Nathalie Lalevée

Effects of Amiodarone and Dronedarone on Voltage‐Dependent Sodium Current in Human Cardiomyocytes

Introduction: Amiodarone (AM) is a highly effective antiarrhythmic agent used in the management of both atrial and ventricular arrhythmias. Its noniodinated analogue dronedarone (SR) may have fewer side effects than AM. In this study, we compared the effects of AM and SR on the sodium current INa in human atrial myocytes.

Control of Cardiac Rhythm by ORK1, a Drosophila Two-Pore Domain Potassium Channel

Unravelling the mechanisms controlling cardiac automatism is critical to our comprehension of heart development and cardiac physiopathology. Despite the extensive characterization of the ionic currents at work in cardiac pacemakers, the precise mechanisms initiating spontaneous rhythmic activity and, particularly, those responsible for the specific control of the pacemaker frequency are still matters of debate and have not been entirely elucidated. By using Drosophila as a model animal to analyze automatic cardiac activity, we have investigated the function of a K+ channel, ORK1 (outwardly rectifying K+ channel-1) in cardiac automatic activity. ORK1 is a two-pore domain K+ (K2P) channel, which belongs to a diverse and highly regulated superfamily of potassium-selective leak channels thought to provide baseline regulation of membrane excitability. Cardiac-specific inactivation of Ork1 led to an increase in heart rhythm. By contrast, when overexpressed, ORK1 completely prevented heart beating. In addition, by recording action potentials, we showed that the level of Ork1 activity sets the cardiac rhythm by controlling the duration of the slow diastolic depolarization phase. Our observations identify a new mechanism for cardiac rhythm control and provide the first demonstration that K2P channels regulate the automatic cardiac activity.

The fabulous destiny of the Drosophila heart

For the last 15 years the fly cardiovascular system has attracted developmental geneticists for its potential as a model system of organogenesis. Heart development in Drosophila indeed provides a remarkable system for elucidating the basic molecular and cellular mechanisms of morphogenesis and, more recently, for understanding the genetic control of cardiac physiology. The success of these studies can in part be attributed to multidisciplinary approaches, the multiplicity of existing genetic tools, and a detailed knowledge of the system. Striking similarities with vertebrate cardiogenesis have long been stressed, in particular concerning the conservation of key molecular regulators of cardiogenesis and the new data presented here confirm Drosophila cardiogenesis as a model not only for organogenesis but also for the study of molecular mechanisms of human cardiac disease.

Response to Mechanical Stress Is Mediated by the TRPA Channel Painless in the Drosophila Heart

Mechanotransduction modulates cellular functions as diverse as migration, proliferation, differentiation, and apoptosis. It is crucial for organ development and homeostasis and leads to pathologies when defective. However, despite considerable efforts made in the past, the molecular basis of mechanotransduction remains poorly understood. Here, we have investigated the genetic basis of mechanotransduction in Drosophila. We show that the fly heart senses and responds to mechanical forces by regulating cardiac activity. In particular, pauses in heart activity are observed under acute mechanical constraints in vivo. We further confirm by a variety of in situ tests that these cardiac arrests constitute the biological force-induced response. In order to identify molecular components of the mechanotransduction pathway, we carried out a genetic screen based on the dependence of cardiac activity upon mechanical constraints and identified Painless, a TRPA channel. We observe a clear absence of in vivo cardiac arrest following inactivation of painless and further demonstrate that painless is autonomously required in the heart to mediate the response to mechanical stress. Furthermore, direct activation of Painless is sufficient to produce pauses in heartbeat, mimicking the pressure-induced response. Painless thus constitutes part of a mechanosensitive pathway that adjusts cardiac muscle activity to mechanical constraints. This constitutes the first in vivo demonstration that a TRPA channel can mediate cardiac mechanotransduction. Furthermore, by establishing a high-throughput system to identify the molecular players involved in mechanotransduction in the cardiovascular system, our study paves the way for understanding the mechanisms underlying a mechanotransduction pathway.

dJun and Vri/dNFIL3 are major regulators of cardiac aging in Drosophila.

