Ana M Gomez

French Institute of Health and Medical Research | Inserm · Unit of Signalling and Cardiovascular Pathophysiology

Background. In addition to show autonomous beating rhythmicity, the physiological functions of the heart present daily periodic oscillations. Notably the ventricular repolarization itself varies throughout the circadian cycle which was mainly related to the periodic expression of K+ channels. However, the involvement of the L-type Ca2+ channel (CaV...

In the last 25 years, EP Europace has published more than 300 basic and translational science articles covering different arrhythmia types (ranging from atrial fibrillation to ventricular tachyarrhythmias), different diseases predisposing to arrhythmia formation (such as genetic arrhythmia disorders and heart failure), and different interventional...

Anthracyclines, such as doxorubicin (Dox), are widely used chemotherapeutic agents for the treatment of solid tumors and hematologic malignancies. However, they frequently induce cardiotoxicity leading to dilated cardiomyopathy and heart failure. This study sought to investigate the role of the Exchange Protein directly Activated by cAMP (EPAC) in...

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...

Heart failure (HF) is a complex syndrome in which death rates are >50%. The main causes of death among HF patients are pump failure and ventricular arrhythmias, but severe bradycardia is also a common cause of sudden cardiac death, pointing to sinoatrial node (SAN) dysfunction. SAN pacemaker activity is regulated by voltage-clock and Ca2+-clock mec...

Heart failure (HF) is a complex syndrome in which death rates are over 50%. The main cause of death among HF patients is pump failure and ventricular arrhythmias, but severe bradycardia is also a common cause of sudden cardiac death, pointing to sinoatrial node (SAN) dysfunction. SAN pacemaker activity is regulated by voltage-clock and Ca2+-clock m...

Specialized proresolving mediators and, in particular, 5(S), (6)R, 7-trihydroxyheptanoic acid methyl ester (BML-111) emerge as new therapeutic tools to prevent cardiac dysfunction and deleterious cardiac damage associated with myocarditis progression. The cardioprotective role of BML-111 is mainly caused by the prevention of increased oxidative str...

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...

Dysfunction of the sinoatrial node (SAN), the natural heart pacemaker, is common in heart failure (HF) patients. SAN spontaneous activity relies on various ion currents in the plasma membrane (voltage clock), but intracellular Ca2+ ([Ca2+]i) release via ryanodine receptor 2 (RYR2; Ca2+ clock) plays an important synergetic role. Whereas remodeling o...

Duchenne muscular dystrophy (DMD) is characterized by progressive muscle degeneration. Two important deleterious features are a Ca2+ dysregulation linked to Ca2+ influxes associated with ryanodine receptor hyperactivation, and a muscular nicotinamide adenine dinucleotide (NAD+ ) deficit. Here, we identified that deletion in mdx mice of CD38, a NAD+...

In mesenteric arteries (MAs), aldosterone (ALDO) binds to the endogenous mineralocorticoid receptor (MR) and increases the expression of the voltage-gated L-type Cav1.2 channel, an essential ion channel for vascular contraction, sarcoplasmic reticulum (SR) Ca2+ store refilling, and Ca2+ spark generation. In mesenteric artery smooth muscle cells (MA...

Urocortin-2 (Ucn-2) has demonstrated cardioprotective actions against myocardial ischemia-reperfusion (I/R) injuries. Herein, we explored the protective role of Ucn-2 through microRNAs (miRNAs) post-transcriptional regulation of apoptotic and pro-fibrotic genes. We determined that the intravenous administration of Ucn-2 before heart's reperfusion i...

Diabetes mellitus is a metabolic disorder with a chronic hyperglycaemic state. Cardiovascular diseases are the primary cause of mortality in patients with diabetes. Increasing evidence supports the existence of diabetic cardiomyopathy, a cardiac dysfunction with impaired cardiac contraction and relaxation, independent of coronary and/or valvular co...

Heart Failure (HF) is defined as the inability of the heart to efficiently pump out enough blood to maintain the body's needs, first at exercise and then also at rest. Alterations in Ca²⁺ handling contributes to the diminished contraction and relaxation of the failing heart. While most Ca²⁺ handling protein expression and/or function has been shown...

