("calcium wave*" OR "ca2+ wave*") AND ("heart" OR "cardiac")

BACKGROUND: Available evidence suggest that Ca2+ /calmodulin-dependent protein kinase type IIδ (CaMKIIδ) and reactive oxygen species (ROS) are important in early ischemia-reperfusion arrhythmias (IRA). Since ROS can activate CaMKIIδ by oxidation of two methionines at positions 281/282, oxidized-CaMKIIδ (Ox-CaMKIIδ) has been proposed to be important for IRA. However, direct evidence for this is missing. METHODS: We exposed Langendorff-perfused hearts and ventricular cardiomyocytes from C57BL/6 mice to global and simulated ischemia, respectively, and recorded arrhythmic events during early reperfusion...

The type 2a sarco/endoplasmic reticulum Ca2+ -ATPase (SERCA2a) plays a central role in the intracellular Ca2+ homeostasis of cardiac myocytes, pumping Ca2+ from the cytoplasm into the sarcoplasmic reticulum (SR) lumen to maintain relaxation (diastole) and prepare for contraction (systole). Diminished SERCA2a function has been reported in several pathological conditions, including heart failure. Therefore, development of new drugs that improve SERCA2a Ca2+ transport is of great clinical significance. In this study, we characterized the effect of a recently identified N-aryl-N-alkyl-thiophene-2-carboxamide (or compound 1) on SERCA2a Ca2+ -ATPase and Ca2+ transport activities in cardiac sarcoplasmic reticulum (SR) vesicles, and on Ca2+ regulation in a HEK293 cell expression system and in mouse ventricular myocytes...

Two alkalinizing mechanisms coexist in cardiac myocytes to maintain intracellular pH: sodium/bicarbonate cotransporter (electroneutral isoform NBCn1 and electrogenic isoform NBCe1) and sodium/proton exchanger (NHE1). Dysfunction of these transporters has previously been reported to be responsible for the development of cardiovascular diseases. The aim of this study was to evaluate the contribution of the downregulation of the NBCe1 to the development of cardiac hypertrophy. To specifically reduce NBCe1 expression, we cloned shRNA into a cardiotropic adeno-associated vector (AAV9-shNBCe1)...

BACKGROUND: Ischemic cardiomyopathy (ICM) is associated with electrical and structural remodelling, leading to arrhythmias. Caveolin-1 (Cav1) is a membrane protein involved in the pathogenesis of ischemic injury. Cav1 deficiency has been associated with arrhythmogenicity. The current study aimed to determine how Cav1 overexpression inhibits arrhythmias and cardiac remodelling in ICM. METHODS: ICM was modelled using left anterior descending (LAD) artery ligation for 4 weeks...

OBJECTIVE: To investigate the changes in myocardial calcium currents in rats subjected to forced running exercise during acute hypoxia and their association with myocardial injury. METHODS: Forty SD rats were randomized into quiescent group and running group either in normal oxygen (NQ and NR groups, respectively) or in acute hypoxia (HQ and HR groups, respectively). Hypoxia was induced by keeping the rats in a hypobaric oxygen chamber (PaO2 =61.6kpa) for 4 h a day; the rats in the two running groups were forced to run on running wheels for 4 h each day...

AIMS: Hypothyroidism is associated with an increased risk of cardiovascular disease and enhanced susceptibility to arrhythmias. In our investigation, we evaluated the potential involvement of late sodium current (INa,late ) in cardiac arrhythmias in an experimental murine model of hypothyroidism. MAIN METHODS: Male Swiss mice were treated with methimazole (0.1 % w/vol, during 21 days) to induce experimental hypothyroidism before ECG, action potential (AP) and intracellular Ca2+ dynamics were evaluated...

KEY POINTS: Transverse-axial tubule systems (TATS) modulate Ca2+ handling and excitation-contraction coupling in atrial myocytes, with TATS remodeling in heart failure and atrial fibrillation associated with altered Ca2+ cycling and subsequent arrhythmogenesis. To investigate the poorly understood mechanisms linking TATS variation and spontaneous Ca2+ release, we built, parameterized and validated a 3D human atrial myocyte model coupling electrophysiology and spatially-detailed subcellular Ca2+ handling governed by the TATS...

Ryanodine receptors (RyRs) exhibit dynamic arrangements in cardiomyocytes, and we previously showed that 'dispersion' of RyR clusters disrupts Ca2+ homeostasis during heart failure (HF) (Kolstad et al., eLife, 2018). Here, we investigated whether prolonged β-adrenergic stimulation, a hallmark of HF, promotes RyR cluster dispersion and examined the underlying mechanisms. We observed that treatment of healthy rat cardiomyocytes with isoproterenol for 1 hr triggered progressive fragmentation of RyR clusters. Pharmacological inhibition of Ca2+ /calmodulin-dependent protein kinase II (CaMKII) reversed these effects, while cluster dispersion was reproduced by specific activation of CaMKII, and in mice with constitutively active Ser2814-RyR...

Optogenetic assays provide a flexible, scalable, and information rich approach to probe compound effects for ion channel drug targets in both heterologous expression systems and associated disease relevant cell types. Despite the potential utility and growing adoption of optogenetics, there remains a critical need for compatible platform technologies with the speed, sensitivity, and throughput to enable their application to broader drug screening applications. To address this challenge, we developed the SwarmTM , a custom designed optical instrument for highly parallelized, multicolor measurements in excitable cells, simultaneously recording changes in voltage and calcium activities at high temporal resolution under optical stimulation...