Cardiac aging is a complex process, which is influenced by both environmental and genetic factors. Deciphering the mechanisms involved in heart senescence therefore requires identifying the molecular pathways that are affected by age in controlled environmental and genetic conditions. We describe a functional genomic investigation of the genetic control of cardiac senescence in Drosophila. Molecular signatures of heart aging were identified by differential transcriptome analysis followed by a detailed bio-informatic analysis. This approach implicated the JNK/dJun pathway and the transcription factor Vri/dNFIL3 in the transcription regulatory network involved in cardiac senescence and suggested the possible involvement of oxidative stress (OS) in the aging process. To validate these predictions, we developed a new in vivo assay to analyze heart performance in various contexts of adult heart-specific gene overexpression and inactivation. We demonstrate that, as in mammals, OS plays a central role in cardiac senescence, and we show that pharmacological interventions impinging on OS slow heart senescence. These observations strengthen the idea that cardiac aging is controlled by evolutionarily conserved mechanisms, further validating Drosophila as a model to study cardiac senescence. In addition, we demonstrate that Vri, the ortholog of the vertebrate NFIL3/E4B4 transcription factor, is a major genetic regulator of cardiac aging. Vri overexpression leads to major heart dysfunctions, but its loss of function significantly reduces age-related cardiac dysfunctions. Furthermore, we unambiguously show that the JNK/AP1 pathway, the role of which in cardiac aging in mammals is controversial, is activated during cardiac aging and has a detrimental effect on cardiac senescence. This data-driven functional genomic analysis therefore led to the identification of key components of the Gene Regulatory Network of cardiac aging in Drosophila and may prompt to investigate the involvement of their counterparts in the cardiac aging process in mammals.

Value of in vivo T2 measurement for myocardial fibrosis assessment in diabetic mice at 11.75 T.

Objective:The aim of the study was to assess the value of in vivo T2 measurements to noninvasively quantify myocardial fibrosis in diabetic mice at 11.75 T. Diabetic cardiomyopathy is characterized by extracellular matrix alteration and microcirculation impairment. These conditions might provide electrical heterogeneity, which is a substrate for arrhythmogenesis. T1 mapping has been proposed to quantify diffuse myocardial fibrosis in cardiac diseases but has several limitations. T2 measurement may represent an alternative for fibrosis quantification at high magnetic field. Materials and Methods:A magnetic resonance imaging protocol including in vivo T2 measurements at 11.75 T was performed in 9 male C57BL/6J mice after 8 weeks of streptozotocin-induced diabetes and in 9 control mice. Programmed ventricular stimulation was performed in both groups. T2 measurements were compared with histologic quantification of fibrosis using picrosirius red staining. Results:Myocardial T2 was significantly lower in diabetic mice (13.8 ± 2.8 ms) than in controls (18.9 ± 2.3 ms, P < 0.001). There was a good correlation between T2 and fibrosis area obtained by histopathology (R2 = 0.947, P < 0.001). During programmed ventricular stimulation, 3 nonsustained ventricular tachycardias were induced in diabetic mice versus none in the control group. Conclusions:The in vivo T2 relaxation time strongly correlated with myocardial fibrosis area assessed with histologic staining in diabetic mice.

Clinical Features, Management, and Outcomes of Immune Checkpoint Inhibitor–Related Cardiotoxicity

Immune checkpoint inhibitors (ICIs) represent a major advance in the treatment of cancer. Although clinical trials reported a low incidence of immune-related cardiovascular adverse events,1 the number of published life-threatening cases of cardiotoxicity is increasing.2 In this descriptive observational analysis, we aimed to describe the clinical manifestations, management, and outcomes of patients who developed ICI-related cardiotoxicity. The medical records of patients with a clinical suspicion of ICI-related cardiotoxicity were reviewed from the databases of 2 cardio-oncology units between March 2015 and April 2017. The patients are managed according to similar protocols. Because no specific follow-up had previously been established for patients receiving ICIs during the study period, the oncologists referred patients receiving ICIs only on the basis of their clinical suspicion of cardiovascular events. These patients had a standardized evaluation including clinical consultation, ECG, transthoracic echocardiography, and measurement of brain natriuretic peptide and troponin I serum levels. The management of cardiotoxicity was left to the physician’s discretion. The study was approved by our institutional review board, and informed consent has been obtained from the subjects. To create a pooled analysis, we also searched PubMed for English articles reporting cases of ICI-related cardiotoxicity until April 2017. We selected …

