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Arrhythmogenic remodeling of ?2 versus ?1 adrenergic signaling in the human failing heart.

ABSTRACT: Arrhythmia is the major cause of death in patients with heart failure, for which ?-adrenergic receptor blockers are a mainstay therapy. But the role of ?-adrenergic signaling in electrophysiology and arrhythmias has never been studied in human ventricles.We used optical imaging of action potentials and [Ca(2+)]i transients to compare the ?1- and ?2-adrenergic responses in left ventricular wedge preparations of human donor and failing hearts. ?1-Stimulation significantly increased conduction velocity, shortened action potential duration, and [Ca(2+)]i transients duration (CaD) in donor but not in failing hearts, because of desensitization of ?1-adrenergic receptor in heart failure. In contrast, ?2-stimulation increased conduction velocity in both donor and failing hearts but shortened action potential duration only in failing hearts. ?2-Stimulation also affected transmural heterogeneity in action potential duration but not in [Ca(2+)]i transients duration. Both ?1- and ?2-stimulation augmented the vulnerability and frequency of ectopic activity and enhanced substrates for ventricular tachycardia in failing, but not in donor, hearts. Both ?1- and ?2-stimulation enhanced Purkinje fiber automaticity, whereas only ?2-stimulation promoted Ca-mediated premature ventricular contractions in heart failure.During end-stage heart failure, ?2-stimulation creates arrhythmogenic substrates via conduction velocity regulation and transmurally heterogeneous repolarization. ?2-Stimulation is, therefore, more arrhythmogenic than ?1-stimulation. In particular, ?2-stimulation increases the transmural difference between [Ca(2+)]i transients duration and action potential duration, which facilitates the formation of delayed afterdepolarizations.

SUBMITTER: Lang D

PROVIDER: S-EPMC4608687 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Arrhythmogenic remodeling of β2 versus β1 adrenergic signaling in the human failing heart.

Lang Di D Holzem Katherine K Kang Chaoyi C Xiao Mengqian M Hwang Hye Jin HJ Ewald Gregory A GA Yamada Kathryn A KA Efimov Igor R IR

Circulation. Arrhythmia and electrophysiology 20150211 2

<h4>Background</h4>Arrhythmia is the major cause of death in patients with heart failure, for which β-adrenergic receptor blockers are a mainstay therapy. But the role of β-adrenergic signaling in electrophysiology and arrhythmias has never been studied in human ventricles.<h4>Methods and results</h4>We used optical imaging of action potentials and [Ca(2+)]i transients to compare the β1- and β2-adrenergic responses in left ventricular wedge preparations of human donor and failing hearts. β1-Stim ...[more]

PMID: 25673629

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Project description:RationaleIntercellular uncoupling and Ca2+ (Ca) mishandling can initiate triggered ventricular arrhythmias. Spontaneous Ca release activates inward current which depolarizes membrane potential (Vm) and can trigger action potentials in isolated myocytes. However, cell-cell coupling in intact hearts limits local depolarization and may protect hearts from this arrhythmogenic mechanism. Traditional optical mapping lacks the spatial resolution to assess coupling of individual myocytes.ObjectiveWe investigate local intercellular coupling in Ca-induced depolarization in intact hearts, using confocal microscopy to measure local Vm and intracellular [Ca] simultaneously.Methods and resultsWe used isolated Langendorff-perfused hearts from control (CTL) and heart failure (HF) mice (HF induced by transaortic constriction). In CTL hearts, 1.4% of myocytes were poorly synchronized with neighboring cells and exhibited asynchronous (AS) Ca transients. These AS myocytes were much more frequent in HF (10.8% of myocytes, P<0.05 versus CTL). Local Ca waves depolarized Vm in HF but not CTL hearts, suggesting weaker gap junction coupling in HF-AS versus CTL-AS myocytes. Cell-cell coupling was assessed by calcein fluorescence recovery after photobleach during intracellular [Ca] recording. All regions in CTL hearts exhibited faster calcein diffusion than in HF, with HF-AS myocyte being slowest. In HF-AS, enhancing gap junction conductance (with rotigaptide) increased coupling and suppressed Vm depolarization during Ca waves. Conversely, in CTL hearts, gap junction inhibition (carbenoxolone) decreased coupling and allowed Ca wave-induced depolarizations. Synchronization of Ca wave initiation and triggered action potentials were observed in HF hearts and computational models.ConclusionsWell-coupled CTL myocytes are effectively voltage-clamped during Ca waves, protecting the heart from triggered arrhythmias. Spontaneous Ca waves are much more common in HF myocytes and these AS myocytes are also poorly coupled, enabling local Ca-induced inward current of sufficient source strength to overcome a weakened current sink to depolarize Vm and trigger action potentials.

Project description:RationaleCardiac resynchronization therapy (CRT) is the only heart failure (HF) therapy documented to improve left ventricular function and reduce mortality. The underlying mechanisms are incompletely understood. Although β-adrenergic signaling has been studied extensively, the effect of CRT on cholinergic signaling is unexplored.ObjectiveWe hypothesized that remodeling of cholinergic signaling plays an important role in the aberrant calcium signaling and depressed contractile and β-adrenergic responsiveness in dyssynchronous HF that are restored by CRT.Methods and resultsCanine tachypaced dyssynchronous HF and CRT models were generated to interrogate responses specific to dyssynchronous versus resynchronized ventricular contraction during hemodynamic decompensation. Echocardiographic, electrocardiographic, and invasive hemodynamic data were collected from normal controls, dyssynchronous HF and CRT models. Left ventricular tissue was used for biochemical analyses and functional measurements (calcium transient, sarcomere shortening) from isolated myocytes (n=42-104 myocytes per model; 6-9 hearts per model). Human left ventricular myocardium was obtained for biochemical analyses from explanted failing (n=18) and nonfailing (n=7) hearts. The M2 subtype of muscarinic acetylcholine receptors was upregulated in human and canine HF compared with nonfailing controls. CRT attenuated the increased M2 subtype of muscarinic acetylcholine receptor expression and Gαi coupling and enhanced M3 subtype of muscarinic acetylcholine receptor expression in association with enhanced calcium cycling, sarcomere shortening, and β-adrenergic responsiveness. Despite model-dependent remodeling, cholinergic stimulation completely abolished isoproterenol-induced triggered activity in both dyssynchronous HF and CRT myocytes.ConclusionsRemodeling of cholinergic signaling is a critical pathological component of human and canine HF. Differential remodeling of cholinergic signaling represents a novel mechanism for enhancing sympathovagal balance with CRT and may identify new targets for treatment of systolic HF.

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Arrhythmogenic remodeling of ?2 versus ?1 adrenergic signaling in the human failing heart.

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Arrhythmogenic remodeling of β2 versus β1 adrenergic signaling in the human failing heart.

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