Cardiac arrhythmias are a major cause of death and disability. A large number of experimental cell and animal models have been developed to study arrhythmogenic diseases. These models have provided important insights into the underlying arrhythmia mechanisms and translational options for their therapeutic management. This position paper from the ES...

Key points In cardiac myocytes, subcellular local calcium release signals, calcium sparks, are recruited to form each cellular calcium transient and activate the contractile machinery. Abnormal timing of recovery of sparks after their termination may contribute to arrhythmias. We developed a method to interrogate recovery of calcium spark trigger p...

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is triggered by exercise or acute emotion in patients with normal resting electrocardiogram. The major disease-causing gene is RYR2, encoding the cardiac ryanodine receptor (RyR2). We report a novel RYR2 variant, p.Asp3291Val, outside the four CPVT mutation hotspots, in three CPVT familie...

Anthracyclines, such as doxorubicin (Dox), are widely used chemotherapeutic agents for the treatment of solid tumors and hematologic malignancies. However, they frequently induce cardiotoxicity leading to dilated cardiomyopathy and heart failure. This study sought to investigate the role of the Exchange Protein directly Activated by cAMP (EPAC) in...

Rationale: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare disease, manifested by syncope or sudden death in children or young adults under stress conditions. Mutations in the Ca ²⁺ release channel/ryanodine receptor (RyR2) gene account for about 60% of the identified mutations. Recently, we found and described a mutation in...

Introduction Norepinephrine and epinephrine provide the most powerful stimulation of cardiac function through activation of β-adrenergic receptors and the cAMP-dependent protein kinase (PKA). The PKA holoenzyme consists of a dimer of regulatory (R) subunits that binds and inhibits two catalytic subunits (C). Two types of PKA are expressed in the he...

Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): ANR (Agence Nationale de la Rercherche) Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a lethal genetic arrhythmia that manifests by syncope or sudden death in children and young adults under stress conditions without o...

Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Agence Nationale de la Recherche Introduction Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is an inherited disease manifested as syncope or sudden death in apparently healthy children or young adults, in the absence of...

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited disease manifested as syncope or sudden death in children and young adults. The ryanodine receptor (RyR2) R420Q mutation was identified in a 14-year-old boy who died suddenly. We generated human induced pluripotent (h-iPS) derived cardiomyocytes from two sisters. As most o...

Background During sympathetic stimulation, the activation of β-adrenergic receptors (βAR) increases cAMP levels, leading to positive chronotropic effect. Among the 6 cardiac cAMP-PDE families, PDE4 is critical for controlling excitation-contraction coupling (ECC) during β-stimulation in atrial and ventricular myocytes. PDE4 may also be important fo...

Introduction Doxorubicin (Dox) is an Anthracycline commonly used to treat many types of cancer; unfortunately this chemotherapeutic agent often induces side effects such as cardiotoxicity leading to cardiomyocyte death and dilated cardiomyopathy (DCM). This cardiotoxicity has been related to reactive oxygen species generation, DNA intercalation, to...

Background Numerous epidemiological and clinical studies have revealed a positive correlation between heart rate (HR) and cardiovascular morbimortality. The autonomic nervous system is the major extracardiac determinant of HR. During sympathetic stimulation, the activation of β-adrenergic receptors (βAR) induces an increase in cAMP levels, leading...

The archetypal store-operated Ca²⁺ channels (SOCs), Orai1, which are stimulated by the endo/sarcoplasmic reticulum (ER/SR) Ca²⁺ sensor stromal interaction molecule 1 (STIM1) upon Ca²⁺ store depletion is traditionally viewed as instrumental for the function of non-excitable cells. In the recent years, expression and function of Orai1 have gained rec...

Palabras clave. Pseudoaneurisma, falso aneurisma, arteria mesentérica superior, quimioterapia R-DAEPOCH, Linfoma B de alto grado. Abreviaturas PSA: Pseudoaneurisma. por biopsia de masa en topografía de cabeza pancreáti-ca. Acude a la guardia, transcurridos cinco meses de su diagnóstico y durante el cuarto ciclo de quimioterapia (R-DAEPOCH), por pre...

