Suppression of ventricular arrhythmias by targeting late L-type Ca2+ current.

Ventricular arrhythmias, a leading cause of sudden cardiac death, can be triggered by cardiomyocyte early afterdepolarizations (EADs). EADs can result from an abnormal late activation of L-type Ca2+ channels (LTCCs). Current LTCC blockers (class IV antiarrhythmics), while effective at suppressing EADs, block both early and late components of ICa,L, compromising inotropy.

Antiarrhythmic Hit to Lead Refinement in a Dish Using Patient-Derived iPSC Cardiomyocytes.

Ventricular cardiac arrhythmia (VA) arises in acquired or congenital heart disease. Long QT syndrome type-3 (LQT3) is a congenital form of VA caused by cardiac sodium channel (I) SCN5A mutations that prolongs cardiac action potential (AP) and enhances I current. Mexiletine inhibits I and shortens the QT interval in LQT3 patients.

Atrial Fibrillation Initiated by Early Afterdepolarization-Mediated Triggered Activity during Acute Oxidative Stress: Efficacy of Late Sodium Current Blockade.

Background: The mechanism of Atrial Fibrillation (AF) that emerges spontaneously during acute oxidative stress is poorly defined and its drug therapy remains suboptimal. We hypothesized that oxidative activation of Ca-calmodulin dependent protein kinase (CaMKII) promotes Early Afterdepolarization-(EAD)-mediated triggered AF in aged fibrotic atria that is sensitive to late Na current (I) blockade.

Method And Results: High-resolution voltage optical mapping of the Left and Right Atrial (LA & RA) epicardial surfaces along with microelectrode recordings were performed in isolated-perfused male Fisher 344 rat hearts in Langendorff setting.

Increased susceptibility of spontaneously hypertensive rats to ventricular tachyarrhythmias in early hypertension.

Hypertension is a risk factor for sudden cardiac death caused by ventricular tachycardia and fibrillation (VT/VF). We hypothesized that, in early hypertension, the susceptibility to stress-induced VT/VF increases. We compared the susceptibility of 5- to 6-month-old male spontaneously hypertensive rats (SHR) and age/sex-matched normotensive rats (NR) to VT/VF during challenge with oxidative stress (H2 O2 ; 0.

Stochastic pacing reveals the propensity to cardiac action potential alternans and uncovers its underlying dynamics.

Key Points: Beat-to-beat alternation (alternans) of the cardiac action potential duration is known to precipitate life-threatening arrhythmias and can be driven by the kinetics of voltage-gated membrane currents or by instabilities in intracellular calcium fluxes. To prevent alternans and associated arrhythmias, suitable markers must be developed to quantify the susceptibility to alternans; previous theoretical studies showed that the eigenvalue of the alternating eigenmode represents an ideal marker of alternans. Using rabbit ventricular myocytes, we show that this eigenvalue can be estimated in practice by pacing these cells at intervals varying stochastically.

Molecular Basis of Hypokalemia-Induced Ventricular Fibrillation.

Background: Hypokalemia is known to promote ventricular arrhythmias, especially in combination with class III antiarrhythmic drugs like dofetilide. Here, we evaluated the underlying molecular mechanisms.

Methods And Results: Arrhythmias were recorded in isolated rabbit and rat hearts or patch-clamped ventricular myocytes exposed to hypokalemia (1.

Perspective: a dynamics-based classification of ventricular arrhythmias.

Despite key advances in the clinical management of life-threatening ventricular arrhythmias, culminating with the development of implantable cardioverter-defibrillators and catheter ablation techniques, pharmacologic/biologic therapeutics have lagged behind. The fundamental issue is that biological targets are molecular factors. Diseases, however, represent emergent properties at the scale of the organism that result from dynamic interactions between multiple constantly changing molecular factors.

Cardiac fibrosis as a determinant of ventricular tachyarrhythmias.

Animal and emerging clinical studies have demonstrated that increased ventricular fibrosis in a setting of reduced repolarization reserve promotes early afterdepolarizations (EADs) and triggered activity that can initiate ventricular tachycardia and ventricular fibrillation (VT/VF). Increased ventricular fibrosis plays a key facilitatory role in allowing oxidative and metabolic stress-induced EADs to manifest as triggered activity causing VT/VF. The lack of such an arrhythmogenic effect by the same stressors in normal non-fibrotic hearts highlights the importance of fibrosis in the initiation of VT/VF.

Cardiac late Na⁺ current: proarrhythmic effects, roles in long QT syndromes, and pathological relationship to CaMKII and oxidative stress.

Myocyte sodium channel current that persists throughout the plateau of the cardiac action potential is referred to as late sodium current (I(Na-L)). The magnitude of I(Na-L) is normally small, but can increase significantly in common acute and chronic pathological settings as a result of inherited and/or acquired Na(+) channelopathies that alter channel opening and closing (ie, gating), location (trafficking), or anchoring and interactions with cytoskeletal proteins. An increase in I(Na-L) reduces repolarization reserve in atrial and ventricular myocytes and prolongs the action potential duration and the QT interval.

Selective inhibition of late sodium current suppresses ventricular tachycardia and fibrillation in intact rat hearts.

Background: Enhanced late inward Na current (INa-L) modulates action potential duration (APD) and plays a key role in the genesis of early afterdepolarizations (EADs) and delayed afterdepolarizations (DADs) and triggered activity.

Objective: The purpose of this study was to define the influence of selective block of INa-L on EAD- and DAD-mediated triggered ventricular tachycardia (VT) and ventricular fibrillation (VF) in intact hearts using (GS967), a selective and potent (IC50 = 0.13 ± 0.

Complete atrial-specific knockout of sodium-calcium exchange eliminates sinoatrial node pacemaker activity.

