Nitric Oxide Synthases and Atrial Fibrillation

Oxidative stress has been implicated in the pathogenesis of atrial fibrillation. There are multiple systems in the myocardium which contribute to redox homeostasis, and loss of homeostasis can result in oxidative stress. Potential sources of oxidants include nitric oxide synthases (NOS), which normally produce nitric oxide in the heart. Two NOS isoforms (1 and 3) are normally expressed in the heart. During pathologies such as heart failure, there is induction of NOS 2 in multiple cell types in the myocardium. In certain conditions, the NOS enzymes may become uncoupled, shifting from production of nitric oxide to superoxide anion, a potent free radical and oxidant. Multiple lines of evidence suggest a role for NOS in the pathogenesis of atrial fibrillation. Therapeutic approaches to reduce atrial fibrillation by modulation of NOS activity may be beneficial, although further investigation of this strategy is needed

Molecular Mechanism and Current Therapies for Catecholaminergic Polymorphic Ventricular Tachycardia

The rhythmic contraction of the heart relies on tightly regulated calcium (Ca) release from the sarcoplasmic reticulum (SR) Ca release channel, Ryanodine receptor (RyR2). Genetic mutations in components of the calcium release unit such as RyR2, cardiac calsequestrin and other proteins have been shown to cause a genetic arrhythmic syndrome known as catecholaminergic polymorphic ventricular tachycardia (CPVT). This book chapter will focus on the following: (1) to describing CPVT as a stress-induced cardiac arrhythmia syndrome and its genetic causes. (2) Discussing the regulation of SR Ca release, and how dysregulation of Ca release contributes to arrhythmogenesis. (3) Discussing molecular mechanisms of CPVT with a focus on impaired Ca signaling refractoriness as a unifying mechanism underlying different genetic forms of CPVT. (4) Discussing pharmacological approaches as CPVT treatments as well as other potential future therapies. Since dysregulated SR Ca release has been implicated in multiple cardiac disorders including heart failure and metabolic heart diseases, knowledge obtained from CPVT studies will also shed light on the development of therapeutic approaches for these devastating cardiac dysfunctions as a whole

Dysfunction in the βII Spectrin-Dependent Cytoskeleton Underlies Human Arrhythmia.

Background: The cardiac cytoskeleton plays key roles in maintaining myocyte structural integrity in health and disease. In fact, human mutations in cardiac cytoskeletal elements are tightly linked with cardiac pathologies including myopathies, aortopathies, and dystrophies. Conversely, the link between cytoskeletal protein dysfunction in cardiac electrical activity is not well understood, and often overlooked in the cardiac arrhythmia field. Methods and Results: Here, we uncover a new mechanism for the regulation of cardiac membrane excitability. We report that βII spectrin, an actin-associated molecule, is essential for the post-translational targeting and localization of critical membrane proteins in heart. βII spectrin recruits ankyrin-B to the cardiac dyad, and a novel human mutation in the ankyrin-B gene disrupts the ankyrin-B/βII spectrin interaction leading to severe human arrhythmia phenotypes. Mice lacking cardiac βII spectrin display lethal arrhythmias, aberrant electrical and calcium handling phenotypes, and abnormal expression/localization of cardiac membrane proteins. Mechanistically, βII spectrin regulates the localization of cytoskeletal and plasma membrane/sarcoplasmic reticulum protein complexes that include the Na/Ca exchanger, RyR2, ankyrin-B, actin, and αII spectrin. Finally, we observe accelerated heart failure phenotypes in βII spectrin-deficient mice. Conclusions: Our findings identify βII spectrin as critical for normal myocyte electrical activity, link this molecule to human disease, and provide new insight into the mechanisms underlying cardiac myocyte biology

Search for high-mass resonances decaying to τν in pp collisions at √s = 13 TeV with the ATLAS detector