Introduction Cardiac ryanodine receptors RyR2 have a crucial role in excitation-contraction coupling by releasing Ca2+ from the sarcoplasmic reticulum (SR). In cardiomyocytes, two FK506 binding proteins (FKBP) of 12 and 12.6 kDa bind and stabilize RyR2 in a closed state. Despite its lower concentration, FKBP12.6 has a stronger affinity for RyR2 tha...

Introduction Anticancer treatments (chemo- and radiation therapies), such as Doxorubicin (Dox), used to treat many types of cancer are associated with many side effects such as cardiotoxicity mainly leading to a dilated cardiomyopathy (DCM) in chronic. Objectives There is a need for new treatment options and strategies aiming at reducing Doxorubic...

Background Numerous epidemiological and clinical studies have revealed a positive correlation between heart rate (HR) and cardiovascular morbimortality. The autonomic nervous system is the major extracardiac determinant of HR. During sympathetic stimulation, the activation of β-adrenergic receptors (βAR) induces an increase in cAMP levels, leading...

Introduction Epidemiological and preclinical studies have pointed out a correlation between hyperglycemia and increasing risk of heart failure. In cardiomyocytes, hyperglycemia has been shown to alter Ca2+ signaling via CaMKII a downstream effector of Epac2, a key player in Ca2+ mishandling. However the role of Epac2 in high-glucose (HG) mediated C...

CD4+T-lymphocytes are relevant in the pathogenesis of rheumatoid arthritis (RA), however, their potential involvement in early RA remains elusive. Methotrexate (MTX) is a commonly used disease-modifying antirheumatic drug (DMARD), but its mechanism has not been fully established. In 47 new-onset DMARD-naïve RA patients, we investigated the pattern...

Cardiomyopathy caused by A-type lamins gene (LMNA) mutations (LMNA cardiomyopathy) is associated with dysfunction of the heart, often leading to heart failure. LMNA cardiomyopathy is highly penetrant with bad prognosis with no specific therapy available. Searching for alternative ways to halt the progression of LMNA cardiomyopathy, we studied the r...

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a stress-induced ventricular arrhythmia associated with rhythm disturbance and impaired sinoatrial node cell (SANC) automaticity (pauses). Mutations associated with dysfunction of Ca²⁺-related mechanisms have been shown to be present in CPVT. These dysfunctions include impaired Ca²⁺ re...

Aim: Cardiovascular complications, including cardiac arrhythmias, result in high morbidity and mortality in patients with type-2 diabetes mellitus (T2DM). Clinical and experimental data suggest electrophysiological impairment of the natural pacemaker of the diabetic heart. The present study examined sinoatrial node (SAN) arrhythmias in a mouse mod...

Background: Orai1 is a critical ion channel subunit, best recognized as a mediator of store-operated Ca2+ entry (SOCE) in nonexcitable cells. SOCE has recently emerged as a key contributor of cardiac hypertrophy and heart failure but the relevance of Orai1 is still unclear. Methods: To test the role of these Orai1 channels in the cardiac pathoph...

Introduction: Major depressive disorder (MDD) patients experience a systemic inflammatory stage. Monocytes play an important role in innate inflammatory responses and may be modulated by bacterial translocation. Our aim was to investigate the subset distribution and function of circulating monocytes, levels of proinflammatory cytokines, gut barrier...

Introduction Doxorubicin (Dox) is an anthracycline commonly used to treat many types of cancer; unfortunately this chemotherapeutic agent induces many side effects such as cardiotoxicity leading to dilated cardiomyopathy (DCM). The cardiotoxicity of Dox has been related to reactive oxygen species generation, DNA intercalation, topoisomerase II inhi...

Background Numerous epidemiological and clinical studies have revealed a positive correlation between heart rate (HR) and cardiovascular morbimortality. The autonomic nervous system is the major extracardiac determinant of HR. During sympathetic stimulation, the activation of β-adrenergic receptors (βAR) induces an increase in cAMP levels, leading...

The cAMP-dependent protein kinase (PKA) consists of two regulatory (R) and two catalytic (C) subunits and comprises two subtypes, PKAI and PKAII, defined by the nature of their regulatory subunits, RIα and RIIα respectively. Whereas PKAII is thought to play a key role in β-adrenergic (β-AR) regulation of cardiac contractility, the function of PKAI...

