Wouter R. Berger

Atrial Fibrosis and Conduction Slowing in the Left Atrial Appendage of Patients Undergoing Thoracoscopic Surgical Pulmonary Vein Isolation for Atrial Fibrillation

Background—Atrial fibrosis is an important component of the arrhythmogenic substrate in patients with atrial fibrillation (AF). We studied the effect of interstitial fibrosis on conduction velocity (CV) in the left atrial appendage of patients with AF. Methods and Results—Thirty-five left atrial appendages were obtained during AF surgery. Preparations were superfused and stimulated at 100 beats per minute. Activation was recorded with optical mapping. Longitudinal CV (CVL), transverse CV (CVT), and activation times (>2 mm distance) were measured. Interstitial collagen was quantified and graded qualitatively. The presence of fibroblasts and myofibroblasts was assessed immunohistochemically. Mean CVL was 0.55±0.22 m/s, mean CVT was 0.25±0.15 m/s, and the mean activation time was 9.31±5.45 ms. The amount of fibrosis was unrelated to CV or patient characteristics. CVL was higher in left atrial appendages with thick compared with thin interstitial collagen strands (0.77±0.22 versus 0.48±0.19 m/s; P=0.012), which were more frequently present in persistent patients with AF. CVT was not significantly different (P=0.47), but activation time was 14.93±4.12 versus 7.95±4.12 ms in patients with thick versus thin interstitial collagen strands, respectively (P=0.004). Fibroblasts were abundantly present and were associated with the presence of thick interstitial collagen strands (P=0.008). Myofibroblasts were not detected in the left atrial appendage. Conclusions—In patients with AF, thick interstitial collagen strands are associated with higher CVL and increased activation time. Our observations demonstrate that the severity and structure of local interstitial fibrosis is associated with atrial conduction abnormalities, presenting an arrhythmogenic substrate for atrial re-entry.

J Curve in Patients Randomly Assigned to Different Systolic Blood Pressure Targets: An Experimental Approach to an Observational Paradigm

Background: Low systolic blood pressure (SBP) values are associated with an increased risk of cardiovascular events, giving rise to the so-called J-curve phenomenon. We assessed the association between on-treatment SBP levels, cardiovascular events, and all-cause mortality in patients randomized to different SBP targets. Methods: Data from 2 large randomized trials that randomly allocated hypertensive patients at high risk for cardiovascular disease to intensive (SBP<120 mm Hg) or conventional (SBP<140 mm Hg) treatment were pooled and harmonized for outcomes and follow-up duration. Using natural cubic splines, we plotted the hazard ratio for all-cause mortality and cardiovascular events against the mean on-treatment SBP per treatment group. Results: The pooled data consisted of 194 875 on-treatment SBP measurements in 13 946 patients (98.9%). During a median follow-up of 3.3 years, cardiovascular events occurred in 1014 patients (7.3%), and 502 patients died (3.7%). For both blood pressure targets, an identical shape of the J curve was present, with a nadir for cardiovascular events and all-cause mortality just below the SBP target. Patients in the lowest SBP stratum were older, had a higher body mass index, smoked more often, and had a higher frequency of diabetes mellitus and cardiovascular events. Conclusions: Low on-treatment SBP levels are associated with increased cardiovascular events and all-cause mortality. This association is independent of the attained blood pressure level because the J curve aligns with the SBP target. Our results suggest that the benefit or risk associated with intensive blood pressure–lowering treatment can be established only via randomized clinical trials. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01206062 and NCT00000620.

Aldosterone Pathway Blockade to Prevent Atrial Fibrillation: A Systematic Review and Meta-Analysis

BACKGROUND Despite advances in therapeutic interventions AF remains a progressive and symptomatic disease. Therefore, novel therapeutic interventions targeting the underlying arrhythmogenic substrate for AF is needed. Atrial fibrosis is an important component of the arrhythmogenic substrate of AF and may be initiated by aldosterone binding to the mineralocorticoid receptor. We hypothesized that aldosterone pathway blockade with mineralocorticoid receptor antagonists (MRA) reduces atrial fibrosis, and thus AF. METHODS We searched OVID MEDLINE, OVID EMBASE and the Cochrane Central Register of Controlled Trials from inception to June 10th, 2016 for randomized controlled trials (RCT) and observational studies addressing MRA and providing information on AF occurrence. Two independent reviewers selected and appraised the data. We performed random-effects meta-analyses. Summary odds ratios (OR) with 95% confidence intervals (CI) were calculated. RESULTS We included 14 studies, 5 RCT and 9 observational cohorts, with a cumulative number of 5332 patients (male: 74.9%, age: 65.3years); 2397 (45.0%) received an MRA (spironolactone or eplerenone). During follow-up, 204 (8.5%) patients treated with MRAs, developed AF, compared to 547 (18.6%) patients, without MRA treatment. Meta-analyses showed a significant overall reduction of AF risk in MRA treated patients (OR: 0.48 CI: 0.38-0.60 p<0.001), including a reduction of new-onset AF (OR: 0.52 CI: 0.37-0.74 p<0.001) and recurrent AF (OR: 0.37 CI: 0.24-0.57 p<0.001), but not post-operative AF (POAF) (OR: 0.60 CI: 0.33-1.09 p=0.09). CONCLUSIONS MRAs significantly reduce new-onset AF and recurrent AF, but not POAF. MRA treatment can be considered an additive therapeutic strategy in AF.

