium, NT-pro-BNP, and ACE/ARB use. C-statistic was 0.61 and 0.60 at respectively internal and external validation for appropriate ICD shock and 0.74 at both internal and external validation for mortality. CONCLUSION: Although this cohort study was specifically designed to develop prediction models, risk stratification still remains challenging and no large group with insufficient benefit of ICD implantation was found. However, the prediction models have some clinical utility as we present several scenarios where ICD implantation might be postponed.

Nurse-led vs. usual-care for atrial fibrillation.

BACKGROUND: Nurse-led integrated care is expected to improve outcome of patients with atrial fibrillation compared with usual-care provided by a medical specialist. METHODS AND RESULTS: We randomized 1375 patients with atrial fibrillation (64 ± 10 years, 44% women, 57% had CHA2DS2-VASc ≥ 2) to receive nurse-led care or usual-care. Nurse-led care was provided by specialized nurses using a decision-support tool, in consultation with the cardiologist. The primary endpoint was a composite of cardiovascular death and cardiovascular hospital admissions. Of 671 nurse-led care patients, 543 (81%) received anticoagulation in full accordance with the guidelines against 559 of 683 (82%) usual-care patients. The cumulative adherence to guidelines-based recommendations was 61% under nurse-led care and 26% under usual-care. Over 37 months of follow-up, the primary endpoint occurred in 164 of 671 patients (9.7% per year) under nurse-led care and in 192 of 683 patients (11.6% per year) under usual-care [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.69 to 1.04, P = 0.12]. There were 124 vs. 161 hospitalizations for arrhythmia events (7.0% and 9.4% per year), and 14 vs. 22 for heart failure (0.7% and 1.1% per year), respectively. Results were not consistent in a pre-specified subgroup analysis by centre experience, with a HR of 0.52 (95% CI 0.37-to 0.71) in four experienced centres and of 1.24 (95% CI 0.94-1.63) in four less experienced centres (P for interaction <0.001). CONCLUSION: Our trial failed to show that nurse-led care was superior to usual-care. The data suggest that nurse-led care by an experienced team could be clinically beneficial (ClinicalTrials.gov NCT01740037). TRIAL REGISTRATION NUMBER: ClinicalTrials.gov (NCT01740037).

Effect of PR interval and pacing mode on persistent atrial fibrillation incidence in dual chamber pacemaker patients: a sub-study of the international randomized MINERVA trial.

AIMS: Per standard of care, dual-chamber pacemakers are programmed in DDDR mode with fixed atrioventricular (AV) delay or with long AV delay to minimize ventricular pacing. We aimed to evaluate whether the PR interval may be a specific criterion of choice between standard DDDR, to preserve AV synchrony in long PR patients, and managed ventricular pacing (MVP), to avoid ventricular desynchronization imposed by right ventricle apical pacing, in short PR patients. METHODS AND RESULTS: In the MINERVA trial, 1166 patients were randomized to Control DDDR, MVP, or atrial anti-tachycardia pacing plus MVP (DDDRP + MVP). We evaluated the interaction of PR interval with pacing mode by comparing the risk of atrial fibrillation (AF) longer than 7 consecutive days as a function of PR interval. Out of 906 patients with available data, the median PR interval was 180 ms. The PR interval was found to significantly (P = 0.012) interact with pacing mode for AF incidence: the risk of AF > 7 days was lower [hazard ratio (HR) 0.58, 95% confidence interval (95% CI) 0.34-0.99; P = 0.047] in patients with short PR (shorter than median PR) if programmed in MVP mode compared with DDDR mode and it was lower (HR 0.65, 95% CI 0.43-0.99; P = 0.049) in patients with long PR (equal to or longer than median PR) if programmed in DDDR mode compared with MVP. CONCLUSION: Our data show that PR interval may be used as a selection criterion to identify the optimal physiological pacing mode. Persistent AF incidence was lower in short PR patients treated by right ventricular pacing minimization and in long PR patients treated by standard dual-chamber pacing.

Targeted therapy of underlying conditions improves quality of life in patients with persistent atrial fibrillation: results of the RACE 3 study.