Cardiac ryanodine receptors (RyR2) have a key role in excitation-contraction coupling by releasing Ca2+ from sarcoplasmic reticulum (SR). In cardiomyocytes, two FK506 binding protein (FKBP) isoforms have been shown to bind and to stabilize RyR2 opening: FKBP12 and FKBP12.6, the later having a stronger affinity for RyR2 despite its lower abundance....

Cardiac ryanodine receptors (RyR2) have a key role in excitation-contraction coupling by releasing Ca²⁺ from sarcoplasmic reticulum (SR). In cardiomyocytes, 2 FK506 binding protein (FKBP) isoforms have been shown to bind and to stabilize RyR2 opening: FKBP12 and FKBP12.6, the later having a stronger affinity for RyR2 despite its lower abundance. Ca...

Introduction Epidemiological and preclinical studies have pointed out a correlation between hyperglycemia and increasing risk of heart failure and cardiac death. In cardiomyocytes, hyperglycemia has been shown to alter Ca2 + signalling via CaMKII. Yet, the underlying mechanisms are still unclear. Objective To determine the molecular basis of high...

The cAMP-dependent protein kinase (PKA) consists of two regulatory (R) and two catalytic (C) subunits and comprises two subtypes, PKAI and PKAII, defined by the nature of their regulatory subunits, RIα and RIIα respectively. Whereas PKAII is thought to play a key role in β-adrenergic (β-AR) regulation of cardiac contractility, the function of PKAI...

Cardiovascular complications are the primary death cause in type 2 diabetes, where inflammation can play a role. We, and others, have previously shown that, in diabetic cardiomyopathy, cardiac dysfunction is associated with Ca2+ mishandling. It is possible that diabetic cardiomyopathy differently affects men and women, as the latter present higher...

Cardiac failure is a common complication in cancer survivors treated with anthracyclines. Here we followed up cardiac function and excitation-contraction (EC) coupling in an in vivo doxorubicin (Dox) treated mice model (iv, total dose of 10 mg/Kg divided once every three days). Cardiac function was evaluated by echocardiography at 2, 6 and 15 weeks...

Background: Monoallelic mutations in the gene encoding bone morphogenetic protein receptor 2 ( Bmpr2) are the main genetic risk factor for heritable pulmonary arterial hypertension (PAH) with incomplete penetrance. Several Bmpr2 transgenic mice have been reported to develop mild spontaneous PAH. In this study, we examined whether rats with the Bmp...

Aim: Deletion of QKP1507-1509 amino-acids in SCN5A gene product, the voltage-gated Na+ channel Nav1.5, has been associated with a large phenotypic spectrum of type 3 long QT syndrome, conduction disorder, dilated cardiomyopathy and high incidence of sudden death. The aim of this study was to develop and characterize a novel model of type 3 long QT...

Aims: Urocortin-2 (Ucn-2) is a potent cardioprotector against Ischemia and Reperfusion (I/R) injuries. However, little is known about its role in the regulation of intracellular Ca²⁺ concentration ([Ca²⁺]i) under I/R. Here, we examined whether the addition of Ucn-2 in reperfusion promotes cardioprotection focusing on ([Ca²⁺]i handling. Methods and...

The ryanodine receptors RyR2 have a key role in cardiac excitation-contraction coupling (ECC) and are regulated, among others, by FK506 binding proteins (FKBP). FKBP12 is more abundant than FKBP12.6 in cardiomyocytes with a low affinity for RyR2, whereas FKBP12.6 with stronger affinity is less abundant. In heart failure, FKBP expression decreases a...

Introduction Epac2 (Exchange Protein directly Activated by cAMP) has recently emerged as a critical player in heart failure and arrhythmia, also seen in diabetes. Hyperglycemia induces SR Ca²⁺ leak and arrhythmia via CaMKII, a downstream effector of Epac2. However, the role of Epac2 in hyperglycemia-mediated SR Ca²⁺ leak is unknown. Objective To d...

Duchenne muscular dystrophy (DMD) is a genetic disease due to the lack of dystrophin, a subsarcolemmal protein, which leads to muscle plasmatic membrane fragility. The patients suffer from a progressive weakness and degeneration (necrosis) accompanied by inflammation of skeletal and cardiac muscles. The main cause of patient death, in DMD adults, i...