The origin of sinoatrial node (SAN) pacemaker activity in the heart is controversial. The leading candidates are diastolic depolarization by "funny" current (If) through HCN4 channels (the "Membrane Clock" hypothesis), depolarization by cardiac Na-Ca exchange (NCX1) in response to intracellular Ca cycling (the "Calcium Clock" hypothesis), and a combination of the two ("Coupled Clock"). To address this controversy, we used Cre/loxP technology to generate atrial-specific NCX1 KO mice.

Early afterdepolarizations in cardiac myocytes: beyond reduced repolarization reserve.

Early afterdepolarizations (EADs) are secondary voltage depolarizations during the repolarizing phase of the action potential, which can cause lethal cardiac arrhythmias. The occurrence of EADs requires a reduction in outward current and/or an increase in inward current, a condition called reduced repolarization reserve. However, this generalized condition is not sufficient for EAD genesis and does not explain the voltage oscillations manifesting as EADs.

Bifurcation theory and cardiac arrhythmias.

In this paper we review two types of dynamic behaviors defined by the bifurcation theory that are found to be particularly useful in describing two forms of cardiac electrical instabilities that are of considerable importance in cardiac arrhythmogenesis. The first is action potential duration (APD) alternans with an underlying dynamics consistent with the period doubling bifurcation theory. This form of electrical instability could lead to spatially discordant APD alternans leading to wavebreak and reentrant form of tachyarrhythmias.

Oxidative stress, fibrosis, and early afterdepolarization-mediated cardiac arrhythmias.

Animal and clinical studies have demonstrated that oxidative stress, a common pathophysiological factor in cardiac disease, reduces repolarization reserve by enhancing the L-type calcium current, the late Na, and the Na-Ca exchanger, promoting early afterdepolarizations (EADs) that can initiate ventricular tachycardia and ventricular fibrillation (VT/VF) in structurally remodeled hearts. Increased ventricular fibrosis plays a key facilitatory role in allowing oxidative-stress induced EADs to manifest as triggered activity and VT/VF, since normal non-fibrotic hearts are resistant to arrhythmias when challenged with similar or higher levels of oxidative stress. The findings imply that antifibrotic therapy, in addition to therapies designed to suppress EAD formation at the cellular level, may be synergistic in reducing the risk of sudden cardiac death.

Dynamics of early afterdepolarization-mediated triggered activity in cardiac monolayers.

Early afterdepolarizations (EADs) are voltage oscillations that occur during the repolarizing phase of the cardiac action potential and cause cardiac arrhythmias in a variety of clinical settings. EADs occur in the setting of reduced repolarization reserve and increased inward-over-outward currents, which intuitively explains the repolarization delay but does not mechanistically explain the time-dependent voltage oscillations that are characteristic of EADs. In a recent theoretical study, we identified a dual Hopf-homoclinic bifurcation as a dynamical mechanism that causes voltage oscillations during EADs, depending on the amplitude and kinetics of the L-type Ca(2+) channel (LTCC) current relative to the repolarizing K(+) currents.

Enhanced sensitivity of aged fibrotic hearts to angiotensin II- and hypokalemia-induced early afterdepolarization-mediated ventricular arrhythmias.

Unlike young hearts, aged hearts are highly susceptible to early afterdepolarization (EAD)-mediated ventricular fibrillation (VF). This differential may result from age-related structural remodeling (fibrosis) or electrical remodeling of ventricular myocytes or both. We used optical mapping and microelectrode recordings in Langendorff-perfused hearts and patch-clamp recordings in isolated ventricular myocytes from aged (24-26 mo) and young (3-4 mo) rats to assess susceptibility to EADs and VF during either oxidative stress with ANG II (2 μM) or ionic stress with hypokalemia (2.

Targeting cardiac fibrosis: a new frontier in antiarrhythmic therapy?

Cardiac fibrosis is known to alter cardiac conduction and promote reentry. Recent evidence indicates that fibrosis characterized by increased interstitial collagen accumulation and increased myofibroblast proliferation also promotes enhanced automaticity and early afterdepolarizations (EADs) causing triggered activity. Fibrosis then becomes an effective therapeutic target for the management of lethal cardiac arrhythmias.

Spontaneous ventricular fibrillation in right ventricular failure secondary to chronic pulmonary hypertension.

Background: Right ventricular failure (RVF) in pulmonary hypertension (PH) is associated with increased incidence of sudden death by a poorly explored mechanism. We test the hypothesis that PH promotes spontaneous ventricular fibrillation (VF) during a critical post-PH onset period characterized by a sudden increase in mortality.

Methods And Results: Rats received either a single subcutaneous dose of monocrotaline (MCT, 60 mg/kg) to induce PH-associated RVF (PH, n=24) or saline (control, n=17).

Spontaneous atrial fibrillation initiated by tyramine in canine atria with increased sympathetic nerve sprouting.

Background: Chronic left ventricular myocardial infarction (LVMI) promotes atrial and pulmonary veins (PV) sympathetic nerve sprouting.

Objectives: To test the hypothesis that sympathetic stimulation with tyramine initiates atrial fibrillation (AF) by early after depolarization (EAD)-mediated triggered activity at the left atrial PV (LAPV) junction.

Methods: LVMI was created in 6 dogs and 6 dogs served as controls.

Cigarette smoke radioactivity and lung cancer risk.

Introduction: To determine the tobacco industry's policy and action with respect to radioactive polonium 210 ((210)Po) in cigarette smoke and to assess the long-term risk of lung cancer caused by alpha particle deposits in the lungs of regular smokers.

Methods: Analysis of major tobacco industries' internal secret documents on cigarette radioactivity made available online by the Master Settlement Agreement in 1998.

Results: The documents show that the industry was well aware of the presence of a radioactive substance in tobacco as early as 1959.