A search for high-mass resonances decaying to τ ν using proton-proton collisions at √ s = 13     TeV produced by the Large Hadron Collider is presented. Only τ -lepton decays with hadrons in the final state are considered. The data were recorded with the ATLAS detector and correspond to an integrated luminosity of 36.1     fb − 1 . No statistically significant excess above the standard model expectation is observed; model-independent upper limits are set on the visible τ ν production cross section. Heavy W ′ bosons with masses less than 3.7 TeV in the sequential standard model and masses less than 2.2–3.8 TeV depending on the coupling in the nonuniversal G ( 221 ) model are excluded at the 95% credibility level

Dietary omega-3 fatty acids promote arrhythmogenic remodeling of cellular Ca2+ handling in a postinfarction model of sudden cardiac death.

It has been proposed that dietary omega-3 polyunsaturated fatty acids (n-3 PUFAs) can reduce the risk of ventricular arrhythmias in post-MI patients. Abnormal Ca(2+) handling has been implicated in the genesis of post-MI ventricular arrhythmias. Therefore, we tested the hypothesis that dietary n-3 PUFAs alter the vulnerability of ventricular myocytes to cellular arrhythmia by stabilizing intracellular Ca(2+) cycling. To test this hypothesis, we used a canine model of post-MI ventricular fibrillation (VF) and assigned the animals to either placebo (1 g/day corn oil) or n-3 PUFAs (1-4 g/day) groups. Using Ca(2+) imaging techniques, we examined the intracellular Ca(2+) handling in myocytes isolated from post-MI hearts resistant (VF-) and susceptible (VF+) to VF. Frequency of occurrence of diastolic Ca(2+) waves (DCWs) in VF+ myocytes from placebo group was significantly higher than in placebo-treated VF- myocytes. n-3 PUFA treatment did not decrease frequency of DCWs in VF+ myocytes. In contrast, VF- myocytes from the n-3 PUFA group had a significantly higher frequency of DCWs than myocytes from the placebo group. In addition, n-3 PUFA treatment increased beat-to-beat alterations in the amplitude of Ca(2+) transients (Ca(2+) alternans) in VF- myocytes. These n-3 PUFAs effects in VF- myocytes were associated with an increased Ca(2+) spark frequency and reduced sarcoplasmic reticulum Ca(2+) content, indicative of increased activity of ryanodine receptors. Thus, dietary n-3 PUFAs do not alleviate intracellular Ca(2+) cycling remodeling in myocytes isolated from post-MI VF+ hearts. Furthermore, dietary n-3 PUFAs increase vulnerability of ventricular myocytes to cellular arrhythmia in post-MI VF- hearts by destabilizing intracellular Ca(2+) handling

Chronic Omega-3 Polyunsaturated Fatty Acid Treatment Variably Affects Cellular Repolarization in a Healed Post-MI Arrhythmia Model

Introduction: Over the last 40 years omega-3 polyunsaturated fatty acids (PUFAs) have been shown to be anti-arrhythmic or pro-arrhythmic depending on the method and duration of administration and model studied. We previously reported that omega-3 PUFAs do not confer anti-arrhythmic properties and are pro-arrhythmic in canine model of sudden cardiac death (SCD). Here, we evaluated the effects of chronic omega-3 PUFA treatment in post-MI animals susceptible (VF+) or resistant (VF-) to ventricular tachyarrhythmias. Methods: Perforated patch clamp techniques were used to measure cardiomyocyte action potential durations (APD) at 50 and 90% repolarization and short term variability of repolarization. The early repolarizing transient outward potassium current I-to was also studied. Results: Omega-3 PUFAs prolonged the action potential in VF- myocytes at both 50 and 90% repolarization. Short term variability of repolarization was increased in both untreated and treated VF- myocytes vs. controls. Ito was unaffected by omega-3 PUFA treatment. Omega-3 PUFA treatment attenuated the action potential prolongation in VF+ myocytes, but did not return repolarization to control values. Conclusions: Omega-3 PUFAs do not confer anti arrhythmic properties in the setting of healed myocardial infarction in a canine model of SCD. In canines previously resistant to ventricular fibrillation (VF-), omega-3 PUFA treatment prolonged the action potential in VF- myocytes, and may contribute to pro-arrhythmic responses.National Institutes of Health [HL089836, HL086700]SCI(E)[email protected]; [email protected]

Dietary n-3 PUFAs increase frequency of Ca²⁺ sparks in VF- myocytes.

