Calcium cycling disturbances and arrhythmogenesis

In this work, a detailed multiscale computational model of Ca cycling and action potential in a ventricular myocyte is developed and used to study mechanisms of arrhythmias associated with mutations in the ryanodine receptor (RyR). The multiscale ventricular myocyte model reproduces experimentally observed Ca dynamics both at the local dyadic scale and at the global whole-cell scale, while also simulating the action potential (AP) shaped by membrane ionic currents. The model represents stochastic activation of L-type Ca channels (LCCs) and RyRs in the dyads and simulates random generation of Ca sparks both during excitation-contraction coupling (ECC) and during diastole. The kinetic model of RyR includes regulation of its openings by calsequestrin (CSQN). The model reproduces graded release and variable gain at the cellular level, i.e total sarcoplasmic reticulum (SR) release is a graded function of the amplitude of L-type calcium current (ICaL) and of voltage. The model was used to simulate whole-cell (macroscopic) consequences of changes in local (microscopic) dyadic properties associated with pathologies such as heart failure or impairment of CSQN function. In addition, the model is used to study mechanisms of cellular arrhythmogenic behaviors associated with Ca handling abnormalities. Specifically, we study Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) associated with mutations in RyR. Results indicate that increased cytosolic Ca sensitivity of RyRs as a result of mutations, in combination with β-adrenergic stimulation (βAS), results in increased propensity for formation of spontaneous SR Ca release and Ca waves. The spontaneous release activates the electrogenic Na-Ca exchange current (INaCa) which can prolong the AP to cause reactivation of ICaL to form early afterdepolarizations (EADs) when it occurs during the phase-2 of AP. During diastole, the spontaneous Ca waves can activate INaCa generating delayed afterdepolarizations (DADs) which can then reach the threshold for activation of ICaL to form triggered activity (TA). The mechanistic basis for prevention of triggered arrhythmias in CPVT by the pharmacological agent flecainide was found to be due to its effect on mean open time of RyR rather than due to its effect on blocking the fast Na current (INa). However, such preventive action was not associated with abolition of Ca waves. EADs and TA also occurred in a simulated hypoxic ventricular myocyte in the presence of βAS. These arrhythmogenic events were due to increased sensitivity of ICaL to βAS during hypoxic conditions

Lepton polarization asymmetry in radiative dileptonic B-meson decays in MSSM

In this paper we study the polarization asymmetries of the final state lepton in the radiative dileptonic decay of B meson (\bsllg) in the framework of Minimal Supersymmetric Standard Model (MSSM) and various other unified models within the framework of MSSM e.g. mSUGRA, SUGRA (where condition of universality of scalar masses is relaxed) etc. Lepton polarization, in addition of having a longitudinal component (\pl), can have two other components, \pt and \pn, lying in and perpendicular to the decay plane, which are proportional to \ml and hence are significant for final state being $\mu^+ ~ \mu^-$ or $\tau^+ \~\tau^-$. We analyse the dependence of these polarization asymmetries on the parameters of the various models.Comment: typos corrected to match with published versio

Propagation Failure by TRPM4 Overexpression

Transient receptor potential melastatin member 4 (TRPM4) channels are nonselective monovalent cationic channels found in human atria and conduction system. Overexpression of TRPM4 channels has been found in families suffering from inherited cardiac arrhythmias, notably heart block. In this study, we integrate a mathematical formulation of the TRPM4 channel into a Purkinje cell model (Pan-Rudy model). Instead of simply adding the channel to the model, a combination of existing currents equivalent to the TRPM4 current was constructed, based on TRPM4 current dynamics. The equivalent current was then replaced by the TRPM4 current to preserve the model action potential. Single-cell behavior showed early afterdepolarizations for increases in TRPM4 channel expression above twofold. In a homogeneous strand of tissue, propagation conducted faithfully for lower expression levels but failed completely for more than a doubling of TRPM4 channel expression. Only with a heterogeneous distribution of channel expression was intermittent heart block seen. This study suggests that in Purkinje fibers, TRPM4 channels may account for sodium background current (INab), and that a heterogeneous expression of TRPM4 channels in the His/Purkinje system is required for type II heart block, as seen clinically

B physics : WHEPP-XI working group report

We present the report of the B physics working group of the Workshop on High Energy Physics Phenomenology (WHEPP-XI), held at the Physical Research Laboratory, Ahmedabad, in January 2010

Disrupted junctional membrane complexes and hyperactive ryanodine receptors after acute junctophilin knockdown in mice

Background- Excitation-contraction coupling in striated muscle requires proper communication of plasmalemmal voltage-activated Ca(2+) channels and Ca(2+) release channels on sarcoplasmic reticulum within junctional membrane complexes. Although previous studies revealed a loss of junctional membrane complexes and embryonic lethality in germ-line junctophilin-2 (JPH2) knockout mice, it has remained unclear whether JPH2 plays an essential role in junctional membrane complex formation and the Ca(2+)-induced Ca(2+) release process in the heart. Our recent work demonstrated loss-of-function mutations in JPH2 in patients with hypertrophic cardiomyopathy. Methods and Results- To elucidate the role of JPH2 in the heart, we developed a novel approach to conditionally reduce JPH2 protein levels using RNA interference. Cardiac-specific JPH2 knockdown resulted in impaired cardiac contractility, which caused heart failure and increased mortality. JPH2 deficiency resulted in loss of excitation-contraction coupling gain, precipitated by a reduction in the number of junctional membrane complexes and increased variability in the plasmalemma-sarcoplasmic reticulum distance. Conclusions- Loss of JPH2 had profound effects on Ca(2+) release channel inactivation, suggesting a novel functional role for JPH2 in regulating intracellular Ca(2+) release channels in cardiac myocytes. Thus, our novel approach of cardiac-specific short hairpin RNA-mediated knockdown of junctophilin-2 has uncovered a critical role for junctophilin in intracellular Ca(2+) release in the hear