Background Atrial fibrillation (AF) often progresses from paroxysmal to more stable forms. It is well-recognized that patients vary in their AF progression, but underlying mechanisms remain unclear. This work, performed in a sheep AF-model, aimed to identify atrial redox and energetic status differences between animals developing stable AF (AF-S) versus those resistant to AF-stabilization (AF-R). Methods AF was monitored with telemetry and maintained with bursts of atrial tachystimulation whenever sinus rhythm resumed. Electrophysiological remodeling was assessed via contact mapping. Structural remodeling was described by histology. Proteomic, metabolomic, enzymatic and bioenergetic remodeling were evaluated using frozen left atrial appendage (LAA) tissues and isolated LAA mitochondria. Healthy young rats were used to investigate if an induced metabolic challenge could stabilize AF episodes upon transesophageal atrial tachypacing challenge. Results AF-S sheep developed stable AF (>24-hours self-sustained) after 13 days on average, whereas AF-R sheep failed to develop self-sustained AF despite 120 days of electrically-maintained AF. Contact mapping and histological analysis revealed similar electro-structural remodeling in both groups. Metabolic analysis showed significant differences in tricarboxylic acid (TCA) cycle enzymes activities and a 45% increase in AF-S LAA succinate content versus AF-R. AF-S mitochondria showed abnormal mitochondrial succinate oxidation, associated with a significant 20% decrease in ATP synthesis rate, 22% increase in ROS emission and mitochondrial inner membrane hyperpolarization. The ratios of ATP to ADP, NAD+ to NADH, and Complex I/II were disturbed in AF-S compared to AF-R. Calculated mitochondrial NAD+ to NADH ratios suggest a reduced state of in-vivo AF-R mitochondria compared to the oxidized state of AF-S. Exogenous succinate was metabolized when incubated with rat atrial cardiomyocytes and altered redox balance, while intravenous succinate stabilized atrial arrhythmias induced by tachypacing in vivo . Conclusions Sheep resistant to AF-progression showed specific TCA cycle, energetic and redox adaptations compared to animals that developed self-sustained AF. In this animal model, mitochondrial TCA cycle remodeling and associated redox and energetic responses determined the resistance to AF domestication, with potential relevance to identify new mechanistic determinants of AF progression in humans. ### Competing Interest Statement The authors have declared no competing interest. Agence Nationale de la Recherche, ANR-17-CE14-0029-01, ANR-10-IAHU-04

Introduction Women increased risk of early mortality following ST-segment elevation myocardial infarction (STEMI) has been attributed to older age, more comorbidities, and less primary revascularization (PCI). Data on long-term outcomes is conflicting, and younger patients' specific evidence is limited. Purpose Compare gender outcomes following STEMI within a cohort of younger (≤55 years) and older (>55 years) individuals. Methods Retrospective analysis of consecutive patients with STEMI who underwent PCI within 48 h of symptom onset, between 2010 and 2015. Adverse outcomes were defined as 30-day, 1-year and 5-year all-cause mortality, and 5-year MACE. Propensity score matching for age, CV risk factors, and prior CV disease aimed to establish a well-balanced subset of male and female individuals. Results Among 882 patients, 26.8 % were females. Women were older and had higher clinical severity. Although clinical and PCI success were similar, over a mean follow-up of 91 months, women demonstrated nearly three times the risk of 30-day mortality (10.4 % vs 3.7 %, HR 2.88; p ≤0.001) and double the risk of 5-year death (31.9 % vs 17.0 %, HR 2.07; p < 0.001) and MACE (39.0 % vs 17.6 %, HR 1.95; p < 0.001). Sex differences in the younger subgroup were seen for 1-year (HR 3.74, p < 0.001), and long-term outcomes: HR 2.20 (p = 0.05) for 5-year mortality; HR 2.10 (p = 0.027) for 5-year MACE. After propensity matching, sex remained an independent predictor of adverse outcomes. Conclusions Females showed more CV events following STEMI, even after adjusting for potential confounders. These findings raise awareness for women risk and the need for strict post-STEMI surveillance.

