Eleonora Grandi

Eleonora Grandi
University of California, Davis | UCD · Department of Pharmacology

MS, PhD

About

175
Publications
18,776
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4,537
Citations
Additional affiliations
December 2016 - December 2016
University of California, Davis
Position
  • Professor (Assistant)

Publications

Publications (175)
Chapter
Mechanistic modeling and simulations have become fundamental techniques for studying cardiac excitation-contraction coupling, to dissect the complex mechanisms that interact nonlinearly to link cardiomyocyte electrical excitation to Ca2+ signaling to contractile response. By complementing the classical wet experimentation, modeling studies have led...
Preprint
Full-text available
Sex differences in cardiac electrophysiology are a crucial factor affecting arrhythmia risk and treatment responses. It is well-documented that females are at a higher risk of drug-induced Torsade de Pointes and sudden cardiac death, largely due to longer QTc intervals compared to males. However, the underrepresentation of females in both basic and...
Article
The importance of biological sex on disease etiology and outcomes has long been underinvestigated. While recent focus on characterizing sex differences in cardiac pathophysiology has led to improved inclusion of both sexes in scientific studies and clinical trials, much is still unknown about underlying differences in normal cardiac physiology. Thi...
Article
Background Increased vascular Ca V 1.2 channel function causes enhanced arterial tone during hypertension. This is mediated by elevations in angiotensin II/protein kinase C signaling. Yet, the mechanisms underlying these changes are unclear. We hypothesize that α1 C phosphorylation at serine 1928 (S1928) is a key event mediating increased Ca V 1.2...
Article
Full-text available
Idiopathic ventricular fibrillation (IVF) is an unrefined diagnosis representing a heterogeneous patient group without a structural or genetic definition. IVF treatment is not mechanistic-based due to the lack of experimental patient-models. We sought to create a methodology to assess cellular arrhythmia mechanisms for IVF as a proof-of-concept stu...
Article
Background and Aim: Substantial sex-based differences have been reported in atrial fibrillation (AF), with female patients experiencing worse symptoms, more complications from treatment, and greater risk of stroke and mortality. Recent studies revealed sex-specific alterations in AF-associated Ca ²⁺ dysregulation, whereby female myocytes more frequ...
Article
Background: Sex-based differences in cardiac electrophysiology and their potential to impact susceptibility to cardiac arrhythmia and response to treatment are widely recognized. For example, female sex is an independent risk factor for drug-induced Long QT syndrome, Torsade de Pointes, and sudden cardiac death. However, arrhythmia studies have bee...
Article
Background: Idiopathic VF (IVF) represents an unmet clinical need with ~50% of patients having no known monogenic cause. This has resulted in the lack of an appropriate experimental model system, limiting effective treatment through an evidence-based approach. Within IVF, several subphenotypes have emerged through Deep Phenotyping. We recruited pat...
Preprint
Full-text available
Background Heart rhythm relies on complex interactions between the electrogenic membrane proteins and intracellular Ca ²⁺ signaling in sinoatrial node (SAN) myocytes; however, the mechanisms underlying the functional organization of the proteins involved in SAN pacemaking and its structural foundation remain elusive. Caveolae are nanoscale, plasma...
Preprint
Full-text available
Background and Aims Substantial sex-based differences have been reported in atrial fibrillation (AF), with female patients experiencing worse symptoms, increased complications from drug side effects or ablation, and elevated risk of AF-related stroke and mortality. Recent studies revealed sex-specific alterations in AF-associated Ca ²⁺ dysregulatio...
Chapter
Mathematical modeling and simulation are well-established and powerful tools to integrate experimental data of individual components of cardiac electrophysiology, excitation-contraction coupling, and regulatory signaling pathways, to gain quantitative and mechanistic insight into pathophysiological processes and guide therapeutic strategies. Here,...
Article
By sensing changes in intracellular Ca2+, small-conductance Ca2+-activated K+ (SK) channels dynamically regulate the dynamics of the cardiac action potential (AP) on a beat-to-beat basis. Given their predominance in atria vs. ventricles, SK channels are considered a promising atrial-selective pharmacological target against atrial fibrillation (AF),...
Article
Full-text available
Aims Atrial fibrillation (AF), the most prevalent clinical arrhythmia, is associated with atrial remodelling manifesting as acute and chronic alterations in expression, function, and regulation of atrial electrophysiological and Ca2+-handling processes. These AF-induced modifications crosstalk and propagate across spatial scales creating a complex...
Article
Recent studies have provided valuable insight into the key mechanisms contributing to the spatiotemporal regulation of intracellular Ca2+ release and Ca2+ signaling in the heart. In this research highlight, we focus on the latest findings published in Biophysical Journal examining the structural organization of Ca2+ handling proteins and assessing...
Preprint