Background Numerous epidemiological and clinical studies have revealed a positive correlation between heart rate (HR) and cardiovascular morbimortality. The autonomic nervous system is the major extracardiac determinant of HR. During sympathetic stimulation, the activation of β-adrenergic receptors (βAR) induces an increase in cAMP levels, leading...

QSOX1, a sulfhydryl oxidase, was shown to be upregulated in the heart upon acute heart failure (AHF). The aim of the study was to unravel QSOX1 roles during AHF. We generated and characterized mice with QSOX1 gene deletion. The QSOX1-/- mice were viable but adult male exhibited a silent dilated cardiomyopathy. The QSOX1-/- hearts were characterized...

Rationale: The mineralocorticoid receptor (MR) antagonists belong to the current therapeutic armamentarium for the management of cardiovascular diseases, but the mechanisms conferring their beneficial effects are poorly understood. Part of the cardiovascular effects of MR are due to the regulation of L-type Cav1.2 Ca2+channel expression, which is...

Sorcin, a penta-EF hand Ca2+-binding protein expressed in cardiomyocytes, is known to interact with ryanodine receptors and other Ca2+ regulatory proteins. To investigate sorcin's influence on cardiac excitation-contraction coupling and its role in the development of cardiac malfunctions, we generated a sorcin knockout (KO) mouse model. Sorcin KO m...

Calcium (Ca²⁺) is a universal intracellular second messenger. In the heart, it plays a key role by activating contraction through the excitation-contraction coupling (EC coupling) mechanism. Although this is its key role in the heart, Ca²⁺ has other important functions, not only being involved in cell growth (in the heart named excitation-transcrip...

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a lethal genetic arrhythmia that manifests syncope or sudden death in children and young adults under stress conditions. CPVT patients often present bradycardia and sino-atrial node (SAN) dysfunction. However, the mechanism remains unclear. We analyzed SAN function in two CPVT families...

Key points: Leptin, is a 16?kDa pleiotropic peptide, primary secreted by adipocytes, but also produced by other tissues including the heart. Controversy exists regarding the adverse and beneficial effects of Leptin on the heart We analysed the effect of a non-hypertensive dose of leptin on cardiac function, [Ca(2+) ]i handling and cellular electro...

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a genetic disease characterized by stress-induced syncope and/or sudden death. CPVT1 mutations are clustered in three regions: the N-terminal, the central, and the C-terminal domains of the cardiac Ca2+ release channel (type-2 ryanodine receptor, RyR2). We have created a knock-in (KI)...

The Store-Operated Ca2+ Entry (SOCE) has emerged as an important mechanism in cardiac pathology. However, the signals that upregulate SOCE in the heart remain unexplored. Clinical trials have emphasized the beneficial role of mineralocorticoid receptor (MR) signaling blockade in heart failure and associated arrhythmias. Accumulated evidences sugges...

Although cardiac cytosolic cyclic 3',5'-adenosine monophosphate (cAMP) regulates multiple processes, such as beating, contractility, metabolism and apoptosis, little is known yet on the role of this second messenger within cardiac mitochondria. Using cellular and subcellular approaches, we demonstrate here the local expression of several actors of...

The main mechanisms underlying doxorubicin (Dox)-induced cardiotoxicity involve classically reactive oxygen species generation, DNA intercalation and topoisomerase II (TopII) inhibition which lead ultimately to cardiomyocyte death. However, new signalling pathways are now emerging. β-adrenergic signalling with Epac (exchange protein directly activa...

The Duchenne muscular dystrophy (DMD) is caused by an absence or mutation of the protein dystrophin, which leads to smooth, skeletal and cardiac muscles degeneration. Intracellular calcium deregulation, notably abnormally high cytosolic calcium concentration, is thought to contribute to muscle necrosis and to cardiomyopathy development. Despite its...

Background Numerous epidemiological and clinical studies have revealed a positive correlation between heart rate (HR) and cardiovascular morbimortality. The autonomic nervous system is the major extracardiac determinant of HR. During sympathetic stimulation, the activation of β- adrenergic receptors (βAR) induces an increase in cAMP levels, leading...