The knowledge of the cardiac microstructure and the 3D myofiber architecture grow years after years with the multiplication and the upgrade of imaging technologies. However, the course of events of pathophysiological processes like cardiac remodeling, and the link with clinical phenotypes are not yet clearly understood. Some concerns have been raised regarding the interpretation of the late gadolinium enhancement (LGE) at the right ventricle attachment or insertion point (RVIP) however 3D microstructure organization of the RVIP has not been extensively described in the literature.

The pericardium plays an important role in mechanical interactions between the right (RV) and left (LV) ventricles, referred to as ventricular interdependence. However, the exact mechanisms of its supportive role remain unknown. The present study aimed to evaluate specifically ventricular interdependence in a model of isolated biventricular working heart of large mammal, which is in absence of neurohormonal influence or series interactions, and to evaluate the impacts of intact pericardium on this phenomenon. Pig hearts were excised with the pericardium intact and connected to a biventricular working mode setup. Low and high ventricular preloads and afterloads were imposed on the hearts by changing independently the left (LA) and right (RA) atrial pressures, or the aortic (Ao) and pulmonary artery (PA) pressures, respectively, in the presence or absence of an intact pericardium. In the presence of the pericardium, increasing atrial pressures mainly impacted the ipsilateral ventricular haemodynamics, including an increase in ventricular outflow and end-diastolic pressures, independent of the contralateral atrial pressure. LV haemodynamics were also mainly altered by the increase in the ipsilateral afterload (Ao pressure). By contrast, RV haemodynamics, including the PA flow, were not only affected by increasing its ipsilateral (PA pressure), but also by its contralateral (Ao pressure) ventricular afterload. The preload but not afterload-dependent effects were abolished after removing the pericardium. Our work indicates that RV haemodynamics are highly impacted by the pericardiectomy. This highlights the requirement of keeping the pericardium intact to explore accurately cardiac haemodynamics, particularly in the RV. KEY POINTS: Pericardium has an important role in maintaining mechanical interventricular interaction, even if it is not essential for life. We used an ex vivo biventricular working pig heart model to explore intrinsic ventricular responses to independent variations of left and right preload and afterload, in the presence and absence of the pericardium. We show that, in the presence of the pericardium, the right ventricular haemodynamics is impacted by the ipsilateral preload as well as the ipsi- and contralateral afterloads, whereas the left ventricular haemodynamics is only impacted by its ipsilateral pre- and afterload. The preload but not afterload-dependent effects are abolished after removing the pericardium. These results demonstrate a critical function of the pericardium in maintaining RV haemodynamics, as well as preload-dependent ventricular interactions.

INTRODUCTION:Myocarditis is the most lethal cardiovascular immune related adverse events with a low incidence, depending on the studies. We prospectively studied the potential interest of a systematic screening to early detect immune related myocarditis and confirm the incidence of immune-induced myocarditis in advanced lung cancer and the impact of troponin systematic screening in early detection of other major cardiovascular events (MACE). MATERIAL AND METHODS:This prospective bicentric study includes adults who received at least one dose of immune checkpoint inhibitor (ICI) for advanced lung cancer. Cardiac biomarkers dosage, ECG and transthoracic echography (TTE) were done at baseline. Diagnosis of myocarditis was based on European Society of Cardiology recommendations. MACEs were reported during the observation period. RESULTS:Among 298 patients, 5 (1.68 %) immune-induced myocarditis occurred, all being asymptomatic with at first troponin elevation, treated by corticosteroids and ICI's discontinuation. No attributable death occurred, and no specific clinical characteristics were identified with myocarditis onset. Three patients were rechallenged with ICI after troponin normalization in the absence of other therapeutic options. Recurrence occurred in 2 patients, with a re-increase of troponin and a de novo modification of the ECG. Systematic cardiovascular screening also led to 14 cardiovascular diseases detection and 11 MACEs during ICI. CONCLUSION:Systematic cardiovascular screening has uncovered slightly more immuno-induced myocarditis cases than reported previously, but without altering treatment strategies due to their subclinical nature. Additionally, it helps detecting other cardiovascular diseases in this comorbid population.