AIMS: Atrial fibrillation (AF) reduces quality of life (QoL). We aim to evaluate effects of targeted therapy of underlying conditions on QoL in patients with AF and heart failure (HF). METHODS AND RESULTS: The Routine versus Aggressive risk factor driven upstream rhythm Control for prevention of Early atrial fibrillation in heart failure (RACE 3) study randomized patients with early persistent AF and HF to targeted or conventional therapy. Both groups received guideline-driven treatment. The targeted group received four additional therapies: mineralocorticoid receptor antagonists; statins; angiotensin converting enzyme inhibitors and/or receptor blockers; and cardiac rehabilitation including physical activity, dietary restrictions, and counselling. Quality of life was analysed in 230 patients at baseline and 1 year with available Medical Outcomes Study Short-Form Health Survey (SF-36), University of Toronto AF Severity Scale (AFSS) questionnaires, and European Heart Rhythm Association (EHRA) class. Improvements in SF-36 subscales were larger in the targeted group for physical functioning (Δ12 ± 19 vs. Δ6 ± 22, P = 0.007), physical role limitations (Δ32 ± 41 vs. Δ17 ± 45, P = 0.018), and general health (Δ8 ± 16 vs. Δ0 ± 17, P < 0.001). Dyspnoea at rest improved more (Δ-0.8 ± 1.3 vs. Δ-0.4 ± 1.2, P = 0.018) and EHRA class was lower at 1-year follow-up in the targeted group. Patients with AF at 1 year, improvement in physical functioning (Δ9 ± 9 vs. Δ-3 ± 16, P = 0.001), general health (Δ7 ± 16 vs. Δ-7 ± 19, P = 0.004), and social functioning (Δ6 ± 23 vs. Δ-4 ± 16, P = 0.041) were larger in the targeted group. CONCLUSION: A strategy aiming to treat underlying conditions improved QoL more compared with conventional therapy in patients with early persistent AF and HF. Its benefit was even observed in patients in AF at 1 year. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov NCT00877643.

Targeted therapy of underlying conditions improves sinus rhythm maintenance in patients with persistent atrial fibrillation: results of the RACE 3 trial.

Aims: Atrial fibrillation (AF) is a progressive disease. Targeted therapy of underlying conditions refers to interventions aiming to modify risk factors in order to prevent AF. We hypothesised that targeted therapy of underlying conditions improves sinus rhythm maintenance in patients with persistent AF. Methods and results: We randomized patients with early persistent AF and mild-to-moderate heart failure (HF) to targeted therapy of underlying conditions or conventional therapy. Both groups received causal treatment of AF and HF, and rhythm control therapy. In the intervention group, on top of that, four therapies were started: (i) mineralocorticoid receptor antagonists (MRAs), (ii) statins, (iii) angiotensin converting enzyme inhibitors and/or receptor blockers, and (iv) cardiac rehabilitation including physical activity, dietary restrictions, and counselling. The primary endpoint was sinus rhythm at 1 year during 7 days of Holter monitoring. Of 245 patients, 119 were randomized to targeted and 126 to conventional therapy. The intervention led to a contrast in MRA (101 [85%] vs. 5 [4%] patients, P < 0.001) and statin use (111 [93%] vs. 61 [48%], P < 0.001). Angiotensin converting enzyme inhibitors/angiotensin receptor blockers were not different. Cardiac rehabilitation was completed in 109 (92%) patients. Underlying conditions were more successfully treated in the intervention group. At 1 year, sinus rhythm was present in 89 (75%) patients in the intervention vs. 79 (63%) in the conventional group (odds ratio 1.765, lower limit of 95% confidence interval 1.021, P = 0.042). Conclusions: RACE 3 confirms that targeted therapy of underlying conditions improves sinus rhythm maintenance in patients with persistent AF. Trial Registration number: Clinicaltrials.gov NCT00877643.

Atrial antitachycardia pacing and managed ventricular pacing in bradycardia patients with paroxysmal or persistent atrial tachyarrhythmias: the MINERVA randomized multicentre international trial.