By sensing changes in intracellular Ca2+, small-conductance Ca2+-activated K+ (SK) channels dynamically regulate the dynamics of the cardiac action potential (AP) on a beat-to-beat basis. Given their predominance in atria vs. ventricles, SK channels are considered a promising atrial-selective pharmacological target against atrial fibrillation (AF),...
Article
Full-text available
Atrial fibrillation (AF) is a common and genetically inheritable form of cardiac arrhythmia; however, it is currently not known how these genetic predispositions contribute to the initiation and/or maintenance of AF-associated phenotypes. One major barrier to progress is the lack of experimental systems enabling to rapidly explore gene function on...
Article
Background: Small-conductance Ca2+-activated K+ (SK)-channel inhibitors have antiarrhythmic effects in animal models of atrial fibrillation (AF), presenting a potential novel antiarrhythmic option. However, the regulation of SK-channels in human atrial cardiomyocytes and its modification in patients with AF are poorly understood and were the objec...
Article
Full-text available
This white paper is the outcome of the seventh UC Davis Cardiovascular Research Symposium on Systems Approach to Understanding Cardiovascular Disease and Arrhythmia. This biannual meeting aims to bring together leading experts in subfields of cardiovascular biomedicine to focus on topics of importance to the field. The theme of the 2022 Symposium w...
Article
Full-text available
The sympathetic nervous system fight-or-flight response is characterized by a rapid increase in heart rate, which is mediated by an increase in the spontaneous action potential (AP) firing rate of pacemaker cells in the sinoatrial node. Sympathetic neurons stimulate sinoatrial myocytes (SAMs) by activating β adrenergic receptors (βARs) and increasi...
Article
Full-text available
Intracellular calcium (Ca²⁺) cycling is tightly regulated in the healthy heart ensuring effective contraction. This is achieved by transverse (t)‐tubule membrane invaginations that facilitate close coupling of key Ca²⁺‐handling proteins such as the L‐type Ca²⁺ channel and Na⁺‐Ca²⁺ exchanger (NCX) on the cell surface with ryanodine receptors (RyRs)...
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Full-text available
Previously we showed the generation of a protein trap library made with the gene-break transposon (GBT) in zebrafish (Danio rerio) that could be used to facilitate novel functional genome annotation towards understanding molecular underpinnings of human diseases (Ichino et al, 2020). Here, we report a significant application of this library for dis...
Article
Full-text available
Disruption of the transverse‐axial tubule system (TATS) in diseases such as heart failure and atrial fibrillation occurs in combination with changes in the expression and distribution of key Ca²⁺‐handling proteins. Together this ultrastructural and ionic remodelling is associated with aberrant Ca²⁺ cycling and electrophysiological instabilities tha...
Preprint
Atrial fibrillation (AF) is the most common form of sustained cardiac arrhythmia in humans, present in > 33 million people worldwide. Although AF is often developed secondary to cardiovascular diseases, endocrine disorders, or lifestyle factors, recent GWAS studies have identified >200 genetic variants that substantially contribute to AF risk. Howe...
Chapter
Calcium (Ca) is a key regulator of cardiac function. Through interactions with various molecular binding partners, Ca controls both acute processes, such as ion channel gating and myofilament contraction, and long-term events such as transcriptional changes that regulate myocardial development, growth, and death. Cardiac myocyte Ca levels are modul...
Preprint
Disruption of the transverse-axial tubule system (TATS) in diseases such as heart failure and atrial fibrillation occurs in combination with changes in the expression and distribution of key Ca ²⁺ - handling proteins. Together this ultrastructural and ionic remodeling is associated with aberrant Ca ²⁺ cycling and electrophysiological instabilities...
Preprint
Intracellular calcium (Ca ²⁺ ) cycling is tightly regulated in the healthy heart ensuring effective contraction. This is achieved by transverse (t)-tubule membrane invaginations that facilitate close coupling of key Ca ²⁺ -handling proteins such as the L-type Ca ²⁺ channel (LCC) and Na ⁺ -Ca ²⁺ exchanger (NCX) on the cell surface with ryanodine rec...
Article
Full-text available
Atrial fibrillation (AF) is the most common cardiac arrhythmia worldwide, with an unmet therapeutic need. Fibrotic remodeling, in which collagen-producing atrial fibroblasts play a crucial role, substantially contributes to arrhythmia promotion and progression. In this issue of the JCI, Lai, Tsai, and co-authors reveal that TGF-β1 promoted endothel...
Preprint
Full-text available
The sympathetic nervous system fight-or-flight response is characterized by a rapid increase in heart rate, which is mediated by an increase in the spontaneous action potential (AP) firing rate of pacemaker cells in the sinoatrial node. Sympathetic neurons stimulate sinoatrial myocytes (SAMs) by activating β adrenergic receptors (βARs) and increasi...
Preprint
Atrial fibrillation (AF), the most prevalent clinical arrhythmia, is associated with atrial remodeling manifesting as acute and chronic alterations in expression, function, and regulation of atrial electrophysiological and Ca ²⁺ -handling processes. These AF-induced modifications crosstalk and propagate across spatial scales creating a complex path...
Article
Full-text available