Description of the cardiac myofiber architecture in pathological or even physiological conditions is essential for image-based modeling in electrophysiology or mechanical studies. While diffusion tensor imaging (DTI) is one of the best modalities to capture myofiber orientation of large mammalian hearts, validations of putative myofiber’s main orientation from DTI in whole hearts of large mammals is limited. First we design an experimental protocol for sheep (N = 1) and human (N = 1) whole hearts that combine a standardized sample preparation with high-resolution diffusion MRI at 600 µm3 using low angular resolution (6 directions) followed by a tissue air-drying approach coupled with X-ray imaging at 42 µm3. Secondly, we propose a standardized post-processing pipeline for symmetric multimodal mapping allowing the comparison of myofiber orientation computed from DTI and structure tensor imaging (STI), respectively. We then identified region-of-interest (ROI) exhibiting small or sharp spatial variations in myofiber orientation and compared the putative myofiber orientation for both methods. In conclusion, we show a good correspondence of structural features between the two imaging modalities and identify new unexpected and complex cardiomyocytes organization such as oscillating patterns or clear separation of opposing fiber-bundles.

While the microstructure of the left ventricle (LV) has been largely described, only a few studies investigated the right ventricular insertion point (RVIP). It was accepted that the aggregate cardiomyocytes organization was much more complex due to the intersection of the ventricular cavities but a precise structural characterization in the human heart was lacking even if clinical phenotypes related to right ventricular wall stress or arrhythmia were observed in this region. MRI-derived anatomical imaging (150 µm3) and diffusion tensor imaging (600 µm3) were performed in large mammalian whole hearts (human: N = 5, sheep: N = 5). Fractional anisotropy, aggregate cardiomyocytes orientations and tractography were compared within both species. Aggregate cardiomyocytes orientation on one ex-vivo sheep whole heart was then computed using structure tensor imaging (STI) from 21 µm isotropic acquisition acquired with micro computed tomography (MicroCT) imaging. Macroscopic and histological examination were performed. Lastly, experimental cardiomyocytes orientation distribution was then compared to the usual rule-based model using electrophysiological (EP) modeling. Electrical activity was modeled with the monodomain formulation. The RVIP at the level of the inferior ventricular septum presented a unique arrangement of aggregate cardiomyocytes. An abrupt, mid-myocardial change in cardiomyocytes orientation was observed, delimiting a triangle-shaped region, present in both sheep and human hearts. FA’s histogram distribution (mean ± std: 0.29 ± 0.06) of the identified region as well as the main dimension (22.2 mm ± 5.6 mm) was found homogeneous across samples and species. Averaged volume is 0.34 cm3 ± 0.15 cm3. Both local activation time (LAT) and morphology of pseudo-ECGs were strongly impacted with delayed LAT and change in peak-to-peak amplitude in the simulated wedge model. The study was the first to describe the 3D cardiomyocytes architecture of the basal inferoseptal left ventricle region in human hearts and identify the presence of a well-organized aggregate cardiomyocytes arrangement and cardiac structural discontinuities. The results might offer a better appreciation of clinical phenotypes like RVIP-late gadolinium enhancement or uncommon idiopathic ventricular arrhythmias (VA) originating from this region.

A key component of the cardiac conduction system is the atrioventricular (AV) node where the His bundle (HB) divides into the right (RBB) and left (LBB) bundles branches. The RBB is connected to the right ventricle (RV) via the moderator band (MB).