Intensive Blood Pressure Lowering in Patients With and Patients Without Type 2 Diabetes: A Pooled Analysis From Two Randomized Trials

OBJECTIVE The Action to Control Cardiovascular Risk in Diabetes Blood Pressure (ACCORD-BP) study did not find a significant beneficial effect of intensive systolic blood pressure (SBP) lowering on cardiovascular events in hypertensive patients with type 2 diabetes mellitus (T2DM), while the Systolic Blood Pressure Intervention Trial (SPRINT) did find a significant beneficial effect in patients without T2DM. The objective of this analysis was to assess the effect of both T2DM and baseline cardiovascular disease risk on the treatment effect of intensive blood pressure lowering. RESEARCH DESIGN AND METHODS The individual patient data from the ACCORD-BP and SPRINT studies were pooled and follow-up durations harmonized. Both studies randomized hypertensive patients to an SBP target of <120 mmHg or a target of <140 mmHg. The composite primary end point consisted of unstable angina, myocardial infarction, acute heart failure, stroke, and cardiovascular death. The interaction between intensive blood pressure lowering and both T2DM and 10-year cardiovascular risk was assessed using Cox proportional hazards models. RESULTS The cohort consisted of 14,094 patients with mean age 66 ± 8.9 years and mean baseline SBP 139.5 ± 15.6 mmHg; 33.6% had T2DM. The hazard ratio for the primary composite end point was 0.82 (95% CI 0.73–0.93), P = 0.0017. The interaction between intensive blood pressure lowering and T2DM was nonsignificant (P = 0.13). The 10-year cardiovascular risk was higher in primary prevention patients with T2DM, but risk did not interact with the treatment effect (P = 0.84). CONCLUSIONS Intensive blood pressure lowering may have a similar favorable effect and appears to decrease cardiovascular events in both patients with and patients without T2DM.

Electrophysiologically Guided Thoracoscopic Surgery for Advanced Atrial Fibrillation

Patients with symptomatic atrial fibrillation (AF) may require catheter or surgical ablation after antiarrhythmic drugs (AAD) have failed. Thoracoscopic surgical approaches aim to combine the reported efficacy of Cox-Maze procedures with less invasiveness, but long-term follow-up is unavailable. We

MicroRNAs in Atrial Fibrillation: from Expression Signatures to Functional Implications

Atrial fibrillation (AF) is the most common sustained arrhythmia and is associated with pronounced morbidity and mortality. Its prevalence, expected to further increase for the forthcoming years, and associated frequent hospitalizations turn AF into a major health problem. Structural and electrical atrial remodelling underlie the substrate for AF, but the exact mechanisms driving this remodelling remain incompletely understood. Recent studies have shown that microRNAs (miRNA), short non-coding RNAs that regulate gene expression, may be involved in the pathophysiology of AF. MiRNAs have been implicated in AF-induced ion channel remodelling and fibrosis. MiRNAs could therefore provide insight into AF pathophysiology or become novel targets for therapy with miRNA mimics or anti-miRNAs. Moreover, circulating miRNAs have been suggested as a new class of diagnostic and prognostic biomarkers of AF. However, the origin and function of miRNAs in tissue and plasma frequently remain unknown and studies investigating the role of miRNAs in AF vary in design and focus and even present contradicting results. Here, we provide a systematic review of the available clinical and functional studies investigating the tissue and plasma miRNAs in AF and will thereafter discuss the potential of miRNAs as biomarkers or novel therapeutic targets in AF.

Disparate response of high-frequency ganglionic plexus stimulation on sinus node function and atrial propagation in patients with atrial fibrillation

BACKGROUND In patients with atrial fibrillation (AF), the autonomic nervous system is supposed to play an role in triggering AF; however, little is known of the effect on atrial conduction characteristics. OBJECTIVE The purpose of this study was to study the effect of ganglionic plexus (GP) stimulation during sinus rhythm on atrial and pulmonary vein conduction in patients during thoracoscopic surgery for AF METHODS: In 25 patients, the anterior right ganglionic plexus (ARGP) was stimulated (16 Hz, at 1, 2, and 5 mA). Epicardial electrograms were recorded using a 48-electrode map from the right pulmonary vein (RPV) or right atrial (RA). Intra-atrial activation time (IAT), local activation time (LAT), and inhomogeneity of conduction (IIC) were determined. ECG parameters (P-P, P-R interval) were measured. RESULTS P-P interval was 956 ± 157 ms (range 768-1368 ms), and P-R interval was 203 ± 37 ms (range 136-280 ms). After ARGP stimulation, a short-lasting increase of P-P interval was observed, more prominent at higher output (1 mA = 82 ms, 2 mA = 180 ms, 5 mA = 268 ms, all P <.01 vs baseline). P-R interval remained unchanged. IAT was 34.4 ms (range 5.6-50.3 ms) at the RA and 105.8 ms (range 79.7-163.3 ms) at the RPV. After 1-mA stimulation IAT increased, in patients taking beta-blockers (P = .001), or it decreased, and this change persisted after subsequent stimulation at higher current (1 mA, P = .001; 2 mA, P = .401; 5 mA, P = .593). Similar changes were observed for LAT and IIC. CONCLUSION ARGP stimulation results in a short-lasting, output-dependent decrease in sinus node frequency due to a parasympathetic response. Stimulation of the ARGP induced a prolonged increase or decrease in conduction characteristics in patients with AF, consistent with a persistent differential parasympathetic and/or sympathetic response.