AIMS: Atrial fibrillation (AF) is a common comorbidity in bradycardia patients. Advanced pacemakers feature atrial preventive pacing and atrial antitachycardia pacing (DDDRP) and managed ventricular pacing (MVP), which minimizes unnecessary right ventricular pacing. We evaluated whether DDDRP and MVP might reduce mortality, morbidity, or progression to permanent AF when compared with standard dual-chamber pacing (Control DDDR). METHODS AND RESULTS: In a randomized, parallel, single-blind, multi-centre trial we enrolled 1300 patients with bradycardia and previous atrial tachyarrhythmias, in whom a DDDRP pacemaker had recently been implanted. History of permanent AF and third-degree atrioventricular block were exclusion criteria. After a 1-month run-in period, 1166 eligible patients, aged 74 ± 9 years, 50% females, were randomized to Control DDDR, DDDRP + MVP, or MVP. Analysis was intention-to-treat. The primary outcome, i.e. the 2-year incidence of a combined endpoint composed of death, cardiovascular hospitalizations, or permanent AF, occurred in 102/385 (26.5%) Control DDDR patients, in 76/383 (19.8%) DDDRP + MVP patients [hazard ratio (HR) = 0.74, 95% confidence interval 0.55-0.99, P = 0.04 vs. Control DDDR] and in 85/398 (21.4%) MVP patients (HR = 0.89, 95% confidence interval 0.77-1.03, P = 0.125 vs. Control DDDR). When compared with Control DDDR, DDDRP + MVP reduced the risk for AF longer than 1 day (HR = 0.66, 95% CI 0.52-0.85, P < 0.001), AF longer than 7 days (HR = 0.52, 95% CI 0.36-0.73, P < 0.001), and permanent AF (HR = 0.39, 95% CI 0.21-0.75, P = 0.004). CONCLUSION: In patients with bradycardia and atrial tachyarrhythmias, DDDRP + MVP is superior to standard dual-chamber pacing. The primary endpoint was significantly lowered through the reduction of the progression of atrial tachyarrhythmias to permanent AF. CLINICALTRIALSGOV IDENTIFIER: NCT00262119.

Previous Exercise Levels and Outcome in Patients with New Atrial Fibrillation: "Past Achievements Do Not Predict the Future".

INTRODUCTION: Long-term endurance exercise is suspect to elevate the risk of atrial fibrillation (AF), but little is known about cardiovascular outcome and disease progression in this subgroup of AF patients. We investigated whether previous exercise level determines cardiovascular outcome. METHODS: In this post hoc analysis of the RACE 4 randomized trial, we analyzed all patients with a completed questionnaire on sports participation. Three subgroups were made based on lifetime sports hours up to randomization and previous compliance to the international physical activity guidelines. High lifetime hours of high dynamic activity patients were defined as more than 150 min·wk -1 of high-intensity physical exercise. The primary endpoint was a composite of cardiovascular death and hospital admissions. RESULTS: A total of 879 patients were analyzed, divided in 203 high lifetime hours of high dynamic activity, 192 high lifetime hours of activity, and 484 low lifetime hours of activity patients. Over a mean follow-up of 36 months (±14), the primary endpoint occurred in 61 out of 203 (30%) high lifetime hours of high dynamic activity, 53 out of 192 (27%) high lifetime hours of activity, and 135 out of 484 (28%) low lifetime hours of activity patients ( P = 0.74). During follow-up, 42 high lifetime hours of high dynamic activity (35%), 43 high lifetime hours of activity (32%), and 104 low lifetime hours of activity patients (34%) with paroxysmal AF received electrical or chemical cardioversion or atrial ablation ( P = 0.90). CONCLUSIONS: In patients included in the RACE 4, there seems to be no relation between previous activity levels and cardiovascular outcome and the need for electrical or chemical cardioversion or atrial ablation. Cardiovascular outcome was driven by AF-related arrhythmic events.

Impact of a Chronic Total Coronary Occlusion on the Incidence of Appropriate Implantable Cardioverter-Defibrillator Shocks and Mortality: A Substudy of the Dutch Outcome in ICD Therapy (DO-IT)) Registry.

