Increased Risk for Atrial Alternans in Rabbit Heart Failure: The Role of Ca/Calmodulin-Dependent Kinase II and Inositol-1,4,5-trisphosphate Signaling.

Heart failure (HF) increases the probability of cardiac arrhythmias, including atrial fibrillation (AF), but the mechanisms linking HF to AF are poorly understood. We investigated disturbances in Ca signaling and electrophysiology in rabbit atrial myocytes from normal and failing hearts and identified mechanisms that contribute to the higher risk of atrial arrhythmias in HF. Ca transient (CaT) alternans-beat-to-beat alternations in CaT amplitude-served as indicator of increased arrhythmogenicity.

The 'Reverse FDUF' Mechanism of Atrial Excitation-Contraction Coupling Sustains Calcium Alternans-A Hypothesis.

Cardiac calcium alternans is defined as beat-to-beat alternations of Ca transient (CaT) amplitude and has been linked to cardiac arrhythmia, including atrial fibrillation. We investigated the mechanism of atrial alternans in isolated rabbit atrial myocytes using high-resolution line scan confocal Ca imaging. Alternans was induced by increasing the pacing frequency until stable alternans was observed (1.

Activation of small conductance Ca -activated K channels suppresses Ca transient and action potential alternans in ventricular myocytes.

At the cellular level, cardiac alternans is observed as beat-to-beat alternations in contraction strength, action potential (AP) morphology and Ca transient (CaT) amplitude, and is a risk factor for cardiac arrhythmia. The (patho)physiological roles of small conductance Ca -activated K (SK) channels in ventricles are poorly understood. We tested the hypothesis that in single rabbit ventricular myocytes pharmacological modulation of SK channels plays a causative role for the development of pacing-induced CaT and AP duration (APD) alternans.

Mechanism of carvedilol induced action potential and calcium alternans.

Carvedilol is a nonspecific β-blocker clinically used for the treatment of cardiovascular diseases but has also been shown to have profound effects on excitation-contraction coupling and Ca signaling at the cellular level. We investigate the mechanism by which carvedilol facilitates Ca transient (CaT) and action potential duration (APD) alternans in rabbit atrial myocytes. Carvedilol lowered the frequency threshold for pacing-induced CaT alternans and facilitated alternans in a concentration-dependent manner.

L-type Ca channel recovery from inactivation in rabbit atrial myocytes.

Adaptation of the myocardium to varying workloads critically depends on the recovery from inactivation (RFI) of L-type Ca channels (LCCs) which provide the trigger for cardiac contraction. The goal of the present study was a comprehensive investigation of LCC RFI in atrial myocytes. The study was performed on voltage-clamped rabbit atrial myocytes using a double pulse protocol with variable diastolic intervals in cells held at physiological holding potentials, with intact intracellular Ca release, and preserved Na current and Na /Ca exchanger (NCX) activity.

Inositol 1,4,5-trisphosphate receptor - reactive oxygen signaling domain regulates excitation-contraction coupling in atrial myocytes.

The inositol 1,4,5-trisphosphate receptor (InsPR) is up-regulated in patients with atrial fibrillation (AF) and InsP-induced Ca release (IICR) is linked to pro-arrhythmic spontaneous Ca release events. Nevertheless, knowledge of the physiological relevance and regulation of InsPRs in atrial muscle is still limited. We hypothesize that InsPR and NADPH oxidase 2 (NOX2) form a functional signaling domain where NOX2 derived reactive oxygen species (ROS) regulate InsPR agonist affinity and thereby Ca release.

Fatty acid oxidation and autophagy promote endoxifen resistance and counter the effect of AKT inhibition in ER-positive breast cancer cells.

Tamoxifen (TAM) is the first-line endocrine therapy for estrogen receptor-positive (ER+) breast cancer (BC). However, acquired resistance occurs in ∼50% cases. Meanwhile, although the PI3K/AKT/mTOR pathway is a viable target for treatment of endocrine therapy-refractory patients, complex signaling feedback loops exist, which can counter the effectiveness of inhibitors of this pathway.

Mitochondrial calcium uniporter complex activation protects against calcium alternans in atrial myocytes.

Cardiac alternans, defined as beat-to-beat alternations in action potential duration, cytosolic Ca transient (CaT) amplitude, and cardiac contraction is associated with atrial fibrillation (AF) and sudden cardiac death. At the cellular level, cardiac alternans is linked to abnormal intracellular calcium handling during excitation-contraction coupling. We investigated how pharmacological activation or inhibition of cytosolic Ca sequestration via mitochondrial Ca uptake and mitochondrial Ca retention affects the occurrence of pacing-induced CaT alternans in isolated rabbit atrial myocytes.

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.

The role of fibroblast - Cardiomyocyte interaction for atrial dysfunction in HFpEF and hypertensive heart disease.

Aims: Atrial contractile dysfunction is associated with increased mortality in heart failure (HF). We have shown previously that a metabolic syndrome-based model of HFpEF and a model of hypertensive heart disease (HHD) have impaired left atrial (LA) function in vivo (rat). In this study we postulate, that left atrial cardiomyocyte (CM) and cardiac fibroblast (CF) paracrine interaction related to the inositol 1,4,5-trisphosphate signalling cascade is pivotal for the manifestation of atrial mechanical dysfunction in HF and that quantitative atrial remodeling is highly disease-dependent.

Action potential shortening rescues atrial calcium alternans.

Key Points: Cardiac alternans refers to a beat-to-beat alternation in contraction, action potential (AP) morphology and Ca transient (CaT) amplitude, and represents a risk factor for cardiac arrhythmia, including atrial fibrillation. We developed strategies to pharmacologically manipulate the AP waveform with the goal to reduce or eliminate the occurrence of CaT and contraction alternans in atrial tissue. With combined patch-clamp and intracellular Ca measurements we investigated the effect of specific ion channel inhibitors and activators on alternans.

p53 promotes AKT and SP1-dependent metabolism through the pentose phosphate pathway that inhibits apoptosis in response to Nutlin-3a.

