Search

Sok-Sithikun Bun, Decebal Gabriel Lațcu, Ahmed Mostfa Wedn, Karim Hasni, Nadir SaoudiDepartment of Cardiology, Princess Grace Hospital, Monaco (Principality), Monaco, MonacoAbstract: The precise circuit of cavotricuspid isthmus (CTI)-dependent atrial flutters (AFLs) has been well characterized, but the recent arrival of ultrahigh-resolution mapping systems has further improved our understanding of this “old” arrhythmia. CTI-dependent AFL may be the arrhythmia for which the electrocardiograph (ECG) correlation with the mechanism may be the highest. Once the diagnosis is made (predominantly based upon the surface ECG), the therapeutic options are precisely defined, with radiofrequency catheter ablation representing an efficient strategy with a high success rate and few complications. This article will focus on the clinical perspectives for CTI-dependent AFL.Keywords: typical atrial flutter, cavotricuspid isthmus-dependent, catheter ablation

Breast cancer affects 1/8 of women throughout their lifetimes, with 90% of cancer deaths being caused by metastasis. However, metastasis poses unique challenges to research, as complex changes in the microenvironment in different metastatic sites and difficulty obtaining tissue for study hinder the ability to examine in depth the changes that occur during metastasis. Rapid autopsy programs thus fill a unique need in advancing metastasis research. Here, we describe our protocol and processes for establishing and improving the US-based Hope for OTHERS (Our Tissue Helping Enhance Research and Science) program for organ donation in metastatic breast cancer. Our results reveal key logistical and protocol improvements that are uniquely beneficial to certain programs based on identifiable features, such as working closely with patient advocates, methods to rescue RNA quality in cases where tissue quality may degrade due to time delays, as well as guidelines and future expansions of our program with new research and novel research findings in patient outcomes, metastatic phylogeny, living model development and more., Competing Interests: Conflict of Interest Statement The authors have no conflicts of interest related to this work. Author RB is a former consultant for GE Health (now ended), and current Speaker’s Bureau member for AstraZeneca. Author AB is a current consultant for AstraZeneca, Pfizer, Novartis, Lilly, Genentech/Roche, Daiichi Sankyo, Merck, Agendia, Sanofi, Puma, Myriad, Gilead, Bria-Cell, and receives research support from Agendia and AstraZeneca.

Objective: Invasive lobular breast cancer (ILC) is the most common special type of breast cancer and has unique clinicopathological and molecular hallmarks that differentiate it from the more common invasive carcinoma-no special type (NST). Despite these differences, ILC and NST are treated as a single entity and there is a lack of ILC-targeted therapies. To fill this gap, we sought to identify novel molecular alterations in ILC that could be exploited for targeted therapies., Methods: Differential gene expression and Geneset Enrichment and Variation analyses were performed on RNA-seq data from three large public breast cancer databases-the Sweden Cancerome Analysis Network-Breast (SCAN-B; luminal A ILC N = 263, luminal A NST N = 1162), The Cancer Genome Atlas (TCGA; luminal A ILC N = 157, luminal A NST N = 307) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC; luminal A ILC N = 65, luminal A NST N = 533). Pathways enriched in overlapping differentially expressed genes from these datasets were clustered using Jaccard similarity to identify pathways enriched in ILC. The cAMP/PKA/CREB signaling was studied in ILC, ILC-like and NST cell lines and patient-derived organoids (PDOs) using forskolin, an activator of the pathway., Results: Clinicopathological features of patients with ILC and NST in SCAN-B were similar to prior population-based studies. There was a consistent pattern of up-regulation of cAMP/PKA/CREB related signaling in ILC compared to NST in SCAN-B, TCGA and METABRIC. Treatment with forskolin resulted in a greater increase in phospho-CREB in ILC cell lines and organoids than NST. CRISPR deletion of CDH1 in NST cell lines did not alter response of cells to forskolin as measured by phospho-CREB. Forskolin treatment caused growth inhibition in ILC and NST, with ILC cell lines being more sensitive to forskolin-mediated growth inhibition., Conclusion: In three separate datasets, cAMP/PKA/CREB signaling was identified to be higher in ILC than NST. This in silico finding was validated in cell line and organoid models. Loss of CDH1 was not sufficient to mediate this phenotype. Future studies should investigate the mechanisms for differential cAMP/PKA/CREB signaling and the potential for therapeutic targeting in patients with ILC., (© 2024. The Author(s).)