BACKGROUND: Chronic total coronary occlusions (CTO) substantially increase the risk for sudden cardiac death. Among patients with chronic ischemic heart disease at risk for sudden cardiac death, an implantable cardioverter defibrillator (ICD) is the favored therapy for primary prevention of sudden cardiac death. This study sought to investigate the impact of CTOs on the risk for appropriate ICD shocks and mortality within a nationwide prospective cohort. METHODS AND RESULTS: This is a subanalysis of the nationwide Dutch-Outcome in ICD Therapy (DO-IT) registry of primary prevention ICD recipients in The Netherlands between September 2014 and June 2016 (n=1442). We identified patients with chronic ischemic heart disease (n=663) and assessed available coronary angiograms for CTO presence (n=415). Patients with revascularized CTOs were excluded (n=79). The primary end point was the composite of all-cause mortality and appropriate ICD shocks. Clinical follow-up was conducted for at least 2 years. A total of 336 patients were included, with an average age of 67±9 years, and 20.5% was female (n=69). An unrevascularized CTO was identified in 110 patients (32.7%). During a median follow-up period of 27 months (interquartile range, 24-32), the primary end point occurred in 21.1% of patients with CTO (n=23) compared with 11.9% in patients without CTO (n=27; P=0.034). Corrected for baseline characteristics including left ventricular ejection fraction, and the presence of a CTO was an independent predictor for the primary end point (hazard ratio, 1.82 [95% CI, 1.03-3.22]; P=0.038). CONCLUSIONS: Within this nationwide prospective registry of primary prevention ICD recipients, the presence of an unrevascularized CTO was an independent predictor for the composite outcome of all-cause mortality and appropriate ICD shocks.

Serial cardiac biomarkers, pulmonary artery pressures and traditional parameters of fluid status in relation to prognosis in patients with chronic heart failure: Design and rationale of the BioMEMS study.

AIMS: Heart failure (HF), a global pandemic affecting millions of individuals, calls for adequate predictive guidance for improved therapy. Congestion, a key factor in HF-related hospitalizations, further underscores the need for timely interventions. Proactive monitoring of intracardiac pressures, guided by pulmonary artery (PA) pressure, offers opportunities for efficient early-stage intervention, since haemodynamic congestion precedes clinical symptoms. METHODS: The BioMEMS study, a substudy of the MONITOR-HF trial, proposes a multifaceted approach integrating blood biobank data with traditional and novel HF parameters. Two additional blood samples from 340 active participants in the MONITOR-HF trial were collected at baseline, 3-, 6-, and 12-month visits and stored for the BioMEMS biobank. The main aims are to identify the relationship between temporal biomarker patterns and PA pressures derived from the CardioMEMS-HF system, and to identify the biomarker profile(s) associated with the risk of HF events and cardiovascular death. CONCLUSION: Since the prognostic value of single baseline measurements of biomarkers like N-terminal pro-B-type natriuretic peptide is limited, with the BioMEMS study we advocate a dynamic, serial approach to better capture HF progression. We will substantiate this by relating repeated biomarker measurements to PA pressures. This design rationale presents a comprehensive review on cardiac biomarkers in HF, and aims to contribute valuable insights into personalized HF therapy and patient risk assessment, advancing our ability to address the evolving nature of HF effectively.

Lenient versus strict rate control in patients with atrial fibrillation.

BACKGROUND: Rate control is often the therapy of choice for atrial fibrillation. Guidelines recommend strict rate control, but this is not based on clinical evidence. We hypothesized that lenient rate control is not inferior to strict rate control for preventing cardiovascular morbidity and mortality in patients with permanent atrial fibrillation. METHODS: We randomly assigned 614 patients with permanent atrial fibrillation to undergo a lenient rate-control strategy (resting heart rate <110 beats per minute) or a strict rate-control strategy (resting heart rate <80 beats per minute and heart rate during moderate exercise <110 beats per minute). The primary outcome was a composite of death from cardiovascular causes, hospitalization for heart failure, and stroke, systemic embolism, bleeding, and life-threatening arrhythmic events. The duration of follow-up was at least 2 years, with a maximum of 3 years. RESULTS: The estimated cumulative incidence of the primary outcome at 3 years was 12.9% in the lenient-control group and 14.9% in the strict-control group, with an absolute difference with respect to the lenient-control group of -2.0 percentage points (90% confidence interval, -7.6 to 3.5; P<0.001 for the prespecified noninferiority margin). The frequencies of the components of the primary outcome were similar in the two groups. More patients in the lenient-control group met the heart-rate target or targets (304 [97.7%], vs. 203 [67.0%] in the strict-control group; P<0.001) with fewer total visits (75 [median, 0], vs. 684 [median, 2]; P<0.001). The frequencies of symptoms and adverse events were similar in the two groups. CONCLUSIONS: In patients with permanent atrial fibrillation, lenient rate control is as effective as strict rate control and is easier to achieve. (ClinicalTrials.gov number, NCT00392613.)