Abstract Aims From a patient and health system perspective, managing worsening heart failure (WHF) as an outpatient has become a priority. Remote management allows early detection of WHF, enabling timely intervention with the aim of preventing hospitalization. The objective of the study was to evaluate the feasibility and safety of remotely managing WHF events using a multiparametric platform. Methods and results All patients enrolled in the heart failure remote management programme of the Bordeaux University Hospital Telemedicine Center between 1 January and 31 December 2021 were included in the study. Follow‐up data were collected until 1 March 2022. Inclusion criteria were chronic heart failure (HF) with New York Heart Association ≥II symptoms and an elevated B‐type natriuretic peptide (BNP > 100 pg/mL or N‐terminal‐pro‐BNP > 1000 pg/mL). Patient assessments were performed remotely and included measurements of body weight, blood pressure, heart rate, symptoms, biochemical parameters, and data from cardiac implantable electronic devices when available. In total, 161 patients (71 ± 11 years old, 79% male) were followed for a mean of 291 ± 66 days with a mean adherence to the remote monitoring system of 80 ± 20%. Over this period, 52 (32.3%) patients had 105 WHF events, of which 66 (63%) were successfully managed remotely, the remaining requiring hospitalization. Freedom from WHF events and hospitalization at 300 days were 66% and 85%, respectively (P < 0.001 for the difference). Increased level of BNP was associated with an increased risk of WHF event [hazard ratio (HR) per unit increase in BNP: 1.001; 95% confidence interval (CI) 1–1.002; P = 0.001] and hospitalization (HR 1.002; 95% CI 1.002–1.003; P = 0.002). A decrease in the level of glomerular filtration rate was associated with an increased risk of hospitalization (HR per unit decrease in estimated glomerular filtration rate: 0.946; 95% CI 0.906–0.989; P = 0.014). WHF event recurrence and (re)hospitalization rates at 1‐month were similar among patients managed remotely (18% and 12%, respectively) and those requiring hospitalization (21% and 10%, respectively). Iatrogenic complications occurred more often during hospitalization than remote management (26% vs. 3%, P < 0.001). Conclusions Our study suggests that remote management of WHF events based on a multiparametric approach led by a telemedical centre is feasible and safe. Adopting such a strategy for patients with chronic HF could reduce HF‐related hospitalizations with expected benefits for patients, care providers, and health care systems.

Structural remodeling is a common consequence of chronic pathological stresses imposed on the heart. Understanding the architectural and compositional properties of diseased tissue is critical to determine their interactions with arrhythmic behavior. Microscale tissue remodeling, below the clinical resolution, is emerging as an important source of lethal arrhythmia, with high prevalence in young adults. Challenges remain in obtaining high imaging contrast at sufficient microscale resolution for preclinical models, such as large mammalian whole hearts. Moreover, tissue composition-selective contrast enhancement for three-dimensional high-resolution imaging is still lacking. Non-destructive imaging using micro-computed tomography shows promise for high-resolution imaging. The objective was to alleviate sufferance from X-ray over attenuation in large biological samples. Hearts were extracted from healthy pigs (N = 2), and sheep (N = 2) with either induced chronic myocardial infarction and fibrotic scar formation or induced chronic atrial fibrillation. Excised hearts were perfused with: a saline solution supplemented with a calcium ion quenching agent and a vasodilator, ethanol in serial dehydration, and hexamethyldisilizane under vacuum. The latter reinforced the heart structure during air-drying for 1 week. Collagen-dominant tissue was selectively bound by an X-ray contrast-enhancing agent, phosphomolybdic acid. Tissue conformation was stable in air, permitting long-duration microcomputed tomography acquisitions to obtain high-resolution (isotropic 20.7 µm) images. Optimal contrast agent loading by diffusion showed selective contrast enhancement of the epithelial layer and sub-endocardial Purkinje fibers in healthy pig ventricles. Atrial fibrillation (AF) hearts showed enhanced contrast accumulation in the posterior walls and appendages of the atria, attributed to greater collagen content. Myocardial infarction hearts showed increased contrast selectively in regions of cardiac fibrosis, which enabled the identification of interweaving surviving myocardial muscle fibers. Contrast-enhanced air-dried tissue preparations enabled microscale imaging of the intact large mammalian heart and selective contrast enhancement of underlying disease constituents.

