Phosphatidylinositol-4,5-Bisphosphate Binding to Amphiphysin-II Modulates T-Tubule Remodeling: Implications for Heart Failure.

BIN1 (amphyphysin-II) is a structural protein involved in T-tubule (TT) formation and phosphatidylinositol-4,5-bisphosphate (PIP2) is responsible for localization of BIN1 to sarcolemma. The goal of this study was to determine if PIP2-mediated targeting of BIN1 to sarcolemma is compromised during the development of heart failure (HF) and is responsible for TT remodeling. Immunohistochemistry showed co-localization of BIN1, Cav1.

Role of t-tubule remodeling on mechanisms of abnormal calcium release during heart failure development in canine ventricle.

The goal of this work was to investigate the role of t-tubule (TT) remodeling in abnormal Ca cycling in ventricular myocytes of failing dog hearts. Heart failure (HF) was induced using rapid right ventricular pacing. Extensive changes in echocardiographic parameters, including left and right ventricular dilation and systolic dysfunction, diastolic dysfunction, elevated left ventricular filling pressures, and abnormal cardiac mechanics, indicated that severe HF developed.

Attenuation of Oxidative Injury With Targeted Expression of NADPH Oxidase 2 Short Hairpin RNA Prevents Onset and Maintenance of Electrical Remodeling in the Canine Atrium: A Novel Gene Therapy Approach to Atrial Fibrillation.

Background: Atrial fibrillation (AF) is the most common heart rhythm disorder in adults and a major cause of stroke. Unfortunately, current treatments of AF are suboptimal because they are not targeted to the molecular mechanisms underlying AF. Using a highly novel gene therapy approach in a canine, rapid atrial pacing model of AF, we demonstrate that NADPH oxidase 2 (NOX2) generated oxidative injury causes upregulation of a constitutively active form of acetylcholine-dependent K current (), called ; this is an important mechanism underlying not only the genesis, but also the perpetuation of electric remodeling in the intact, fibrillating atrium.

Triggered Ca Waves Induce Depolarization of Maximum Diastolic Potential and Action Potential Prolongation in Dog Atrial Myocytes.

Background: We have identified a novel form of abnormal Ca wave activity in normal and failing dog atrial myocytes which occurs during the action potential (AP) and is absent during diastole. The goal of this study was to determine if triggered Ca waves affect cellular electrophysiological properties.

Methods: Simultaneous recordings of intracellular Ca and APs allowed measurements of maximum diastolic potential and AP duration during triggered calcium waves (TCWs) in isolated dog atrial myocytes.

Remodeling Promotes Proarrhythmic Disruption of Calcium Homeostasis in Failing Atrial Myocytes.

It is well known that heart failure (HF) typically coexists with atrial fibrillation (AF). However, until now, no clear mechanism has been established that relates HF to AF. In this study, we apply a multiscale computational framework to establish a mechanistic link between atrial myocyte structural remodeling in HF and AF.

Region-specific parasympathetic nerve remodeling in the left atrium contributes to creation of a vulnerable substrate for atrial fibrillation.

Atrial fibrillation (AF) is the most common heart rhythm disorder and a major cause of stroke. Unfortunately, current therapies for AF are suboptimal, largely because the molecular mechanisms underlying AF are poorly understood. Since the autonomic nervous system is thought to increase vulnerability to AF, we used a rapid atrial pacing (RAP) canine model to investigate the anatomic and electrophysiological characteristics of autonomic remodeling in different regions of the left atrium.

Oxidative stress creates a unique, CaMKII-mediated substrate for atrial fibrillation in heart failure.

The precise mechanisms by which oxidative stress (OS) causes atrial fibrillation (AF) are not known. Since AF frequently originates in the posterior left atrium (PLA), we hypothesized that OS, via calmodulin-dependent protein kinase II (CaMKII) signaling, creates a fertile substrate in the PLA for triggered activity and reentry. In a canine heart failure (HF) model, OS generation and oxidized-CaMKII-induced (Ox-CaMKII-induced) RyR2 and Nav1.

Synchronization of Triggered Waves in Atrial Tissue.

