Etiology-Specific Remodeling in Ventricular Tissue of Heart Failure Patients and Its Implications for Computational Modeling of Electrical Conduction

With an estimated 64.3 million cases worldwide, heart failure (HF) imposes an enormous burden on healthcare systems. Sudden death from arrhythmia is the major cause of mortality in HF patients. Computational modeling of the failing heart provides insights into mechanisms of arrhythmogenesis, risk stratification of patients, and clinical treatment. However, the lack of a clinically informed approach to model cardiac tissues in HF hinders progress in developing patient-specific strategies. Here, we provide a microscopy-based foundation for modeling conduction in HF tissues. We acquired 2D images of left ventricular tissues from HF patients (n = 16) and donors (n = 5). The composition and heterogeneity of fibrosis were quantified at a sub-micrometer resolution over an area of 1 mm2. From the images, we constructed computational bidomain models of tissue electrophysiology. We computed local upstroke velocities of the membrane voltage and anisotropic conduction velocities (CV). The non-myocyte volume fraction was higher in HF than donors (39.68 ± 14.23 vs. 22.09 ± 2.72%, p < 0.01), and higher in ischemic (IC) than nonischemic (NIC) cardiomyopathy (47.2 ± 16.18 vs. 32.16 ± 6.55%, p < 0.05). The heterogeneity of fibrosis within each subject was highest for IC (27.1 ± 6.03%) and lowest for donors (7.47 ± 1.37%) with NIC (15.69 ± 5.76%) in between. K-means clustering of this heterogeneity discriminated IC and NIC with an accuracy of 81.25%. The heterogeneity in CV increased from donor to NIC to IC tissues. CV decreased with increasing fibrosis for longitudinal (R2 = 0.28, p < 0.05) and transverse conduction (R2 = 0.46, p < 0.01). The tilt angle of the CV vectors increased 2.1° for longitudinal and 0.91° for transverse conduction per 1% increase in fibrosis. Our study suggests that conduction fundamentally differs in the two etiologies due to the characteristics of fibrosis. Our study highlights the importance of the etiology-specific modeling of HF tissues and integration of medical history into electrophysiology models for personalized risk stratification and treatment planning.

Location and coupling interval of an ectopic excitation determine the initiation of atrial fibrillation from the pulmonary veins

Background and Objective: Ectopic beats originating from the pulmonary vein (PV) trigger atrial fibrillation (AF). The purpose of this study was to clarify the electrophysiological determinant of AF initiation from the PVs. Methods: Pacing studies were performed with a single extra stimulus mimicking an ectopic beat in the left superior pulmonary veins (LSPVs) in 62 patients undergoing AF ablation. Inducibility of AF, effective refractory period (ERP) and conduction properties within the PVs were analyzed. Results: A single extra stimulus in LSPV induced AF in 20 patients (32% of all patients) at the mean coupling interval (CI) of 172 ms. A CI-dependent anisotropic conduction at the AF onset was visualized in a 3D-mapping. Onset of AF was site-specific with reproducibility in each individual. Mean ERP in LSPV in the AF inducible group was shorter than that in the AF non-inducible group (182 ± 55 ms vs 254 ± 51 ms, P<0.0001). LSPV ERP dispersion was greater in the AF inducible group than in the AF non-inducible group (45 ± 28 ms vs 27 ± 19 ms, P<0.01). Circumferential intra-PV conduction time (IPVCT) exhibited decremental properties in response to shortening of CI, and the prolongation of IPVCT in the AF inducible site was greater than that in the AF non-inducible site (P<0.05) in each individual. Conclusions: Location and coupling interval of an ectopic excitation ultimately determine the initiation of AF from the PVs. ERP dispersion and circumferential conduction delay may lead to anisotropic conduction and reentry within the PVs that initiate AF.

Anisotropic Cardiac Conduction

Anisotropy is the property of directional dependence. In cardiac tissue, conduction velocity is anisotropic and its orientation is determined by myocyte direction. Cell shape and size, excitability, myocardial fibrosis, gap junction distribution and function are all considered to contribute to anisotropic conduction. In disease states, anisotropic conduction may be enhanced, and is implicated, in the genesis of pathological arrhythmias. The principal mechanism responsible for enhanced anisotropy in disease remains uncertain. Possible contributors include changes in cellular excitability, changes in gap junction distribution or function and cellular uncoupling through interstitial fibrosis. It has recently been demonstrated that myocyte orientation may be identified using diffusion tensor magnetic resonance imaging in explanted hearts, and multisite pacing protocols have been proposed to estimate myocyte orientation and anisotropic conduction in vivo. These tools have the potential to contribute to the understanding of the role of myocyte disarray and anisotropic conduction in arrhythmic states.

