Effect of ablation pattern on mechanical function in the atrium.

BACKGROUND: Atrial fibrillation (AF) is often treated with catheter ablation, which induces scar formation to isolate misfiring electrical signals in the left atrium. Successful ablation restores sinus rhythm at the cost of replacing viable myocardium with scar. The impact of ablation scar on mechanical function of the left atrium is poorly understood. OBJECTIVE: We used a computational model to simulate various ablation patterns and determine their effect on atrial global and regional mechanical function. METHODS: A coupled finite-element and hemodynamic circuit model of the left atrium that represents the regional and global mechanics in paroxysmal AF patients was modified to simulate different ablation patterns: step-wise pulmonary vein isolation (PVI), wide area circumferential ablation (WACA), and a posterior ablation developed by nContact, Inc (Morrisville, NC, USA). Atrial pressure-volume relationships and regional wall motion were compared among the models. RESULTS: Ablation increased passive stiffness and decreased active work performed by the atrium. Active emptying volume decreased with increasing scar by up to 44% (11 mL) at a scar volume of 31%. At matched scar volumes, WACA decreased active emptying more severely than PVI and nContact. Similarly, wall motion was depressed most in the WACA model because WACA involved portions of the lateral wall with higher baseline motion. CONCLUSION: Simulated ablation depressed atrial mechanical function to an extent that depended on both scar volume and location, primarily through reducing active emptying. Placing ablation scar in regions with high baseline motion resulted in greater depression of active function, while ablation of the posterior wall was less disruptive.

Network Architecture Predisposes an Enzyme to Either Pharmacologic or Genetic Targeting.

Chemical inhibition and genetic knockdown of enzymes are not equivalent in cells, but network-level mechanisms that cause discrepancies between knockdown and inhibitor perturbations are not understood. Here we report that enzymes regulated by negative feedback are robust to knockdown but susceptible to inhibition. Using the Raf-MEK-ERK kinase cascade as a model system, we find that ERK activation is resistant to genetic knockdown of MEK but susceptible to a comparable degree of chemical MEK inhibition. We demonstrate that negative feedback from ERK to Raf causes this knockdown-versus-inhibitor discrepancy in vivo. Exhaustive mathematical modeling of three-tiered enzyme cascades suggests that this result is general: negative autoregulation or feedback favors inhibitor potency, whereas positive autoregulation or feedback favors knockdown potency. Our findings provide a rationale for selecting pharmacologic versus genetic perturbations in vivo and point out the dangers of using knockdown approaches in search of drug targets.

Changes in Global and Regional Mechanics Due to Atrial Fibrillation: Insights from a Coupled Finite-Element and Circulation Model.

Atrial fibrillation (AF) is a rhythm disorder with rapidly increasing prevalence due to the aging of the population. AF triggers structural remodeling and a gradual loss of function; however, the relative contributions of specific features of AF-induced remodeling to changes in atrial mechanical function are unclear. We constructed and validated a finite-element model (FEM) of the normal human left atrium using anatomic information from cardiac magnetic resonance imaging, material properties and fiber orientations from published studies, and an iterative algorithm to estimate unloaded geometry. We coupled the FEM to a circuit model to capture hemodynamic interactions between the atrium, pulmonary circulation, and left ventricle. The normal model reproduced measured volumes within 1 SD, as well as most metrics of regional mechanics. Using this validated human model as a starting point, we explored the impact of individual features of atrial remodeling on atrial mechanics and found that a combination of dilation, increased pressure, and fibrosis can explain most of the observed changes in mechanics in patients with paroxysmal AF. However, only impaired ventricular relaxation could reproduce the increased reliance on active emptying we observed in these patients. The resulting model provides new insight into the mechanics of AF and a platform for exploring future therapies.

Wall-motion based analysis of global and regional left atrial mechanics.

Atrial fibrillation is an increasingly prevalent cardiovascular disease; changes in atrial structure and function induced by atrial fibrillation and its treatments are often spatially heterogeneous. However, spatial heterogeneity of function is difficult to assess with standard imaging techniques. This paper describes a method to assess global and regional mechanical function by combining cardiac magnetic resonance imaging and finite-element surface fitting. We used this fitted surface to derive measures of left atrial volume, regional motion, and spatial heterogeneity of motion in 23 subjects, including healthy volunteers and atrial fibrillation patients. We fit the surfaces using a Newton optimization scheme in under 1 min on a standard laptop, with a root mean square error of 2.3 ± 0.5 mm, less than 9% of the mean fitted radius, and an inter-operator variability of less than 10%. Fitted surfaces showed clear definition of the phases of left atrial motion (filling, passive emptying, active contraction) in both volume-time and regional radius-time curves. Averaged surfaces of healthy volunteers and atrial fibrillation patients provided evidence of substantial regional variation in both amount and timing of regional motion, indicating spatial heterogeneity of function, even in healthy adults.