Animal experimentation is key in the evaluation of cardiac efficacy and safety of novel therapeutic compounds. However, interspecies differences in the mechanisms regulating excitation-contraction coupling can limit the translation of experimental findings from animal models to human physiology and undermine the assessment of drugs’ efficacy and sa...
Article
Significance The funny current (I f ) is critical for spontaneous activity in cardiac pacemaker cells; however, its precise role remains enigmatic because it activates mostly outside the physiological voltage range and its kinetics are slow relative to the cardiac cycle. I f is typically considered as an inward current; however, we show that I f is...
Article
Full-text available
Background: The mechanisms underlying dysfunction in the sinoatrial node (SAN), the heart’s primary pacemaker, are incompletely understood. Electrical and Ca2+-handling remodeling have been implicated in SAN dysfunction associated with heart failure, aging, and diabetes. Cardiomyocyte [Na+]i is also elevated in these diseases, where it contributes...
Preprint
Full-text available
Sinoatrial node myocytes (SAMs) act as cardiac pacemaker cells by firing spontaneous action potentials (APs) that initiate each heartbeat. The funny current, I f , is critical for the generation of these spontaneous APs; however, its precise role during the pacemaking cycle remains unresolved. We used the AP-clamp technique to quantify I f during t...
Article
Full-text available
Torsade de Pointes (TdP), a rare but lethal ventricular arrhythmia, is a toxic side effect of many drugs. To assess TdP risk, safety regulatory guidelines require quantification of hERG channel block in vitro and QT interval prolongation in vivo for all new therapeutic compounds. Unfortunately, these have proven to be poor predictors of torsadogeni...
Preprint
Full-text available
Animal experimentation is key in the evaluation of cardiac efficacy and safety of novel therapeutic compounds. However, inter-species differences in the mechanisms regulating excitation-contraction coupling can limit the translation of experimental findings from animal models to human physiology, and undermine the assessment of drugs' efficacy and...
Preprint
Full-text available
Torsade de Pointes (TdP), a rare but lethal ventricular arrhythmia, is a potential cardiac side effect of drugs. To assess TdP risk, safety regulatory guidelines require to quantify the effects of new therapeutic compounds on hERG channel block in vitro and QT interval prolongation in vivo. Unfortunately, these have proven to be poor predictors of...
Article
Background and Purpose Pharmacotherapy of atrial fibrillation (AF), the most common cardiac arrhythmia, remains unsatisfactory due to low efficacy and safety concerns. New therapeutic strategies target atrial‐predominant ion‐channels and involve multichannel block (poly)therapy. As AF is characterized by rapid and irregular atrial activations, comp...
Article
Rationale: Cardiotoxic β1 adrenergic receptor (β1AR)-CaMKII signaling is a major and critical feature associated with development of heart failure. Synapse-associated protein 97 (SAP97) is a multi-functional scaffold protein that binds directly to the C-terminus of β1AR and organizes a receptor signalosome. Objective: We aim to elucidate the dynami...
Article
Background Despite strong evidence of the fundamental connection between the brain and the heart, there is still a poor quantitative and functional understanding of the role of autonomic regulation in normal cardiac excitation‐contraction coupling and pathophysiology, including arrhythmias or contractile dysfunction. The intrinsic electrophysiologi...
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Full-text available
Rationale: Hypokalemia occurs in up to 20% of hospitalized patients, and is associated with increased incidence of ventricular and atrial fibrillation. It is unclear whether these differing types of arrhythmia result from direct and perhaps distinct effects of hypokalemia on cardiomyocytes. Objective: To investigate pro-arrhythmic mechanisms of hyp...
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Full-text available
This white paper presents principles for validating proarrhythmia risk prediction models for regulatory use as discussed at the In Silico Breakout Session of a Cardiac Safety Research Consortium/Health and Environmental Sciences Institute/US Food and Drug Administration–sponsored Think Tank Meeting on May 22, 2018. The meeting was convened to evalu...
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Full-text available
Key points Induced pluripotent stem cell‐derived cardiomyocytes (iPSC‐CMs) capture patient‐specific genotype–phenotype relationships, as well as cell‐to‐cell variability of cardiac electrical activity Computational modelling and simulation provide a high throughput approach to reconcile multiple datasets describing physiological variability, and al...
Article
Full-text available
Key points Cardiac electrophysiology and Ca²⁺ handling change rapidly during the fight‐or‐flight response to meet physiological demands. Despite dramatic differences in cardiac electrophysiology, the cardiac fight‐or‐flight response is highly conserved across species. In this study, we performed physiological sympathetic nerve stimulation (SNS) whi...
Article
Atrial fibrillation (AF) is a complex cardiac arrhythmia with diverse etiology that negatively affects morbidity and mortality of millions of patients. Technological and experimental advances have provided a wealth of information on the pathogenesis of AF, highlighting a multitude of mechanisms involved in arrhythmia initiation and maintenance, and...