[A harmless form of pneumomediastinum: avoid unnecessary diagnostics and treatment]. / Een onschuldige vorm van pneumomediastinum.

BACKGROUND: Pneumomediastinum is a potentially life-threatening condition. Patients can present with a variety of symptoms at the emergency department. Pneumomediastinum can be spontaneous or secondary due to perforation of the esophagus or tracheobronchial tree. CASE DESCRIPTION: A 20-year old man was seen at the emergency department with the suspicion of esophageal perforation. He noticed subcutaneous 'crackles' arising after an episode of severe vomiting. In the emergency room a non-acute ill patient was seen with subcutaneous emphysema of the neck and chest. A CT-scan with oral contrast did not show esophageal contrast leakage or other pathology that could be the cause of his pneumomediastinum. Therefore, we diagnosed the patient with a spontaneous pneumomediastinum. He was discharged after an observation period of 24 hours. CONCLUSION: Spontaneous pneumomediastinum is a rare, self-limiting disease with an excellent prognosis. Differentiating spontaneous pneumomediastinum from more severe secondary causes will avoid unnecessary therapy and prolonged hospitalization.

Anatomical perspective on radiofrequency ablation of AV nodal reentry tachycardia after Mustard correction for transposition of the great arteries.

A case of radiofrequency catheter ablation of atrioventricular (AV) nodal reentry tachycardia, in a patient with transposition of the great arteries after venous rerouting according to Mustard, is described. An electroanatomical map of the His and AV nodal region was created from inside the systemic venous atrium. Retrograde mapping of the pulmonary venous atrium was performed and the arterial catheter retracted to a position in close proximity to the venous catheter inside the intraatrial baffle. This position was chosen to deliver radiofrequency current.

Imaging of programmed cell death in arrhythmogenic right ventricle cardiomyopathy/dysplasia.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a myocardial disease that predominantly affects the right ventricle (RV). Its hallmark feature is fibrofatty replacement of the RV myocardium. Apoptosis in ARVC/D has been proposed as an important process that mediates the slow, ongoing loss of heart muscle cells which is followed by ventricular dysfunction. We aimed to establish whether cardiac apoptosis can be assessed noninvasively in patients with ARVC/D. METHODS: Six patients fulfilling the ARVC/D criteria were studied. Regional myocardial apoptosis was assessed with (99m)Tc-annexin V scintigraphy. RESULTS: Overall, the RV wall showed a higher (99m)Tc-annexin V signal than the left ventricular wall (p = 0.049) and the interventricular septum (p = 0.026). However, significantly increased uptake of (99m)Tc-annexin V in the RV was present in only three of the six ARVC/D patients (p = 0.001, compared to (99m)Tc-annexin V uptake in the RV wall of the other three patients). CONCLUSION: Our results are suggestive of a chamber-specific apoptotic process. Although the role of apoptosis in ARVC/D is unsolved, the ability to assess apoptosis noninvasively may aid in the diagnostic course. In addition, the ability to detect apoptosis in vivo with (99m)Tc-annexin V scintigraphy might allow individual monitoring of disease progression and response to diverse treatments aimed at counteracting ARVC/D progression.

Clinical use of automatic pacemaker algorithms: results of the AUTOMATICITY registry.