Estrogen receptor alpha (ER/ESR1) mutations occur in 30% to 40% of endocrine resistant ER-positive (ER+) breast cancer. Forkhead box A1 (FOXA1) is a key pioneer factor mediating ER-chromatin interactions and endocrine response in ER+ breast cancer, but its role in ESR1-mutant breast cancer remains unclear. Our previous FOXA1 chromatin immunoprecipitation sequencing (ChIP-seq) identified a large portion of redistributed binding sites in T47D genome-edited Y537S and D538G ESR1-mutant cells. Here, we further integrated FOXA1 genomic binding profile with the isogenic ER cistrome, accessible genome, and transcriptome data of T47D cell model. FOXA1 redistribution was significantly associated with transcriptomic alterations caused by ESR1 mutations. Furthermore, in ESR1-mutant cells, FOXA1-binding sites less frequently overlapped with ER, and differential gene expression was less associated with the canonical FOXA1-ER axis. Motif analysis revealed a unique enrichment of retinoid X receptor (RXR) motifs in FOXA1-binding sites of ESR1-mutant cells. Consistently, ESR1-mutant cells were more sensitive to growth stimulation with the RXR agonist LG268. The mutant-specific response was dependent on two RXR isoforms, RXR-α and RXR-β, with a stronger dependency on the latter. In addition, T3, the agonist of thyroid receptor (TR) also showed a similar growth-promoting effect in ESR1-mutant cells. Importantly, RXR antagonist HX531 blocked growth of ESR1-mutant cells and a patient-derived xenograft (PDX)-derived organoid with an ESR1 D538G mutation. Collectively, our data support the evidence for a stronger RXR response associated with FOXA1 reprograming in ESR1-mutant cells, suggesting development of therapeutic strategies targeting RXR pathways in breast tumors with ESR1 mutation., Implications: It provides comprehensive characterization of the role of FOXA1 in ESR1-mutant breast cancer and potential therapeutic strategy through blocking RXR activation., (©2023 American Association for Cancer Research.)

Background: Radiofrequency (RF) ablation of slow pathway (SP) is usually performed in sinus rhythm while monitoring the occurrence of a slow junctional rhythm (JR). JR although sensitive, is not specific for elimination of SP conduction. Our objective was to prospectively evaluate feasibility and safety of SP elimination using fast atrial rate pacing (FAP) during RF delivery., Methods: Consecutive patients admitted for atrioventricular nodal re-rentrant tachycardia (AVNRT) ablation were included. The rate of proximal coronary sinus (CS) pacing was set to a value constantly yielding antegrade SP conduction, while carefully monitoring the AH interval. RF delivery (at the lower part of Koch's triangle) was considered successful if the AH shortened ≥ 14 ms or if transition from Wenckebach (WK) periods to a 1:1 conduction occurred., Results: 24 patients were included (54 ± 20 y). Typical AVNRT was induced in all (cycle length 349 ± 83 ms). RF delivery during CS pacing (335 ± 73 ms) led to AH shortening by 51 ± 25 ms in 13 patients. In 10 patients, a transition from 3:2 or 4:3 WK periods to 1:1 conduction occurred during the successful pulse. In one patient, atrial fibrillation was systematically induced during FAP, requiring conventional ablation. Non-inducibility, and SP conduction disappearance was obtained in all patients. No patient developed AV block. After a follow-up of 12 ± 3 months, no recurrences were observed., Conclusion: SP ablation using FAP during RF delivery allows direct visualisation of its disappearance. In our cohort of patients, this technique was feasible without safety compromise.

