Background—: The pivot is critical to rotors postulated to maintain atrial fibrillation (AF). We reasoned that wavefronts circling the pivot should broaden the amplitude distribution of bipolar electrograms because of directional information encoded in these signals. We aimed to determine whether Shannon entropy (ShEn), a measure of signal amplitude distribution, could differentiate the pivot from surrounding peripheral regions and thereby assist clinical rotor mapping. Methods and Results—: Bipolar electrogram recordings were studied in 4 systems: (1) computer simulations of rotors in a 2-dimensional atrial sheet; (2) isolated rat atria recorded with a multi-electrode array (n=12); (3) epicardial plaque recordings of induced AF in hypertensive sheep (n=11); and (4) persistent AF patients (n=10). In the model systems, rotation episodes were identified, and ShEn calculated as an index of amplitude distribution. In humans, ShEn distribution was analyzed at AF termination sites and with respect to complex fractionated electrogram mean. We analyzed rotation episodes in simulations (4 cycles) and animals (rats: 14 rotors, duration 80±81 cycles; sheep: 13 rotors, 4.2±1.5 cycles). The maximum ShEn bipole was consistently colocated with the pivot zone. ShEn was negatively associated with distance from the pivot zone in simulated spiral waves, rats, and sheep. ShEn was modestly inversely associated with complex fractionated electrogram; however, there was no relationship at the sites of highest ShEn. Conclusions—: ShEn is a mechanistically based tool that may assist AF rotor mapping.

Both ageing and hypertension are known risk factors for atrial fibrillation (AF) although the pathophysiological contribution or interaction of the individual factors remains poorly understood. Here we aim to delineate the arrhythmogenic atrial substrate in mature spontaneously hypertensive rats (SHR). SHR were studied at 12 and 15 months of age (n = 8 per group) together with equal numbers of age-matched normotensive Wistar-Kyoto control rats (WKY). Electrophysiologic study was performed on superfused isolated right and left atrial preparations using a custom built high-density multiple-electrode array to determine effective refractory periods (ERP), atrial conduction and atrial arrhythmia inducibility. Tissue specimens were harvested for structural analysis. Compared to WKY controls, the SHR demonstrated: Higher systolic blood pressure (p<0.0001), bi-atrial enlargement (p<0.05), bi-ventricular hypertrophy (p<0.05), lower atrial ERP (p = 0.008), increased atrial conduction heterogeneity (p = 0.001) and increased atrial interstitial fibrosis (p = 0.006) & CD68-positive macrophages infiltration (p<0.0001). These changes resulted in higher atrial arrhythmia inducibility (p = 0.01) and longer induced AF episodes (p = 0.02) in 15-month old SHR. Ageing contributed to incremental bi-atrial hypertrophy (p<0.01) and atrial conduction heterogeneity (p<0.01) without affecting atrial ERP, fibrosis and arrhythmia inducibility. The limited effect of ageing on the atrial substrate may be secondary to the reduction in CD68-positive macrophages. Significant atrial electrical and structural remodeling is evident in the ageing spontaneously hypertensive rat atria. Concomitant hypertension appears to play a greater pathophysiological role than ageing despite their compounding effect on the atrial substrate. Inflammation is pathophysiologically linked to the pro-fibrotic changes in the hypertensive atria.

Sclerostin is most recognized for its role in controlling bone formation but is also expressed in the heart, aorta, coronary, and peripheral arteries. This review summarizes research on sclerostin’s role in cardiovascular disease. Rodent studies have found sclerostin to be expressed at sites of arterial calcification. In contrast, aortic sclerostin was reported to be downregulated in a mouse model of abdominal aortic aneurysm, and transgenic upregulation or administration of sclerostin was found to prevent abdominal aortic aneurysm and atherosclerosis formation. Sclerostin deficiency was reported to stimulate cardiac rupture in one rodent model. In humans, 7 of 11 studies reported a significant association between high serum sclerostin and high carotid intima media thickness. Ten of 15 studies reported a significant association between high serum sclerostin and severe arterial calcification. Twelve of 14 studies reported a significant association between high serum sclerostin and high arterial stiffness or atherosclerosis severity. Four of 9 studies reported a significant association between high serum sclerostin and high risk of cardiovascular events. A meta-analysis of randomized controlled trials suggested that administration of the sclerostin blocking antibody romosozumab did not significantly increase the risk of major adverse cardiovascular events (risk ratio, 1.14 [95% CI, 0.83–1.57]; P =0.54) or cardiovascular death (risk ratio, 0.92 [95% CI, 0.53–1.59]; P =0.71). Human genetic studies reported variants predisposing to low arterial sclerostin expression were associated with a high risk of cardiovascular events. Overall, past research suggests a cardiovascular protective role of sclerostin but findings have been inconsistent, possibly due to variations in study design, the unique populations and models studied, and the heterogeneous methods used.

Introduction: Recent research has unravelled an increasing list of cardiac conditions and risk factors that may be responsible for the abnormal underlying atrial substrate that predisposes to atrial fibrillation (AF). Atrial fibrosis has been demonstrated as the pivotal structural abnormality underpinning conduction disturbances that promote AF in different disease models. Despite the advancement in our discoveries of the molecular mechanisms involved in the profibrotic milieu, targeted therapeutics against atrial fibrosis remain lacking. Areas covered: This review is focused on detailing the key molecular signalling pathways that contribute to atrial fibrosis including: angiotensin II, transforming growth factor (TGF- ß1), connective tissue growth factor (CTGF) and endothelin-1. We also discussed the potential therapeutic options that may be useful in modulating the abnormal atrial substrate. In addition, we examined the new paradigm of AF care in lifestyle and risk factor management that has been shown to arrest and reverse the atrial remodelling process leading to improved AF outcomes. Expert commentary: The future of AF care is likely to require an integrated approach consisting of aggressive risk factor management in addition to the established paradigm of rate and rhythm management and anticoagulation. Translational studies on molecular therapeutics to combat atrial fibrosis is urgently needed.