AIMS: Follow-up of the ever-increasing numbers of patients with implantable cardiac devices places a heavy burden on clinical departments. Device automaticity may alleviate the follow-up burden by minimizing the time for physician involvement. The aim of the prospective, multicentre AUTOMATICITY registry was to examine the performance of a subset of programmed automatic algorithms during patient follow-up and their acceptance by implanting physicians. METHODS AND RESULTS: The clinical use of automatic algorithms from the Insignia pacemakers (PM; Boston Scientific, St Paul, MN, USA) was evaluated: atrial and ventricular AutoSense (sensitivity adjustment), ventricular Automatic Capture (threshold verification and output setting), AutoLifeStyle (sensor settings adjustment). The objective of the study was to assess the reprogramming rates within 12 months of implant, the reasons for reprogramming and relationship to adverse events. A total of 960 patients were enrolled in the study. The proportion of patients free from any algorithm reprogramming at 12 months was 86.1%. A total of 2736 algorithms were activated at enrolment, with 156 (5.7%) being reprogrammed in 115 patients at 12 months for any reason. Forty-nine reprogrammings (1.8%) were unintentional or related to changes in device settings such that the algorithm was no longer available, 33 (1.2%) were due to suspected sensing issues, and 22 (0.8%) were assumed related to the algorithm. The individual 12-month reprogramming-free rates were: ventricular AutoSense 94.3%, Atrial AutoSense 93.3%, AutoLifeStyle 93.9%, and Automatic Capture 95.9%. CONCLUSION: The results of the AUTOMATICITY registry show that automatic measurement of key settings and automatic adjustment to optimal programming is feasible and safe. The simplicity of PM follow-up and avoidance of frequent reprogramming may contribute to a more effective use of hospital time and resources.

Peripheral Insulin Extraction in Non-Diabetic Subjects and Type 2 Diabetes Mellitus Patients.

BACKGROUND: Insulin has to be transported across the capillary endothelium to stimulate muscle glucose uptake. We investigated insulin uptake from the peripheral circulation in non-diabetic (ND) individuals and in type 2 diabetes (T2D) patients. METHODS: Single-center cross-sectional study involving 40 ND (age 65±11 years) and 30 T2D patients (age 67±8 years). Thirty-six participants were studied in the fasted state (22 ND subjects and 14 T2D patients termed NDF and T2DF) and 34 participants 1-h following a glucose challenge (18 ND subjects and 16 T2D patients indicated as NDG and T2DG). Main outcome measure was fractional extraction (FE) of insulin (FEins) and glucose using the forearm balance method. RESULTS: In NDF, FEins was 18 (10-26) % at lower insulin levels (63 51-80] pmol/l), while in NDG at higher insulin levels (776 [543-1176] pmol/l), FEins was 9 (4-16) % (p = 0.01 vs. NDF). In NDF only, a negative correlation was observed between FEins and arterial plasma insulin load (rho = - 0.575;p = 0.006) and fasting plasma glucose levels (rho = - 0.551;p = 0.01). In T2DF FEins was 6 (1-19) % and not different from FEins in T2DG (10 2-14) %), and was not associated to fasting glucose. FEins tended to be higher in NDF compared to T2DF (p = 0.07). DISCUSSION: We propose that in ND individuals, besides passive diffusion, an active high-affinity pathway with limited capacity around lower physiologic insulin levels exists for insulin transendothelial transport, contributing to glycemic control. In T2D patients, this mechanism of peripheral insulin uptake is diminished or even absent. Modulation of insulin extraction from the circulation may be a novel target to improve glucose metabolism in T2D.

The MINERVA study design and rationale: a controlled randomized trial to assess the clinical benefit of minimizing ventricular pacing in pacemaker patients with atrial tachyarrhythmias.