The cholinergic anti-inflammatory pathway (CAP) is vital for the orchestration of the immune and inflammatory responses under normal and challenged conditions. Over the past two decades, peripheral and central circuits of CAP have been shown to be critically involved in dampening the inflammatory reaction in a wide array of inflammatory disorders. Additionally, emerging evidence supports a key role for CAP in the regulation of the female reproductive system during gestation as well as in the advent of serious pregnancy-related inflammatory insults such as preeclampsia (PE). Within this framework, the modulatory action of CAP encompasses the perinatal maternal and fetal adverse consequences that surface due to antenatal PE programming. Albeit, a considerable gap still exists in our knowledge of the precise cellular and molecular underpinnings of PE/CAP interaction, which hampered global efforts in safeguarding effective preventive or therapeutic measures against PE complications. Here, we summarize reports in the literature regarding the roles of peripheral and reflex cholinergic neuroinflammatory pathways of nicotinic acetylcholine receptors (nAChRs) in reprogramming PE complications in mothers and their progenies. The possible contributions of α7-nAChRs, cholinesterases, immune cells, adhesion molecules, angiogenesis, and endothelial dysfunction to the interaction have also been reviewed., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: Literature supports the existence of drivers as maintainers of atrial fibrillation (AF). Whether ultrahigh density (UHD) contact mapping may detect them is unknown., Methods: We sequentially mapped the left atrial (LA) activation during spontaneous persistent AF and performed circumferential pulmonary vein isolation (CPVI), followed by remapping and ablation of potential drivers (rotational and focal propagation sites) with Rhythmia™ in 90 patients. The time reference was an LA appendage (LAA) electrogram (EGM). Regions with uniform color were defined as "organized." Only patients (51) with no previous ablation were considered for acute results and follow-up reporting., Results: LA maps (175 ± 28 ml, 43578 ± 18013 EGM) were acquired in 23 ± 7 min. In all post-CPVI maps potential drivers (7.3 ± 3.2/patient) were visualized: 85% with rotational propagation and continuous low voltage in the center; the remaining with focal propagation and an organized EGM at the site of earliest activation. The RF delivery time for extra-PV driver ablation was 12.2 ± 7.9 min. There was a progressive increase of AF organization: the LAA cycle length prolonged, the number of potential drivers decreased, and the organized LA surface in AF increased from 14 ± 6% to 28 ± 16% (p = .0007). Termination of AF without cardioversion was obtained in 67%. AF recurrence rate at 15 ± 7.3 months was 17.6% after the first procedure., Conclusions: Sequential UHD contact activation mapping of persistent AF allows visualization of potential drivers. A sequential strategy of CPVI followed by ablation of potential drivers with limited RF time resulted in an increasing organization of AF and good acute and long-term results., (© 2020 Wiley Periodicals LLC.)

Pre-eclampsia (PE)-induced fetal programming predisposes offspring to health hazards in adult life. Here, we tested the hypothesis that pre-eclamptic fetal programming elicits sexually dimorphic inflammatory and cardiovascular complications to endotoxemia in adult rat offspring. PE was induced by oral administration of L-NAME (50 mg/kg per day for seven consecutive days) starting from day 14 of conception. Cardiovascular studies were performed in conscious adult male and female offspring preinstrumented with femoral indwelling catheters. Compared with non-PE male counterparts, intravenous administration of lipopolysaccharide (LPS, 5 mg/kg) to PE male offspring caused significantly greater 1) falls in blood pressure, 2) increases in heart rate, 3) rises in arterial dP/dtmax, a correlate of left ventricular contractility, and 4) decreases in time- and frequency-domain indices of heart rate variability (HRV). By contrast, the hypotensive and tachycardic actions of LPS in female offspring were independent of the pre-eclamptic state and no clear changes in HRV or dP/dtmax were noted. Measurement of arterial baroreflex activity by vasoactive method revealed no sex specificity in baroreflex dysfunction induced by LPS. Immunohistochemical studies showed increased protein expression of toll-like receptor 4 in heart as well as in brainstem neuronal pools of the nucleus of solitary tract and rostral ventrolateral medulla in endotoxic PE male, but not female, offspring. Enhanced myocardial, but not neuronal, expression of monocyte chemoattractant protein-1 was also demonstrated in LPS-treated male offspring. Together, pre-eclamptic fetal programming aggravates endotoxic manifestations of hypotension and autonomic dysfunction in male offspring via exacerbating myocardial and neuromedullary inflammatory pathways. SIGNIFICANCE STATEMENT: Current molecular and neuroanatomical evidence highlights a key role for pre-eclamptic fetal programming in offspring predisposition to health hazards induced by endotoxemia in adult life. Pre-eclampsia accentuates endotoxic manifestations of hypotension, tachycardia, and cardiac autonomic dysfunction in male offspring via exacerbating myocardial and central inflammatory pathways. The absence of such detrimental effects in female littermates suggests sexual dimorphism in the interaction of pre-eclamptic fetal programming with endotoxemia., Competing Interests: The authors declare no conflict of interest., (Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics.)