Ex-vivo simple models are powered tools to study cardiac hypertrophy. It is possible to control the activation of critical genes and thus test the effects of drug therapies before the in vivo tests. A zebrafish cardiac hypertrophy developed by 500 μM phenylephrine (PE) treatment in ex vivo culture has been demonstrated to activate the essential expression of the embryonal genes. These genes are the same as those described in several previous pieces of research on hypertrophic pathology in humans. The efficacy of the chemical drug Blebbistatin (BL) on hypertrophy induced ex vivo cultured hearts is studied in this research...

Cardiovascular disease is the leading cause of death worldwide due in a large part to arrhythmia. In order to understand how calcium dynamics play a role in arrhythmogenesis, normal and dysfunctional Ca2+ signaling in a subcellular, cellular, and tissued level is examined using cardiac ventricular myocytes at a high temporal and spatial resolution using multiscale computational modeling. Ca2+ sparks underlie normal excitation-contraction coupling. However, under pathological conditions, Ca2+ sparks can combine to form Ca2+ waves...

AIMS: Variants in SCN5A encoding Nav1.5 are associated with cardiac arrhythmias. We aimed to determine the mechanism by which c.638G>A in SCNA5 resulting in p.Gly213Asp (G213D) in Nav1.5 altered Na+ channel function and how flecainide corrected the defect in a family with multifocal ectopic Purkinje-related premature contractions (MEPPC)-like syndrome. METHODS AND RESULTS: Five patients carrying the G213D variant were treated with flecainide. Gating pore currents were evaluated in Xenopus laevis oocytes...

All human life starts with a calcium (Ca2+ ) wave. This ion regulates a plethora of cellular functions ranging from fertilisation and birth to development and cell death. A sophisticated system is responsible for maintaining the essential, tight concentration of calcium within cells. Intricate components of this Ca2+ network are store-operated calcium channels in the cells' membrane. The best-characterised store-operated channel is the Ca2+ release-activated Ca2+ (CRAC) channel. Currents through CRAC channels are critically dependent on the correct function of two proteins: STIM1 and Orai1...

BACKGROUND: An aberrant increase in the diastolic calcium concentration ([Ca2+ ]i ) level is a hallmark of heart failure (HF) and the cause of delayed afterdepolarization and ventricular arrhythmia (VA). Although mitochondria play a role in regulating [Ca2+ ]i , whether they can compensate for the [Ca2+ ]i abnormality in ventricular myocytes is unknown. OBJECTIVE: The purpose of this study was to investigate whether enhanced Ca2+ uptake of mitochondria may compensate for an abnormal increase in the [Ca2+ ]i of ventricular myocytes in HF to effectively mitigate VA...

Mutations of the RyR2 are channelopathies that can predispose to life threatening catecholaminergic polymorphic ventricular tachycardias (CPVTs) during exercise or stress. However, the cellular and molecular mechanisms that are causal for the arrhythmias downstream of the β-adrenergic receptor (β-AR) activation are not defined. They may be specific and different for each particular RyR2 mutation. Obvious possibilities are the phosphorylation of the mutated RyR2s or the stimulation of the SR Ca2+ pump (SERCA), which could increase SR Ca2+ loading...

Many acquired or inherited forms of heart disease as well as drugs are known to increase the susceptibility of patients to arrhythmias. To predict arrhythmogenic events and discover new therapeutic strategies to mitigate them, approaches to efficiently quantify the velocity of propagation in engineered cardiac tissues are important research tools. In this chapter, we describe how to collect videos of propagating calcium waves in engineered cardiac tissues with a high-speed camera mounted on an inverted fluorescence microscope...

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Heterozygous missense variants of the cardiac ryanodine receptor gene (RYR2) cause catecholaminergic polymorphic ventricular tachycardia (CPVT). These missense variants of RYR2 result in a gain of function of the ryanodine receptors, characterized by increased sensitivity to activation by calcium that results in an increased propensity to develop calcium waves and delayed afterdepolarizations. We have recently detected a nonsense variant in RYR2 in a young patient who suffered an unexplained cardiac arrest...

Caveolin-3 is a muscle-specific protein on the membrane of myocytes correlated with a variety of cardiovascular diseases. It is now clear that the caveolin-3 plays a critical role in the cardiovascular system and a significant role in cardiac protective signaling. Mutations in the gene encoding caveolin-3 cause a broad spectrum of clinical phenotypes, ranging from persistent elevations in the serum levels of creatine kinase in asymptomatic humans to cardiomyopathy. The influence of Caveolin-3(CAV-3) mutations on current density parallels the effect on channel trafficking...

BACKGROUND: Oxidative stress in cardiac disease promotes proarrhythmic disturbances in Ca2+ homeostasis, impairing luminal Ca2+ regulation of the sarcoplasmic reticulum (SR) Ca2+ release channel, the RyR2 (ryanodine receptor), and increasing channel activity. However, exact mechanisms underlying redox-mediated increase of RyR2 function in cardiac disease remain elusive. We tested whether the oxidoreductase family of proteins that dynamically regulate the oxidative environment within the SR are involved in this process...