EDITORIAL article Front. Physiol., 08 December 2022Sec. Cardiac Electrophysiology Volume 13 - 2022 | https://doi.org/10.3389/fphys.2022.1092009

Background Immune checkpoint inhibitors (ICIs) are widely used in lung cancer management. However, myocarditis, which is a rare, yet potentially severe adverse-related event associated with ICIs, could be under-reported. Objectives This study is aimed to prospectively evaluate the cumulative incidence rate of myocarditis, through systematic screening, among patients receiving ICIs for lung cancer. Methods All patients who received the first administration of ICIs for non-small cell (NSCLC) and small cell lung cancer (SCLC), between May and November 2020, in the pulmonary department of Bordeaux University Hospital, were included. Echocardiography (ECG), troponin-I, and natriuretic peptide dosages before ICIs' first administration and before each infusion were recorded. ECG and magnetic resonance imaging (MRI) were done additionally, in case of at least three times increase in troponin levels, ECG modifications, and the onset of cardiovascular symptoms. Second, if possible, coronarography than endomyocardial biopsy was assessed. The primary outcome was defined as ICIs related to myocarditis onset, while secondary outcomes included other cardiovascular events, disease-free, and overall survival. Results During the period of interest, 99 patients received their first infusion of ICIs for lung cancer (mean age 64 ± 9 years; 52 men, 67% with adenocarcinoma). Three cases of myocarditis without major adverse cardiac events (MACEs) occurred (two definite and one possible), and the mean duration between the first ICIs' administration and myocarditis onset was 144 ± 3 days. Median disease-free survival and overall survival were 169 [102; 233] days and 209 [147; 249] days, respectively. Conclusion In our study, systematic screening of myocarditis associated with ICIs leads to a more frequent incidence and a later onset than previously reported. None of them were severe. Additional prospective evidence is needed before we could adopt routine cardiac screening in unselected patients starting ICIs; however, these data shed new light on the risk of myocarditis associated with ICIs administration.

Abstract Introduction Although primary percutaneous coronary intervention (pPCI) is not a class I recommendation in all patients (pts) presenting within 12 to 48h of symptom onset (late ST-segment Elevation Myocardial Infarction, STEMI), there is increasing evidence supporting its routine use in this population. Data on long-term clinical outcomes is sparse. Objective To evaluate long-term MACE in late-STEMI pts submitted to pPCI and compare with clinical outcomes of early reperfusion groups. Methods Retrospective analysis of consecutive pts submitted to pPCI due to STEMI between 2010 and 2015 in a pPCI centre. Included pts were stratified in 5 groups according to symptom-to-balloon time (SBT): <3h; 3–6h; 6–12h; 12–24h; 24–48h. Of a total of 903 pts, 19 pts were excluded due to SBT >48h. Long-term events were established as 5y mortality and 5y-MACE (a composite endpoint of death, re-infarction, heart failure hospital admission and ischemic stroke). The cumulative incidence of long-term outcomes was calculated by the Cox regression analysis and presented according to the Kaplan-Meier method. Results Of the 884 pts included in the study, stratification according to SBT was: pPCI<3h (47.4%), pPCI 3–6h (24.9%), pPCI 6–12h (16.5%), pPCI 12–24h (8.0%), and pPCI 24–48h (3.2%). These groups showed no significant difference in terms of demographic characteristics (age, CV risk factors, previous coronary disease or heart failure), clinical severity (systolic arterial pressure, Killip-Kimball class, left ventricle ejection fraction) and angiography findings (multivessel disease, complete revascularization and PCI success). After a median follow-up of 76 (56; 98) months, 5-year mortality was 20.6% (182 pts) and 5-year MACE was 23.3% (206 pts). MACE was associated with increased median SBT: 5.0 (2.0; 9.0) hours vs 4.0 (2.0; 6.5) hours, p<0.001. Of the MACE components, the only that showed a significant association with higher median SBT was mortality: 5.0 (2.0; 10.0) hours vs 4.0 (2.0; 6.0), p<0.001. Differences in long-term outcomes were significant when considering SBT stratified by revascularization time (Figure 1). Conclusions As expected, there is a clinical benefit of early reperfusion for long-term cardiovascular events. Within the late-STEMI group, there seems to be a clear distinction between pPCI<24h and >24h, although the clinical benefit of pPCI timing most probably acts a continuum. Funding Acknowledgement Type of funding sources: None.