Management and research in cancer treatment-related cardiovascular toxicity: Challenges and perspectives

Cardiovascular toxicity is a potentially serious complication that can result from the use of various cancer therapies and can impact the short- and long-term prognosis of treated patients as well as cancer survivors. In addition to their potential acute cardiovascular adverse events, new treatments can lead to late toxicity even after their completion because patients who survive longer generally have an increased exposure to the cancer therapies combined to standard cardiovascular risk factors. These complications expose the patient to the risk of cardiovascular morbi-mortality, which makes managing cardiovascular toxicity a significant challenge. Cardio-oncology programs offer the opportunity to improve cardiovascular monitoring, safety, and management through a better understanding of the pathogenesis of toxicity and interdisciplinary collaborations. In this review, we address new challenges, perspectives, and research priorities in cancer therapy-related cardiovascular toxicity to identify strategies that could improve the overall prognosis and survival of cancer patients. We also focus our discussion on the contribution of cardio-oncology in each step of the development and use of cancer therapies.

Deletion of Nkx2-5 in trabecular myocardium reveals the developmental origins of pathological heterogeneity associated with ventricular non-compaction cardiomyopathy

Left ventricular non-compaction (LVNC) is a rare cardiomyopathy associated with a hypertrabeculated phenotype and a large spectrum of symptoms. It is still unclear whether LVNC results from a defect of ventricular trabeculae development and the mechanistic basis that underlies the varying severity of this pathology is unknown. To investigate these issues, we inactivated the cardiac transcription factor Nkx2-5 in trabecular myocardium at different stages of trabecular morphogenesis using an inducible Cx40-creERT2 allele. Conditional deletion of Nkx2-5 at embryonic stages, during trabecular formation, provokes a severe hypertrabeculated phenotype associated with subendocardial fibrosis and Purkinje fiber hypoplasia. A milder phenotype was observed after Nkx2-5 deletion at fetal stages, during trabecular compaction. A longitudinal study of cardiac function in adult Nkx2-5 conditional mutant mice demonstrates that excessive trabeculation is associated with complex ventricular conduction defects, progressively leading to strain defects, and, in 50% of mutant mice, to heart failure. Progressive impaired cardiac function correlates with conduction and strain defects independently of the degree of hypertrabeculation. Transcriptomic analysis of molecular pathways reflects myocardial remodeling with a larger number of differentially expressed genes in the severe versus mild phenotype and identifies Six1 as being upregulated in hypertrabeculated hearts. Our results provide insights into the etiology of LVNC and link its pathogenicity with compromised trabecular development including compaction defects and ventricular conduction system hypoplasia.

Response by Thuny et al to Letter Regarding Article, “Clinical Features, Management, and Outcomes of Immune Checkpoint Inhibitor–Related Cardiotoxicity”

We thank Campochairo et al for the interesting 3 points they raised about our work.1 First, there are no criteria for establishing diagnosis of immune checkpoint inhibitor (ICI)-related cardiotoxicity. Thus, the cause-effect relationship is not simple when cardiovascular events occur. Because immune-mediated myocarditis is the most widely recognized mechanism for this cardiotoxicity,2 the evidence of signs of myocarditis under ICIs would make it possible to establish a definite relationship between the cardiovascular event and ICIs. The gold standard for myocarditis diagnosis is based on the endomyocardial biopsy (EMB), which is not always achieved because of its invasive aspect and lack of sensitivity.3 Cardiac magnetic resonance imaging (CMR) can strongly help in …