When an atrial cell is paced rapidly, calcium (Ca) waves can form on the cell boundary and propagate to the cell interior. These waves are referred to as "triggered waves" because they are initiated by Ca influx from the L-type Ca channel and occur during the action potential. However, the consequences of triggered waves in atrial tissue are not known.

Interventricular differences in sodium current and its potential role in Brugada syndrome.

Brugada syndrome (BrS) is an inherited disease associated with ST elevation in the right precordial leads, polymorphic ventricular tachycardia (PVT), and sudden cardiac death in adults. Mutations in the cardiac sodium channel account for a large fraction of BrS cases. BrS manifests in the right ventricle (RV), which led us to examine the biophysical and molecular properties of sodium channel in myocytes isolated from the left (LV) and right ventricle.

T-tubule remodeling and increased heterogeneity of calcium release during the progression to heart failure in intact rat ventricle.

A highly organized transverse-tubule (TT) system is essential to normal Ca cycling and cardiac function. We explored the relationship between the progressive disruption of TTs and resulting Ca cycling during the development of heart failure (HF). Confocal imaging was used to measure Ca transients and 2-D z-stack images in left ventricular epicardial myocytes of intact hearts from spontaneously hypertensive rats (SHR) and Wistar-Kyoto control rats.

Triggered intracellular calcium waves in dog and human left atrial myocytes from normal and failing hearts.

Aims: Abnormal intracellular Ca2+ cycling contributes to triggered activity and arrhythmias in the heart. We investigated the properties and underlying mechanisms for systolic triggered Ca2+ waves in left atria from normal and failing dog hearts.

Methods And Results: Intracellular Ca2+ cycling was studied using confocal microscopy during rapid pacing of atrial myocytes (36 °C) isolated from normal and failing canine hearts (ventricular tachypacing model).

Mechanism for Triggered Waves in Atrial Myocytes.

Excitation-contraction coupling in atrial cells is mediated by calcium (Ca) signaling between L-type Ca channels and Ryanodine receptors that occurs mainly at the cell boundary. This unique architecture dictates essential aspects of Ca signaling under both normal and diseased conditions. In this study we apply laser scanning confocal microscopy, along with an experimentally based computational model, to understand the Ca cycling dynamics of an atrial cell subjected to rapid pacing.

Biophysical and molecular comparison of sodium current in cells isolated from canine atria and pulmonary vein.

The collar of the pulmonary vein (PV) is the focal point for the initiation of atrial arrhythmias, but the mechanisms underlying how PV cells differ from neighboring left atrial tissue are unclear. We examined the biophysical and molecular properties of I in cells isolated from the canine pulmonary sleeve and compared the properties to left atrial tissue. PV and left atrial myocytes were isolated and patch clamp techniques were used to record I.

Regional distribution of T-tubule density in left and right atria in dogs.

Background: The peculiarities of transverse tubule (T-tubule) morphology and distribution in the atrium-and how they contribute to excitation-contraction coupling-are just beginning to be understood.

Objectives: The objectives of this study were to determine T-tubule density in the intact, live right and left atria in a large animal and to determine intraregional differences in T-tubule organization within each atrium.

Methods: Using confocal microscopy, T-tubules were imaged in both atria in intact, Langendorf-perfused normal dog hearts loaded with di-4-ANEPPS.

Constitutive Expression of a Dominant-Negative TGF-β Type II Receptor in the Posterior Left Atrium Leads to Beneficial Remodeling of Atrial Fibrillation Substrate.

Rationale: Fibrosis is an important structural contributor to formation of atrial fibrillation (AF) substrate in heart failure. Transforming growth factor-β (TGF-β) signaling is thought to be intricately involved in creation of atrial fibrosis.

Objective: We hypothesized that gene-based expression of dominant-negative type II TGF-β receptor (TGF-β-RII-DN) in the posterior left atrium in a canine heart failure model will sufficiently attenuate fibrosis-induced changes in atrial conduction and restitution to decrease AF.

Searching for "order" in atrial fibrillation using electrogram morphology recurrence plots.

Background: Bipolar electrograms recorded during atrial fibrillation (AF) can have an appearance of chaotic/random behavior. The aim of this study was to use a novel electrogram morphology recurrence (EMR) analysis to quantify the level of order in the morphology patterns in AF.

