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Nonequilibrium arrhythmic states and transitions in a mathematical model for diffuse fibrosis in human cardiac tissue.

ABSTRACT: We present a comprehensive numerical study of spiral- and scroll-wave dynamics in a state-of-the-art mathematical model for human ventricular tissue with fiber rotation, transmural heterogeneity, myocytes, and fibroblasts. Our mathematical model introduces fibroblasts randomly, to mimic diffuse fibrosis, in the ten Tusscher-Noble-Noble-Panfilov (TNNP) model for human ventricular tissue; the passive fibroblasts in our model do not exhibit an action potential in the absence of coupling with myocytes; and we allow for a coupling between nearby myocytes and fibroblasts. Our study of a single myocyte-fibroblast (MF) composite, with a single myocyte coupled to N(f) fibroblasts via a gap-junctional conductance G(gap), reveals five qualitatively different responses for this composite. Our investigations of two-dimensional domains with a random distribution of fibroblasts in a myocyte background reveal that, as the percentage P(f) of fibroblasts increases, the conduction velocity of a plane wave decreases until there is conduction failure. If we consider spiral-wave dynamics in such a medium we find, in two dimensions, a variety of nonequilibrium states, temporally periodic, quasiperiodic, chaotic, and quiescent, and an intricate sequence of transitions between them; we also study the analogous sequence of transitions for three-dimensional scroll waves in a three-dimensional version of our mathematical model that includes both fiber rotation and transmural heterogeneity. We thus elucidate random-fibrosis-induced nonequilibrium transitions, which lead to conduction block for spiral waves in two dimensions and scroll waves in three dimensions. We explore possible experimental implications of our mathematical and numerical studies for plane-, spiral-, and scroll-wave dynamics in cardiac tissue with fibrosis.

SUBMITTER: Majumder R

PROVIDER: S-EPMC3466321 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Nonequilibrium arrhythmic states and transitions in a mathematical model for diffuse fibrosis in human cardiac tissue.

Majumder Rupamanjari R Nayak Alok Ranjan AR Pandit Rahul R

PloS one 20121008 10

We present a comprehensive numerical study of spiral- and scroll-wave dynamics in a state-of-the-art mathematical model for human ventricular tissue with fiber rotation, transmural heterogeneity, myocytes, and fibroblasts. Our mathematical model introduces fibroblasts randomly, to mimic diffuse fibrosis, in the ten Tusscher-Noble-Noble-Panfilov (TNNP) model for human ventricular tissue; the passive fibroblasts in our model do not exhibit an action potential in the absence of coupling with myocyt ...[more]

PMID: 23071505

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Project description:Background Cardiac fibrosis is the excessive deposition of extracellular matrix in the heart, triggered by a cardiac insult, aging, genetics, or environmental factors. Molecular imaging of the cardiac extracellular matrix with targeted probes could improve diagnosis and treatment of heart disease. However, although this technology has been used to demonstrate focal scarring arising from myocardial infarction, its capacity to demonstrate extracellular matrix expansion and diffuse cardiac fibrosis has not been assessed. Methods and Results Here, we report the use of collagen-targeted peptides labeled with near-infrared fluorophores for the detection of diffuse cardiac fibrosis in the β2-AR (β-2-adrenergic receptor) overexpressing mouse model and in ischemic human hearts. Two approaches were evaluated, the first based on a T peptide that binds matrix metalloproteinase-2-proteolyzed collagen IV, and the second on the cyclic peptide EP-3533, which targets collagen I. The systemic and cardiac uptakes of both peptides (intravenously administered) were quantified ex vivo by near-infrared imaging of whole organs, tissue sections, and heart lysates. The peptide accumulation profiles corresponded to an immunohistochemically-validated increase in collagen types I and IV in hearts of transgenic mice versus littermate controls. The T peptide could encouragingly demonstrate both the intermediate (7 months old) and severe (11 months old) cardiomyopathic phenotypes. Co-immunostainings of fluorescent peptides and collagens, as well as reduced collagen binding of a control peptide, confirmed the collagen specificity of the tracers. Qualitative analysis of heart samples from patients with ischemic cardiomyopathy compared with nondiseased donors supported the collagen-enhancement capabilities of these peptides also in the clinical settings. Conclusions Together, these observations demonstrate the feasibility and translation potential of molecular imaging with collagen-binding peptides for noninvasive imaging of diffuse cardiac fibrosis.

Dataset Information

Nonequilibrium arrhythmic states and transitions in a mathematical model for diffuse fibrosis in human cardiac tissue.

Publications

Nonequilibrium arrhythmic states and transitions in a mathematical model for diffuse fibrosis in human cardiac tissue.

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