<p><b>A</b>, Representative line-scan images of Ca²⁺ sparks recorded in saponin-permeabilized myocytes from indicated groups. Insets show scaled up image of Ca²⁺ spark with corresponding time-dependent fluorescence profile. <b>B</b>, Representative traces of Ca²⁺ transients evoked by 10 mM caffeine recorded in permeabilized myocytes from indicated groups. <b>C</b>, Average Ca²⁺ spark frequency (in 100 µm^-1*s^-1) was 1.23±0.13 (n=52) in untreated control myocytes, 2.01±0.19 (n=47) and 3.31±0.38 (n=45) in untreated and n-3 PUFA-treated VF- myocytes, respectively. <b>D</b>, Average amplitude of caffeine-induced Ca²⁺ transients ([Ca²⁺]_CAFF, ΔF/F₀) was 2.76±0.34 (n=7) in untreated control myocytes, 2.19±0.11 (n=5) and 1.42±0.06 (n=4) in untreated and n-3 PUFA-treated VF- myocytes, respectively. *, P<0.05 <i>vs</i>. control; †, P<0.05 <i>vs</i>. VF- untreated.</p

Dietary n-3 PUFAs do not affect expression and phosphorylation levels of proteins involved in cardiac Ca²⁺ cycling.

<p><b>A</b>-<b>C</b>, Representative immunoblots of left ventricle homogenates prepared from placebo and n-3 PUFA-treated control (sham) and VF- groups. NCX1, Na⁺/Ca²⁺ exchanger type 1; SERCA2a, cardiac isoform of SR Ca²⁺-ATPase; GAPDH, Glyceraldehyde 3-phosphate dehydrogenase; PLN, phospholamban; Cav1.2, α1C subunit of L-type Ca²⁺ channel. Data were obtained using 2-4 heart samples. Quantitative analysis is presented in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0078414#pone-0078414-t002" target="_blank">Table 2</a>.</p

Dietary n-3 PUFAs induce pro-arrhythmic remodeling of intracellular Ca²⁺ handling in VF- myocytes.

<p>Representative line-scan images and corresponding profiles of Rhod-2 fluorescence during periodic (0.3 Hz) electrical stimulation recorded in myocytes from placebo/untreated and n-3 PUFA-treated controls (<b>A</b>), VF- (B) and VF+ (C) groups, respectively. Data were obtained in the presence of 100 nM isoproterenol, a β-adrenergic receptor agonist. <b>D</b>, Average frequency of DCWs (per second) was: 0.11±0.03 (n=15) and 0.14±0.03 (n=40) in control untreated and n-3 PUFA-treated myocytes, respectively (P=0.5); 0.07±0.03 (n=20) and 0.21±0.04 (n=20) in VF- myocytes from placebo and n-3 PUFAs groups, respectively (P=0.014); 0.23±0.05 (n=8) and 0.32±0.05 (n=8), in VF+ myocytes from placebo and n-3 PUFAs groups, respectively (P=0.22). *, P<0.05 <i>vs</i>. VF- placebo; †, P<0.05 <i>vs</i>. n-3 PUFA-treated controls. <b>E</b>, Bar graph shows proportion of myocytes displaying DCWs. In control groups DCWs were recorded in 9 out of 15 untreated cells and in 24 out of 40 n-3 PUFA-treated cells, respectively. In VF- groups DCWs were recorded in 4 out of 20 placebo-treated cells and in 14 out of 20 n-3 PUFA-treated cells, respectively. In VF+ groups DCWs were recorded in 7 out of 8 placebo-treated cells and in 8 out of 8 n-3 PUFA-treated cells, respectively. </p