The nicotinic/cholinergic antiinflammatory pathway protects against acute kidney injury and other end-organ damages induced by endotoxemia. In this study, we tested the hypothesis that functional α7-nAChRs/heme oxygenase-1 (HO-1) pathway is imperative for the nicotine counteraction of hemodynamic and renovascular dysfunction caused by acute endotoxemia in rats. Renal vasodilations were induced by cumulative bolus injections of acetylcholine (ACh, 0.01 nmol-7.29 nmol) or ethylcarboxamidoadenosine (NECA, adenosine receptor agonist, 1.6 nmol-100 nmol) in isolated phenylephrine-preconstricted perfused kidneys. The data showed that 6-h treatment with lipopolysaccharide (LPS, 5 mg/kg i.p.) decreased systolic blood pressure and renal vasodilations caused by NECA but not Ach. The endotoxic insult also increased the mortality rate and elevated serum urea and creatinine. These LPS effects were sex-unrelated, except hypotension, and enhanced mortality which were more evident in male rodents, and abrogated after co-administration of nicotine (0.5, 1 mg/kg and 2 mg/kg) in a dose-dependent fashion. The advantageous effects of nicotine on NECA vasodilations, survivability, and kidney biomarkers in endotoxic male rats disappeared upon concurrent exposure to methyllycaconitine citrate (α7-nAChR blocker) or zinc protoporphyrin (HO-1 inhibitor) and were reproduced after treatment with bilirubin, but not hemin (HO-1 inducer) or tricarbonyldichlororuthenium (II) dimer (carbon monoxide-releasing molecule). Together, current biochemical and pharmacological evidence suggests key roles for α7-nAChRs and the bilirubin byproduct of the HO-1 signaling in the nicotine counteraction of renal dysfunction and reduced adenosinergic renal vasodilator capacity in endotoxic rats.

Objective: The objective of the study was to test the hypothesis that nicotine guards against endotoxemia-associated renal inflammation and vasoconstrictor dysfunction via the activation of α7-nicotinic acetylcholine receptors (α7-nAChRs)/heme oxygenase-1 (HO-1) cascade., Materials: 91 male and female rats were included in the study., Treatments: Lipopolysaccharide (LPS, 5 mg kg -1 ), nicotine (0.5-2 mg kg -1 ), pentoxifylline (PTX, TNFα inhibitor, 3 mg kg -1 ), methyllycaconitine (MLA, α7-nAChR blocker), zinc protoporphyrin (ZnPP, HO-1 inhibitor), hemin (HO-1 inducer), tricarbonyldichlororuthenium (carbon monoxide-releasing molecule, CORM-2) or bilirubin was administered before LPS., Methods: Isolated perfused kidney was used to evaluate renal vasoconstriction and immunohistochemistry to assess inflammatory cytokines., Results: LPS reduced renal vasoconstrictions induced by phenylephrine or vasopressin in perfused kidneys of male, but not female, rats. Higher elevations in serum interleukin-1β and renal expressions of inducible nitric oxide synthase (iNOS) and nuclear factor-κB (NF-κB) were observed in LPS-treated male rats, whereas greater HO-1 expression was evident in endotoxic female rats. LPS effects were reversed by nicotine or PTX. Further, the favorable nicotine actions were (i) diminished by MLA or ZnPP and (ii) replicated by hemin or CORM-2, but not bilirubin, and (iii) associated with exaggerated and MLA-sensitive increases in HO-1 expression., Conclusions: α7-nAChR/HO-1/CO signaling mediates nicotine protection against renal inflammation and vasoconstrictor hyporeactivity in endotoxic male rats.

Background: Whether cavotricuspid isthmus (CTI) is a region of conduction slowing during typical flutter has been discussed with conflicting results in the literature. We aimed to evaluate conduction velocity (CV) along the different portions of the typical flutter circuit with a recently proposed method by means of ultra-high-resolution (UHR) mapping., Methods: Consecutive patients referred for typical atrial flutter (AFL) ablation underwent UHR mapping (Rhythmia, Boston Scientific). CVs were measured in the CTI as well as laterally and septally, respectively, from its lateral and septal borders., Results: A total of 33 patients (mean age: 65 ± 13 years; right atrial volume: 134 ± 57 mL) were mapped either during ongoing counterclockwise (n = 25), or clockwise (n = 3) AFL (mean cycle length: 264 ± 38 ms), or during coronary sinus pacing at 400 ms (n = 1), 500 ms (n = 1), or 600 ms (n = 3). A total of 13 671 ± 7264 electrograms were acquired in 14 ± 9 min. CTI CV was significantly lower (0.56  ± 0.18 m/s) in comparison with the lateral CV (1.31 ± 0.29 m/s; P < .0001) and the septal border CV of the CTI (1.29 ± 0.31 m/s; P < .0001)., Conclusion: UHR mapping confirmed that CTI CV was systematically twice lower than atrial conduction velocities outside the CTI., (© 2019 Wiley Periodicals, Inc.)