The change in circulating galectin-3 predicts absence of atrial fibrillation after thoracoscopic surgical ablation

Aims Galectin-3 (Gal-3) is an important mediator of cardiac fibrosis, particularly in heart failure. Increased Gal-3 concentration (Gal-3), associated with increased risk of developing atrial fibrillation (AF), may reflect atrial fibrotic remodelling underlying AF progression. We aimed to investigate whether the change in serum Gal-3 reflects alterations of the arrhythmogenic atrial substrate following thoracoscopic AF surgery, and predicts absence of AF. Methods and results Consecutive patients undergoing thoracoscopic AF surgery were included. Left atrial appendages (LAAs) and serum were collected during surgery and serum again 6 months thereafter. Gal-3 was determined in tissue and serum. Interstitial collagen in the LAA was quantified using Picrosirius red staining. Ninety-eight patients (76% male, mean age 60 ± 9 years) underwent thoracoscopic surgery for advanced AF. Patients with increased Gal-3 after ablation compared to baseline had a higher recurrence rate compared to patients with decreased or unchanged Gal-3 (HR 2.91, P = 0.014). These patients more frequently had persistent AF, longer AF duration and thick atrial collagen strands (P = 0.049). At baseline, Gal-3 was similar between patients with and without AF recurrence: 14.8 ± 3.9 µg/L vs. 13.7 ± 3.7 µg/L, respectively in serum (P = 0.16); 94.5 ± 19.4 µg/L vs. 93.3 ± 30.8µg/L, respectively in atrial myocardium (P = 0.83). There was no correlation between serum Gal-3 and left atrial Gal-3 (P = 0.20), nor between serum Gal-3 and the percentage of fibrosis in LAA (P = 0.18). Conclusion The change of circulating Gal-3, rather than its baseline value, predicts AF recurrence after thoracoscopic ablation. Patients in whom Gal-3 increases after ablation have a high recurrence rate reflecting ongoing profibrotic signalling, irrespective of arrhythmia continuation.

Quality of life improves after thoracoscopic surgical ablation of advanced atrial fibrillation: Results of the Atrial Fibrillation Ablation and Autonomic Modulation via Thoracoscopic Surgery (AFACT) study

Objective: We evaluated health‐related quality of life at 12 months after thoracoscopic surgical ablation in patients enrolled in the Atrial Fibrillation Ablation and Autonomic Modulation via Thoracoscopic Surgery study. The Atrial Fibrillation Ablation and Autonomic Modulation via Thoracoscopic Surgery study assessed the efficacy and safety of ganglion plexus ablation in patients with symptomatic advanced atrial fibrillation undergoing thoracoscopic surgical ablation. Methods: Patients (n = 240) underwent thoracoscopic pulmonary vein isolation with additional ablation lines in patients with persistent atrial fibrillation. Subjects were randomized to additional ganglion plexus ablation or control. Short Form 36 quality of life questionnaires were collected at baseline and at 6 and 12 months of follow‐up. Results: A total of 201 patients were eligible for quality of life analysis (age 59 ± 8 years, 72% were men, 68% had an enlarged left atrium, 57% had persistent atrial fibrillation). Patients improved in physical and mental health at 6 months (both P < .01) and 12 months (both P < .01) relative to baseline, with no difference between the ganglion plexus (n = 101) and control (n = 100) groups. Short Form 36 subscores in patients with 1 or no atrial fibrillation recurrences were similar to those in the general Dutch population after 12 months. Patients with multiple atrial fibrillation recurrences (30%) improved in mental (P < .01), but not physical health, and 6 of 8 Short Form 36 subscales remained below those of the general Dutch population. Patients with irreversible, but not with reversible procedural complications had persistently diminished quality of life scores at 12 months. Conclusions: Thoracoscopic surgery for advanced atrial fibrillation results in improvement in quality of life, regardless of additional ganglion plexus ablation. Quality of life in patients with no or 1 atrial fibrillation recurrence increased to the level of the general Dutch population, whereas in patients with multiple atrial fibrillation recurrences quality of life remained lower. Irreversible but not reversible procedural complications were associated with persistently lower quality of life.

Assessment of the Extravascular Implantable Defibrillator: Feasibility of Substernal Ventricular Pacing: Substernal Pacing in Humans

The objective of this study was to assess feasibility of ventricular pacing and thresholds from within the substernal space to examine a new extravascular ICD configuration with pacing capabilities.