Repression of Pdzrn3 is required for heart maturation and protects against heart failure

Heart failure is the final common stage of most cardiopathies. Cardiomyocytes connect with others via their extremities by intercalated disk protein complexes. This planar and directional organization of myocytes is crucial for mechanical coupling and anisotropic conduction of the electric signal in the heart. One of the hallmarks of heart failure is alterations in the contact sites between cardiomyocytes. Yet no factor on its own is known to coordinate cardiomyocyte polarized organization. We report enhanced levels of an ubiquitine ligase Pdzrn3 in diseased hypertrophic human and mouse myocardium, which correlates with a loss of cardiomyocyte polarized elongation. We provide evidence that Pdzrn3 has a causative role in heart failure. We found that cardiac Pdzrn3 deficiency protected against heart failure while over expression of Pdzrn3 in mouse cardiomyocytes during the first weeks of life, impaired postnatal cardiomyocyte maturation leading to premature death. Our results reveal a novel signaling pathway that controls a genetic program essential for heart maturation and maintenance of overall geometry, as well as the contractile function of cardiomyocytes, and implicates PDZRN3 as a potential therapeutic target for the prevention of human heart failure.

A new concept of a pseudo-Janus structure: employing a Yin-Yang fish structure film with up/down conversion fluorescence and bi-anisotropic conduction to represent the pseudo-Janus structure as a case study

The pseudo-Janus structure is advanced and the Yin-Yang fish structure film is employed to represent the pseudo-Janus structure as a case study.

But what about...: cosmic rays, magnetic fields, conduction, and viscosity in galaxy formation

ABSTRACT We present and study a large suite of high-resolution cosmological zoom-in simulations, using the FIRE-2 treatment of mechanical and radiative feedback from massive stars, together with explicit treatment of magnetic fields, anisotropic conduction and viscosity (accounting for saturation and limitation by plasma instabilities at high β), and cosmic rays (CRs) injected in supernovae shocks (including anisotropic diffusion, streaming, adiabatic, hadronic and Coulomb losses). We survey systems from ultrafaint dwarf ($M_{\ast }\sim 10^{4}\, \mathrm{M}_{\odot }$, $M_{\rm halo}\sim 10^{9}\, \mathrm{M}_{\odot }$) through Milky Way/Local Group (MW/LG) masses, systematically vary uncertain CR parameters (e.g. the diffusion coefficient κ and streaming velocity), and study a broad ensemble of galaxy properties [masses, star formation (SF) histories, mass profiles, phase structure, morphologies, etc.]. We confirm previous conclusions that magnetic fields, conduction, and viscosity on resolved ($\gtrsim 1\,$ pc) scales have only small effects on bulk galaxy properties. CRs have relatively weak effects on all galaxy properties studied in dwarfs ($M_{\ast } \ll 10^{10}\, \mathrm{M}_{\odot }$, $M_{\rm halo} \lesssim 10^{11}\, \mathrm{M}_{\odot }$), or at high redshifts (z ≳ 1–2), for any physically reasonable parameters. However, at higher masses ($M_{\rm halo} \gtrsim 10^{11}\, \mathrm{M}_{\odot }$) and z ≲ 1–2, CRs can suppress SF and stellar masses by factors ∼2–4, given reasonable injection efficiencies and relatively high effective diffusion coefficients $\kappa \gtrsim 3\times 10^{29}\, {\rm cm^{2}\, s^{-1}}$. At lower κ, CRs take too long to escape dense star-forming gas and lose their energy to collisional hadronic losses, producing negligible effects on galaxies and violating empirical constraints from spallation and γ-ray emission. At much higher κ CRs escape too efficiently to have appreciable effects even in the CGM. But around $\kappa \sim 3\times 10^{29}\, {\rm cm^{2}\, s^{-1}}$, CRs escape the galaxy and build up a CR-pressure-dominated halo which maintains approximate virial equilibrium and supports relatively dense, cool (T ≪ 106 K) gas that would otherwise rain on to the galaxy. CR ‘heating’ (from collisional and streaming losses) is never dominant.