Abstract Introduction Balloon pulmonary angioplasty (BPA) is a complex procedure and not risk free. In an attempt to standardize reports of BPA complications in the several centers, a classification of complications was proposed by the task force on chronic thromboembolic hypertension (CTEPH) in the 6th World Symposium on Pulmonary Hypertension (WSPH). Purpose To determine the prevalence of BPA complications according to the classification of 6th WSPH and to identify its predictors. Methods Detailed procedural and technical aspects were collected for consecutive patients (pts) with inoperable, residual/recurrent chronic thromboembolic disease, undergoing BPA at a single institution from December/2017 to December/2020. Per procedure logistic regression analysis was used to evaluate the predictive variables for complications. Results A total of 76 BPA sessions in 15 pts were performed (mean age 63.2±14.0 years; 60.0% women; 86.7% CTEPH). Mean pulmonary artery pressure and pulmonary vascular resistance before the first BPA session were 33.1±13.3 mmHg and 4.8±3.2 woods unit, respectively (73.3% of pts under vasodilator therapy). Femoral access was used for all pts. Mean vessels treated per procedure were 4.3±1.9 (324 vessels in total). Webs, subtotal occlusions, ring-like stenosis and total occlusions were noted in 215 (66.4%), 58 (17.9%), 31 (9.6%) and 20 (6.2%) treated vessels, respectively. We performed 21 pressure-wire-guided sessions (27.6%). Intravascular imaging was used in 6 procedures (7.9%). Average time of fluoroscopy was 60.3±14.0 minutes and volume of contrast 273.0±73.0 mL per session. Procedure-related adverse events occurred in 25.0% of the interventions (27.6% in the first two years vs 16.7% in the last two). Pulmonary artery vascular injuries were noted in 6 BPA vessels (7.9% per procedure and 1.9% per treated vessel): haemoptysis in all, but perforation was only detected angiographically in 3 of them (balloon inflation was performed for 2 distal perforations, and 1 perforation sealed without any intervention). Vascular dissection in distal lesions occurred in 4 cases (5.3%) with no need of transcatheter or surgical procedures. We had 3 lung injuries, all grade 2. None of the pts required oral intubation or mechanical ventilation. Extra-pulmonary complications were illustrated in table. Importantly, there was no peri-procedural death. The occurrence of vascular or lung injuries was 0% in pressure-wire-guided BPA versus 14.5% in non-guided (p=0.098). Multivariate analysis revealed that age (OR 1.05; CI 1.01–1.10; p=0.030) was the only independent predictor of complications. Conclusions In our experience, BPA can be safely performed in inoperable, residual or recurrent CTEPH or CTED pts, with 25% minor procedural-related complications but no major adverse event. Age was the strongest factor related to the occurrence of complications. Funding Acknowledgement Type of funding sources: None.

Modifications of the myocardial architecture can cause abnormal electrical activity of the heart. Fibro-fatty infiltrations have been implicated in various cardiac pathologies associated with arrhythmias and sudden cardiac death, such as arrhythmogenic right ventricular cardiomyopathy (ARVC). Here, we report the development of an MRI protocol to observe these modifications at 9.4 T. Two fixed ex vivo human hearts, one healthy and one ARVC, were imaged with an Iterative decomposition with echo asymmetry and least-square estimations (IDEAL) and a magnetization transfer (MT) 3D sequences. The resulting fat fraction and MT ratio (MTR) were analyzed and compared to histological analysis of the three regions (“ARVC triangle”) primarily involved in ARVC structural remodeling. In the ARVC heart, high fat content was observed in the “ARVC triangle” and the superimposition of the MTR and fat fraction allowed the identification of fibrotic regions in areas without the presence of fat. The healthy heart exhibited twice less fat than the ARVC heart (31.9%, 28.7% and 1.3% of fat in the same regions, respectively). Localization of fat and fibrosis were confirmed by means of histology. This non-destructive approach allows the investigation of structural remodeling in human pathologies where fibrosis and/or fatty tissue infiltrations are expected to occur.