Widely different exposure times to endotoxic insults have been employed in reported studies. The current experimental study systematically evaluated the time-course and sex influences of endotoxic insult on survivability and cardiovascular and renal functions. Rats received i.p. lipopolysaccharide (LPS, 5 mg/kg) once or twice (over 2 successive days). Systolic blood pressure (SBP), biomarkers of renal function and inflammation, and vasodilator responsiveness of isolated perfused kidneys to acetylcholine (ACh) or N-ethylcarboxamidoadenosine (NECA) were evaluated 6 hr after first LPS injection or 1, 2, or 6 days later. A single 6-hr LPS challenge caused (i) sex-unrelated elevations in serum urea and creatinine and reductions in NECA, but not ACh, vasodilations, (ii) more increases in renal NF-κB/iNOS expressions in male than in female rats, and (iii) hypotension and tachycardia only in male rats. These parameters, except for hemodynamic changes, were restored to near-control levels 1 day after single LPS dosing. The 2-days dosing with LPS had no effects on renal function biomarkers, but caused hypotension, tachycardia, and increases in renal NF-κB/iNOS expression and NECA and ACh vasodilations in both rat sexes. None of these parameters were different from control values when measured 6 days after the endotoxic insult. Alternatively, the rat mortality was observed during first 2 days of the study and was notably higher in male than in female rats. Our data suggest that the frequency and time elapsed after LPS exposure as well as rat sex are important determinants of the magnitude and direction of detrimental effects of endotoxemia., Competing Interests: The authors declared that there is no conflict of interest., (© 2019 The Author(s).)

Background: Nicotine alleviates renal inflammation and injury induced by endotoxemia. This study investigated (i) the nicotine modulation of hemodynamic and renal vasodilatory responses to endotoxemia in rats, and (ii) roles of α7 or α4β2-nAChRs and related HSP70/TNFα/iNOS signaling in the interaction., Methods: Endotoxemia was induced by ip lipopolysaccharide (5 mg/kg/day, for 2 days) and changes in systolic blood pressure and vasodilator responsiveness of isolated perfused kidney to acetylcholine or 5'-N-ethylcarboxamidoadenosine (NECA, adenosine receptor agonist) were evaluated., Results: Lipopolysaccharide had no effect on serum creatinine, reduced blood pressure, and increased renal vasodilations induced by acetylcholine or NECA in male and female preparations. Immunohistochemical analyses showed that lipopolysaccharide reduced renal HSP70 expression, but increased α7-nAChRs, α4β2-nAChRs and iNOS expressions. The co-administration of aminoguanidine (iNOS inhibitor), pentoxifylline (TNFα inhibitor), or nicotine attenuated lipopolysaccharide mediation of renal vasodilations and elevations in α7/α4β2-nAChR and iNOS expressions. Nicotine also reversed the downregulating effect of lipopolysaccharide on HSP70 expression. α7-nAChRs (methyllycaconitine citrate, MLA) or α4β2-nAChRs (dihydro-β-erythroidine, DHβE) blockade potentiated the lipopolysaccharide enhancement of renal vasodilations, and abolished the depressant effect of nicotine on lipopolysaccharide responses. A similar abolition of nicotine effects was seen after HSP70 inhibition by quercetin. Alternatively, lipopolysaccharide hypotension was eliminated in rats treated with DHβE/nicotine or quercetin/nicotine regimen in contrast to no effect for nicotine alone or combined with MLA., Conclusions: These findings establish that nicotine offsets lipopolysaccharide facilitation of renal vasodilations possibly through a crosstalk between HSP70 and nAChRs of the α7 and α4β2 types., (Copyright © 2019 Maj Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier B.V. All rights reserved.)

Successful catheter ablation of scar-related atrial tachycardia depends on correct identification of the critical isthmus. Often, this is a represented by a small bundle of viable conducting tissue within a low-voltage area. It's identification depends on the magnitude of the signal/noise ratio. Ultra-high density mapping, multipolar catheters with small (eventually unidirectional) and closely-spaced electrodes improves low-voltage electrogram detection. Background noise limitation is also of major importance for improving the signal/noise ratio. Electrophysiological properties of the critical isthmus and the characteristics of the local bipolar electrograms have been recently demonstrated as hallmarks of successful ablation sites in the setting of scar-related atrial tachycardia., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)