BACKGROUND: Dual-chamber (DDD) pacing has generally been regarded as "physiologic pacing" and therefore expected to be superior to ventricular pacing. Major randomized trials have so far failed to demonstrate significant reductions in the incidences of mortality, stroke, and heart failure. It has been shown that unnecessary ventricular pacing in patients with sinus node dysfunction or only intermittent atrioventricular block is associated with ventricular desynchronization and increased risk of atrial tachyarrhythmias (ATA). METHODS: The MINimizE Right Ventricular pacing to prevent Atrial fibrillation and heart failure (MINERVA) study is a prospective, multi-center, randomized, international, single-blind, controlled trial designed to determine whether physiologic pacing through the managed ventricular pacing (MVP) algorithm combined with preventive atrial pacing (PAP) and atrial antitachycardia pacing (ATP) is superior to standard DDD pacing in terms of 2-year reduction in death, permanent ATA, and cardiovascular hospitalizations. Patients with standard class I or II indications for permanent DDD pacing and history of ATA will receive a Medtronic EnRhythm implantable pacemaker (Medtronic, Minneapolis, MN). After a 1-month run-in period, patients will be randomized in a 1:1:1 manner to the DDD (control group, all OFF), the DDDRP (MVP + PAP + ATP ON), and the MVP group (only MVP ON). Up to 1,300 patients will be included in approximately 70 centers in Europe, the Middle East, and Asia. CONCLUSIONS: The MINERVA study will make an important contribution to the management of patients with paroxysmal ATA and accepted indications for dual-chamber pacemaker implantation by determining whether physiologic pacing combined with PAP and ATP is superior to standard DDD pacing in terms of reduction of mortality, incidence of permanent ATA, and cardiovascular hospitalizations.

Cardiac resynchronization improves microcirculation.

BACKGROUND: Although it is known that cardiac resynchronization therapy (CRT) in heart failure (HF) patients improves systemic circulation, its acute effects on microcirculation are as yet unknown. Therefore we investigated the sublingual microcirculatory changes in HF patients from CRT and right ventricular (RV) pacing by use of orthogonal polarization spectral (OPS) imaging. METHODS AND RESULTS: Twelve consecutive HF patients with a CRT device and 20 healthy individuals (HI) were included. Acute microcirculatory changes were assessed by functional capillary density (FCD) and capillary velocity (CV) measurement 6 months after CRT. FCD and CV were measured in HF patients sublingually after 15 minutes of programming 1 of 3 pacing modalities in random order (no pacing, RV pacing, and CRT). FCD was significantly higher in HI (11.2 +/- 2.1 cm/cm(2)) compared with HF patients with RV pacing (8.9 +/- 1.9 cm/cm(2); P = .03) and no pacing (8.3 +/- 2.4 cm/cm(2); P = .02). CRT (12.1 +/- 2.2 cm/cm(2)) significantly increased FCD in HF patients compared with RV pacing (8.9 +/- 1.9 cm/cm(2); P = .006) and no pacing (8.3 +/- 2.4 cm/cm(2); P = .008). CV was normal in all patients with or without pacing. CONCLUSIONS: CRT improves microcirculatory function as assessed by OPS imaging.

Atrial antitachycardia pacing and atrial remodeling: A substudy of the international, randomized MINERVA trial.

BACKGROUND: Atrial tachycardia (AT) and atrial fibrillation (AF) are common in pacemaker patients and are associated with bad prognoses. OBJECTIVE: The purpose of this study was to evaluate atrial antitachycardia pacing impact on AT/AF-induced atrial remodeling, measured by early recurrence of AT/AF (ERAF) and by change in left atrial diameter (LAD), and to evaluate the impact of AT/AF duration on ERAF incidence. METHODS: Pacemaker patients were randomized to dual-chamber pacing (Control DDDR: 385 patients), managed ventricular pacing (MVP: 398 patients), or atrial antitachycardia pacing plus MVP (DDDRP+MVP: 383 patients). LAD change, estimated by echocardiography, was considered significant if the relative difference between baseline and 24-month measurements was >10%. RESULTS: At median follow-up of 34 months, ERAF incidence was significantly lower in the DDDRP+MVP arm for all AT/AF durations, in particular, ERAF followed AT/AF longer than 3 hours in 53% cases in Control DDDR, in 51% cases in MVP, and in 39% cases in DDDRP+MVP (P <.001 vs other groups). ERAF incidence showed a U-shaped pattern when evaluated as a function of previous AT/AF duration, decreasing for durations from 5 minutes to 12 hours and increasing for longer durations. Among patients with significant LAD change, the proportion of patients with a reduction in LAD was 35% in Control DDDR, 37% in MVP, and 70% in DDDRP+MVP (P <.05 vs other groups). CONCLUSION: Our data suggest that atrial electrical remodeling becomes important after about 12 hours of continuous arrhythmia. Compared to DDDR or MVP, DDDRP+MVP reduces ERAF and favors LAD reduction, suggesting that atrial antitachycardia pacing may reverse electrical and mechanical remodeling.