Methods: Rapid atrial pacing was performed in seven dogs at 600bpm for 3 weeks leading to sustained AF.

Preservation of cardiac function by prolonged action potentials in mice deficient of KChIP2.

Inherited ion channelopathies and electrical remodeling in heart disease alter the cardiac action potential with important consequences for excitation-contraction coupling. Potassium channel-interacting protein 2 (KChIP2) is reduced in heart failure and interacts under physiological conditions with both Kv4 to conduct the fast-recovering transient outward K(+) current (Ito,f) and with CaV1.2 to mediate the inward L-type Ca(2+) current (ICa,L).

Ultrastructural and cellular basis for the development of abnormal myocardial mechanics during the transition from hypertension to heart failure.

Although the development of abnormal myocardial mechanics represents a key step during the transition from hypertension to overt heart failure (HF), the underlying ultrastructural and cellular basis of abnormal myocardial mechanics remains unclear. We therefore investigated how changes in transverse (T)-tubule organization and the resulting altered intracellular Ca(2+) cycling in large cell populations underlie the development of abnormal myocardial mechanics in a model of chronic hypertension. Hearts from spontaneously hypertensive rats (SHRs; n = 72) were studied at different ages and stages of hypertensive heart disease and early HF and were compared with age-matched control (Wistar-Kyoto) rats (n = 34).

Inhibition of the late sodium current slows t-tubule disruption during the progression of hypertensive heart disease in the rat.

The treatment of heart failure (HF) is challenging and morbidity and mortality are high. The goal of this study was to determine if inhibition of the late Na(+) current with ranolazine during early hypertensive heart disease might slow or stop disease progression. Spontaneously hypertensive rats (aged 7 mo) were subjected to echocardiographic study and then fed either control chow (CON) or chow containing 0.

Can triggered arrhythmias arise from propagation of calcium waves between cardiac myocytes?

Intracellular Ca2+ overload can induce regenerative Ca2+ waves that activate inward current in cardiac myocytes, allowing the cell membrane to achieve threshold. The result is a triggered extrasystole that can, under the right conditions, lead to sustained triggered arrhythmias. In this review, we consider the issue of whether or not Ca2+ waves can travel between neighboring myocytes and if this intercellular Ca2+ diffusion can involve enough cells over a short enough period of time to actually induce triggered activity in the heart.

Contribution of fibrosis and the autonomic nervous system to atrial fibrillation electrograms in heart failure.

Background: Fibrotic and autonomic remodeling in heart failure (HF) increase vulnerability to atrial fibrillation (AF). Because AF electrograms (EGMs) are thought to reflect the underlying structural substrate, we sought to (1) determine the differences in AF EGMs in normal versus HF atria and (2) assess how fibrosis and nerve-rich fat contribute to AF EGM characteristics in HF.

Methods And Results: AF was induced in 20 normal dogs by vagal stimulation and in 21 HF dogs (subjected to 3 weeks of rapid ventricular pacing at 240 beats per minute).

Arrhythmia triggers in heart failure: the smoking gun of [Ca2+]i dysregulation.

Among the most serious problems associated with heart failure is the increased likelihood of life-threatening arrhythmias. Both triggered and reentrant arrhythmias in heart failure may arise as a result of aberrant intracellular Ca cycling. This article presents some new ideas, based on recent studies, about how altered Ca cycling in heart failure might serve as the cellular basis for arrhythmogenesis.

Targeted nonviral gene-based inhibition of Gα(i/o)-mediated vagal signaling in the posterior left atrium decreases vagal-induced atrial fibrillation.

Background: Pharmacologic and ablative therapies for atrial fibrillation (AF) have suboptimal efficacy. Newer gene-based approaches that target specific mechanisms underlying AF are likely to be more efficacious in treating AF. Parasympathetic signaling appears to be an important contributor to AF substrate.

Autonomic remodeling in the left atrium and pulmonary veins in heart failure: creation of a dynamic substrate for atrial fibrillation.

Background: Atrial fibrillation (AF) is commonly associated with congestive heart failure (CHF). The autonomic nervous system is involved in the pathogenesis of both AF and CHF. We examined the role of autonomic remodeling in contributing to AF substrate in CHF.