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Behavior of ectopic surface: effects of beta-adrenergic stimulation and uncoupling.

ABSTRACT: By using both experimental and theoretical means, we have addressed the progression of ectopic activity from individual cardiac cells to a multicellular two-dimensional network. Experimental conditions that favor ectopic activity have been created by local perfusion of a small area of cardiomyocyte network (I-zone) with an isoproterenol-heptanol containing solution. The application of this solution initially slowed down and then fully blocked wave propagation inside the I-zone. After a brief lag period, ectopically active cells appeared in the I-zone, followed by evolution of the ectopic clusters into slowly propagating waves. The changing pattern of colliding and expanding ectopic waves confined to the I-zone persisted for as long as the isoproterenol-heptanol environment was present. On restoration of the control environment, the ectopic waves from the I-zone broke out into the surrounding network causing arrhythmias. The observed sequence of events was also modeled by FitzHugh-Nagumo equations and included a cell's arrangement of two adjacent square regions of 20 x 20 cells. The control zone consisted of well-connected, excitable cells, and the I-zone was made of weakly coupled cells (heptanol effect), which became spontaneously active as time evolved (isoproterenol effect). The dynamic events in the system have been studied numerically with the use of a finite difference method. Together, our experimental and computational data have revealed that the combination of low coupling, increased excitability, and spatial heterogeneity can lead to the development of ectopic waves confined to the injured network. This transient condition appears to serve as an essential step for the ectopic activity to "mature" before escaping into the surrounding control network.

SUBMITTER: Arutunyan A

PROVIDER: S-EPMC3031858 | biostudies-literature | 2003 Dec

REPOSITORIES: biostudies-literature

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Behavior of ectopic surface: effects of beta-adrenergic stimulation and uncoupling.

Arutunyan Ara A Pumir Alain A Krinsky Valentin V Swift Luther L Sarvazyan Narine N

American journal of physiology. Heart and circulatory physiology 20030731 6

By using both experimental and theoretical means, we have addressed the progression of ectopic activity from individual cardiac cells to a multicellular two-dimensional network. Experimental conditions that favor ectopic activity have been created by local perfusion of a small area of cardiomyocyte network (I-zone) with an isoproterenol-heptanol containing solution. The application of this solution initially slowed down and then fully blocked wave propagation inside the I-zone. After a brief lag ...[more]

PMID: 12893638

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Project description:AimsThe benefit of the β1-adrenergic receptor (β1-AR) agonist dobutamine for treatment of acute heart failure in peripartum cardiomyopathy (PPCM) is controversial. Cardiac STAT3 expression is reduced in PPCM patients. Mice carrying a cardiomyocyte-restricted deletion of STAT3 (CKO) develop PPCM. We hypothesized that STAT3-dependent signalling networks may influence the response to β-AR agonist treatment in PPCM patients and analysed this hypothesis in CKO mice.Methods and resultsFollow-up analyses in 27 patients with severe PPCM (left ventricular ejection fraction ≤25%) revealed that 19 of 20 patients not obtaining dobutamine improved cardiac function. All seven patients obtaining dobutamine received heart transplantation (n = 4) or left ventricular assist devices (n = 3). They displayed diminished myocardial triglyceride, pyruvate, and lactate content compared with non-failing controls. The β-AR agonist isoproterenol (Iso) induced heart failure with high mortality in postpartum female, in non-pregnant female and in male CKO, but not in wild-type mice. Iso induced heart failure and high mortality in CKO mice by impairing fatty acid and glucose uptake, thereby generating a metabolic deficit. The latter was governed by disturbed STAT3-dependent signalling networks, microRNA-199a-5p, microRNA-7a-5p, insulin/glucose transporter-4, and neuregulin/ErbB signalling. The resulting cardiac energy depletion and oxidative stress promoted dysfunction and cardiomyocyte loss inducing irreversible heart failure, which could be attenuated by the β1-AR blocker metoprolol or glucose-uptake-promoting drugs perhexiline and etomoxir.ConclusionsIso impairs glucose uptake, induces energy depletion, oxidative stress, dysfunction, and death in STAT3-deficient cardiomyocytes mainly via β1-AR stimulation. These cellular alterations may underlie the dobutamine-induced irreversible heart failure progression in PPCM patients who frequently display reduced cardiac STAT3 expression.

Project description:Rationaleβ-Adrenergic receptor stimulation produces sarcoplasmic reticulum Ca(2+) overload and delayed afterdepolarizations in isolated ventricular myocytes. How delayed afterdepolarizations are synchronized to overcome the source-sink mismatch and produce focal arrhythmia in the intact heart remains unknown.ObjectiveTo determine whether local β-adrenergic receptor stimulation produces spatiotemporal synchronization of delayed afterdepolarizations and to examine the effects of tissue geometry and cell-cell coupling on the induction of focal arrhythmia.Methods and resultsSimultaneous optical mapping of transmembrane potential and Ca(2+) transients was performed in normal rabbit hearts during subepicardial injections (50 μL) of norepinephrine (NE) or control (normal Tyrode's solution). Local NE produced premature ventricular complexes (PVCs) from the injection site that were dose-dependent (low-dose [30-60 μmol/L], 0.45±0.62 PVCs per injection; high-dose [125-250 μmol/L], 1.33±1.46 PVCs per injection; P<0.0001) and were inhibited by propranolol. NE-induced PVCs exhibited abnormal voltage-Ca(2+) delay at the initiation site and were inhibited by either sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase inhibition or reduced perfusate [Ca(2+)], which indicates a Ca(2+)-mediated mechanism. NE-induced PVCs were more common at right ventricular than at left ventricular sites (1.48±1.50 versus 0.55±0.89, P<0.01), and this was unchanged after chemical ablation of endocardial Purkinje fibers, which suggests that source-sink interactions may contribute to the greater propensity to right ventricular PVCs. Partial gap junction uncoupling with carbenoxolone (25 μmol/L) increased focal activity (2.18±1.43 versus 1.33±1.46 PVCs per injection, P<0.05), which further supports source-sink balance as a critical mediator of Ca(2+)-induced PVCs.ConclusionsThese data provide the first experimental demonstration that localized β-adrenergic receptor stimulation produces spatiotemporal synchronization of sarcoplasmic reticulum Ca(2+) overload and release in the intact heart and highlight the critical nature of source-sink balance in initiating focal arrhythmias.

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Behavior of ectopic surface: effects of beta-adrenergic stimulation and uncoupling.

Publications

Behavior of ectopic surface: effects of beta-adrenergic stimulation and uncoupling.

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