Nutlin-3a is a MDM2 antagonist and preclinical drug that activates p53. Cells with MDM2 gene amplification are especially prone to Nutlin-3a-induced apoptosis, though the basis for this is unclear. Glucose metabolism can inhibit apoptosis in response to Nutlin-3a through mechanisms that are incompletely understood.

Tissue Specificity: SOCE: Implications for Ca Handling in Endothelial Cells.

Many cellular functions of the vascular endothelium are regulated by fine-tuned global and local, microdomain-confined changes of cytosolic free Ca ([Ca]). Vasoactive agonist-induced stimulation of vascular endothelial cells (VECs) typically induces Ca release through IP receptor Ca release channels embedded in the membrane of the endoplasmic reticulum (ER) Ca store, followed by Ca entry from the extracellular space elicited by Ca store depletion and referred to as capacitative or store-operated Ca entry (SOCE). In vascular endothelial cells, SOCE is graded with the degree of store depletion and controlled locally in the subcellular microdomain where depletion occurs.

The intricacies of atrial calcium cycling during excitation-contraction coupling.

Blatter discusses the initiation and spread of Ca release, Ca store depletion, and release termination in atrial myocytes.

Alternans in atria: Mechanisms and clinical relevance.

Atrial fibrillation is the most common sustained arrhythmia and its prevalence is rapidly rising with the aging of the population. Cardiac alternans, defined as cyclic beat-to-beat alternations in contraction force, action potential (AP) duration and intracellular Ca release at constant stimulation rate, has been associated with the development of ventricular arrhythmias. Recent clinical data also provide strong evidence that alternans plays a central role in arrhythmogenesis in atria.

Membrane potential determines calcium alternans through modulation of SR Ca load and L-type Ca current.

Alternans is a risk factor for cardiac arrhythmia, including atrial fibrillation. At the cellular level alternans is observed as beat-to-beat alternations in contraction, action potential (AP) morphology and magnitude of the Ca transient (CaT). It is widely accepted that the bi-directional interplay between membrane voltage and Ca is crucial for the development of alternans, however recently the attention has shifted to instabilities in cellular Ca handling, while the role of AP alternation remains poorly understood.

The effect of PKA-mediated phosphorylation of ryanodine receptor on SR Ca leak in ventricular myocytes.

Functional impact of cardiac ryanodine receptor (type 2 RyR or RyR2) phosphorylation by protein kinase A (PKA) remains highly controversial. In this study, we characterized a functional link between PKA-mediated RyR2 phosphorylation level and sarcoplasmic reticulum (SR) Ca release and leak in permeabilized rabbit ventricular myocytes. Changes in cytosolic [Ca] and intra-SR [Ca] were measured with Fluo-4 and Fluo-5N, respectively.

A novel mechanism of tandem activation of ryanodine receptors by cytosolic and SR luminal Ca during excitation-contraction coupling in atrial myocytes.

Key Points: In atrial myocytes excitation-contraction coupling is strikingly different from ventricle because atrial myocytes lack a transverse tubule membrane system: Ca release starts in the cell periphery and propagates towards the cell centre by Ca -induced Ca release from the sarcoplasmic reticulum (SR) Ca store. The cytosolic Ca sensitivity of the ryanodine receptor (RyRs) Ca release channel is low and it is unclear how Ca release can be activated in the interior of atrial cells. Simultaneous confocal imaging of cytosolic and intra-SR calcium revealed a transient elevation of store Ca that we termed 'Ca sensitization signal'.

Ca(2+)-activated chloride channel activity during Ca(2+) alternans in ventricular myocytes.

Cardiac alternans, defined beat-to-beat alternations in contraction, action potential (AP) morphology or cytosolic Ca transient (CaT) amplitude, is a high risk indicator for cardiac arrhythmias. We investigated mechanisms of cardiac alternans in single rabbit ventricular myocytes. CaTs were monitored simultaneously with membrane currents or APs recorded with the patch clamp technique.

Calcium-activated chloride current determines action potential morphology during calcium alternans in atrial myocytes.

Cardiac alternans--periodic beat-to-beat alternations in contraction, action potential (AP) morphology or cytosolic calcium transient (CaT) amplitude--is a high risk indicator for cardiac arrhythmias and sudden cardiac death. However, it remains an unresolved issue whether beat-to-beat alternations in intracellular Ca(2+) ([Ca(2+)]i ) or AP morphology are the primary cause of pro-arrhythmic alternans. Here we show that in atria AP alternans occurs secondary to CaT alternans.

p53-regulated autophagy is controlled by glycolysis and determines cell fate.

The tumor suppressor p53 regulates downstream targets that determine cell fate. Canonical p53 functions include inducing apoptosis, growth arrest, and senescence. Non-canonical p53 functions include its ability to promote or inhibit autophagy and its ability to regulate metabolism.

Harnessing the Power of Integrated Mitochondrial Biology and Physiology: A Special Report on the NHLBI Mitochondria in Heart Diseases Initiative.

Mitochondrial biology is the sum of diverse phenomena from molecular profiles to physiological functions. A mechanistic understanding of mitochondria in disease development, and hence the future prospect of clinical translations, relies on a systems-level integration of expertise from multiple fields of investigation. Upon the successful conclusion of a recent National Institutes of Health, National Heart, Lung, and Blood Institute initiative on integrative mitochondrial biology in cardiovascular diseases, we reflect on the accomplishments made possible by this unique interdisciplinary collaboration effort and exciting new fronts on the study of these remarkable organelles.