Background—: Recent clinical studies suggest that endurance sports may promote cardiac arrhythmias. The aim of this study was to use an animal model to evaluate whether sustained intensive exercise training induces potentially adverse myocardial remodeling and thus creates a potential substrate for arrhythmias. Methods and Results—: Male Wistar rats were conditioned to run vigorously for 4, 8, and 16 weeks; time-matched sedentary rats served as controls. Serial echocardiograms and in vivo electrophysiological studies at 16 weeks were obtained in both groups. After euthanasia, ventricular collagen deposition was quantified by histological and biochemical studies, and messenger RNA and protein expression of transforming growth factor-β1, fibronectin-1, matrix metalloproteinase-2, tissue inhibitor of metalloproteinase-1, procollagen-I, and procollagen-III was evaluated in all 4 cardiac chambers. At 16 weeks, exercise rats developed eccentric hypertrophy and diastolic dysfunction, together with atrial dilation. In addition, collagen deposition in the right ventricle and messenger RNA and protein expression of fibrosis markers in both atria and right ventricle were significantly greater in exercise than in sedentary rats at 16 weeks. Ventricular tachycardia could be induced in 5 of 12 exercise rats (42%) and only 1 of 16 sedentary rats (6%; P =0.05). The fibrotic changes caused by 16 weeks of intensive exercise were reversed after an 8-week exercise cessation. Conclusions—: In this animal model, we documented cardiac fibrosis after long-term intensive exercise training, together with changes in ventricular function and increased arrhythmia inducibility. If our findings are confirmed in humans, the results would support the notion that long-term vigorous endurance exercise training may in some cases promote adverse remodeling and produce a substrate for cardiac arrhythmias.

Atrial fibrillation (AF) is generally considered a progressive disease, typically evolving from paroxysmal through persistent to ‘permanent’ forms, a process attributed to electrical and structural remodelling related to both the underlying disease and AF itself. Medical treatment has yet to demonstrate clinical efficacy in preventing progression. Large clinical trials performed to date have failed to show benefit of rhythm control compared with rate control, but these trials primarily included patients at late stages in the disease process. One possible explanation is that intervention at only an early stage of progression may improve prognosis. Evolving observations about the progressive nature of AF, along with the occurrences of major complications such as strokes upon AF presentation, led to the notion that earlier and more active approaches to AF detection, rhythm-reversion, and maintenance of sinus rhythm may be a useful strategy in AF management. Approaches to early and sustained rhythm control include measures that prevent development of the AF substrate, earlier catheter ablation, and novel antiarrhythmic drugs. Improved classifications of AF mechanism, pathogenesis, and remodelling may be helpful to enable patient-specific pathophysiological diagnosis and therapy. Potential novel therapeutic options under development include microRNA-modulation, heatshock protein inducers, agents that influence Ca²⁺ handling, vagal stimulators, and more aggressive mechanism-based ablation strategies. In this review, of research into the basis and management of AF in acute and early settings, it is proposed that progression from paroxysmal to persistent AF can be interrupted, with potentially favourable prognostic impact.

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Late gadolinium enhancement cardiac magnetic resonance (LGE-CMR) provides tissue characterization of ventricular myocardium and scar that can be depicted as pixel signal intensity (PSI) maps. To assess the possible benefit of guiding the ventricular tachycardia (VT) substrate mapping by integrating these PSI maps into the navigation system. In total, 159 consecutive patients (66 ± 11 years old, 151 men [95%]) with scar-related left ventricular (LV) VT were included. VT substrate ablation used the scar dechanneling technique. A CMR-aided ablation using the PSI maps was performed in 54 patients (34%). Procedural data as well as acute and long-term outcomes were compared with those of the remaining 105 patients (66%). Mean procedure duration and fluoroscopy time were 229 ± 67 minutes and 20 ± 9 minutes, respectively, without significant differences between groups. Both the number of radiofrequency (RF) applications and RF delivery time were lower in the CMR-aided group (28 ± 18 applications vs 36 ± 18 applications, P = .037, and 19 ± 12 minutes vs 27 ± 16 minutes, P = .009, respectively). After substrate ablation, monomorphic VT inducibility was lower in the CMR-aided than in the control group (17 [32%] vs 53 [51%] patients, P = .022). After a mean follow-up period of 20 ± 19 months, patients from the CMR-aided group had a lower recurrence rate than those in the control group (10 patients [18.5%] vs 46 patients [43.8%], respectively, P = .002; log-rank P = .017). Multivariate analysis found that CMR-aided ablation (hazard ratio, 0.48 [95% Confirdence Interval (CI) 0.24-0.96], P = .037) was an independent predictor of recurrences. CMR-aided scar dechanneling is associated with a lower need for RF delivery, higher noninducibility rates after substrate ablation, and a higher VT-recurrence-free survival.

Background—: Atrial tissue fibrosis is often an important component of the atrial fibrillation (AF) substrate. Small noncoding microRNAs are important mediators in many cardiac remodeling paradigms. MicroRNA-21 (miR-21) has been suggested to be important in ventricular fibrotic remodeling by downregulating Sprouty-1, a protein that suppresses fibroblast proliferation. The present study examined the potential role of miR-21 in the atrial AF substrate resulting from experimental heart failure after myocardial infarction (MI). Methods and Results—: Large MIs (based on echocardiographic left ventricular wall motion score index) were created by left anterior descending coronary artery ligation in rats. Changes induced by MI versus sham controls were first characterized with echocardiography, histology, biochemistry, and in vivo electrophysiology. Additional MI rats were then randomized to receive anti–miR-21 (KD21) or scrambled control sequence (Scr21) injections into the left atrial myocardium. Progressive left ventricular enlargement, hypocontractility, left atrial dilation, fibrosis, refractoriness prolongation, and AF promotion occurred in MI rats versus sham controls. Atrial tissues of MI rats showed upregulation of miR-21, along with dysregulation of the target genes Sprouty-1, collagen-1, and collagen-3. KD21 treatment reduced atrial miR-21 expression levels in MI rats to values in sham rats, decreased AF duration from 417 (69–1595; median [Q1–Q3]) seconds to 3 (2–16) seconds (8 weeks after MI; P <0.05), and reduced atrial fibrous tissue content from 14.4±1.8% (mean±SEM) to 4.9±1.2% (8 weeks after MI; P <0.05) versus Scr21 controls. Conclusions—: MI-induced heart failure leads to AF-promoting atrial remodeling in rats. Atrial miR-21 knockdown suppresses atrial fibrosis and AF promotion, implicating miR-21 as an important signaling molecule for the AF substrate and pointing to miR-21 as a potential target for molecular interventions designed to prevent AF.