Anatomical Remodeling Research Articles

Left atrial activation and asymmetric anatomical remodeling in patients with atrial fibrillation: The relation between anatomy and function.

BackgroundIdentifying patients with advanced left atrial (LA) remodeling before catheter ablation (CA) of atrial fibrillation (AF) is crucial.HypothesisThis study aimed to identify echocardiographic parameters associated with changes in anatomy and conduction properties of the left atrium (LA).MethodsWe examined 75 AF patients prior to CA and measured the intervals from the P‐wave‐onset to four mitral annulus sites by pulsed‐wave tissue Doppler imaging (PW‐TDI). Patients were grouped to an upward U‐pattern (delayed anterior activation) and a downward D‐pattern (earliest LA activation anterior). CT‐data were used to measure the LA volume (LAV). LAV was divided into anterior‐ (LA‐A) and posterior‐parts by a plane, parallel to the posterior wall and between the veins and the appendage, to calculate the asymmetry index (ASI = LA‐A/LAV).ResultsPatients with U‐pattern (n = 66) had a higher ASI (65 ± 6 vs. 61 ± 3%, p = .014), older age (61 ± 11 vs. 51 ± 11 years, p = .03) and more diastolic dysfunction (71 vs. 22%, p = .008) Multivariate regression showed that age (OR 1.1 per year, CI 1.007–1.199) and diastolic dysfunction (OR 6.36, CI 1.132–35.7, p = .036) were independent predictors of the U‐pattern. Diastolic dysfunction (B 4.49, CI 1.61–7.37, p = .003) was the only independent predictor of ASI in linear regression analysis.ConclusionAF patients with a U‐pattern have an increased LA asymmetry. Diastolic dysfunction is a common cause of this LA activation and remodeling. Therefore, detection of a U‐pattern signifies patients with advanced AF and may facilitate selection for an appropriate ablation strategy.

Structural and functional atrial remodelling after transcatheter closure of patent foramen ovale

Abstract Introduction Patent foramen ovale (PFO) is a common abnormality affecting more than 20% of the adult population. For most people they are accidental findings; however, in some the PFO can open widely enabling paradoxical embolisation. Randomised controlled trials have demonstrated in patients with cryptogenic stroke that transcatheter closure of PFO with a septal occluder device is associated with reduced rates of recurrent stroke. However, the impact of atrial septal closure on left atrial (LA) and right atrial (RA) structural and functional remodelling is less known. Methods We prospectively enrolled 53 patients with cryptogenic ischemic stroke and PFO eligible for transcatheter PFO closure (mean age 46±11 years, 44% females). National Institute of Health Stroke Score (NIHSS), and the modified Rankin score (mRS) were calculated as markers of clinical severity of the index stroke. Presence of any shunt, atrial volumes and functional parameters were evaluated including LA reservoir, conduit and contraction function before PFO closure and 12 months after procedure. Beyond conventional transthoracic echocardiography (Philips Epiq CVx Ultrasound), two dimensional speckle tracking method was used to assess body surface area-indexed LA maximal volume (LAVmaxi), LA minimal volume (LAVmini), LA volume before left atrial contraction (LApreAi), LA ejection fraction (LAEF), LA reservoir strain (LASres), LA conduit strain (LAScond), LA contraction strain (LAScontr), LA peak systolic strain rates (LASRs), LA peak early diastolic strain rate (LASRe) and LA peak late diastolic strain rate (LASRa) using dedicated software on separate workstation (Cardiac Performance; TomTec Imaging, Unterschleissheim, Germany). Results The index stroke was modest and non-disabling, with an NIHSS 3.37±2.63 and mRS 1.67±1.06. Baseline LA, RA volumes and dimensions were in normal range (LAVi 25.5±9.6 ml/m2; LA length 37.6±6.2 mm; LA width 40.4±7.1 mm; RA length 36.6±6.7 mm; RA width 39.5±8.6 mm). Thirty-seven patient had 12 month clinical follow-up examinations revealing no significant differences (all p values >0.05) in atrial volumes, ejection fraction and strain parameters. LASRa was significantly lower after 12 month (p=0.03; baseline LASRa −1.7±0.7 s–1 vs follow-up LASRa −1.3±0.9 s–1) No new cerebral ischaemic events, aortic erosions, atrial fibrillation, significant residual shunts or device thrombosis and displacement were recorded during the follow-up. Conclusion PFO-associated strokes in young individuals are mainly non-disabling. Our study suggests that transcatheter interatrial closure is effective without promoting unfavourable atrial anatomical remodelling during short-term follow-up, however, it may affect active atrial contraction. Long-term follow-up examinations are needed to investigate the potential late impact of occluders on atrial anatomical, functional remodelling. Funding Acknowledgement Type of funding source: None

Incidence and predictors of arrhythmias in patients with systemic sclerosis and no overt cardiac disease

Abstract Background Cardiac involvement in SSc is frequent, mostly subclinical and represents a negative prognostic factor. Speckle tracking derived measurement global longitudinal strain (GLS) has been able to identify primary heart involvement in patients with SSc and no overt cardiac disease. SSc-related cardiomyopathy, defined as a condition affecting the heart primarily and globally, has been proven to progress over time and seems to be correlated to cardiac arrhythmias. Nonetheless, cardiac arrhythmias represent 6% of the overall causes of death in SSc patients. Purpose The aim of our study was to assess the incidence of cardiac arrhythmias in SSc patients with no overt cardiac disease and to identify potential predictors. Methods Prospective longitudinal study enrolling all consecutive patients with a diagnosis of SSc and no overt cardiac disease or pulmonary hypertension. Echocardiographic parameters and GLS were obtained at baseline and at each follow up. Presence of atrial fibrillation (AF), atrial tachycardia (AT), ventricular ectopic beats >1000/24 h (VEB), supraventricular ectopic beats (SVEB), bundle branch block (BBB) and atrioventricular block (AVB) was assessed through clinical history, ECG and 24-Holter monitoring over time. Results Among 67 consecutive patients with SSc, 11 (16.7%) had at least one episode of AF or AT. Moreover, respectively 12 (17.9%) and 16 (23.9%) had a significant amount of SVEB and VEB at Holter monitoring. Conduction defects were common, with 4 (4.6%) of all patients with grade I AVB, 1 (1.5%) with grade II AVB and 1 (1.5%) with complete heart block. Complete right BBB was seen in 6 (6.9%) of patients. Four patients (4.6%) experienced a sudden cardiac death during follow-up (median 20 months, 1st-3rd quartile 12–24 months). Years from SSc diagnosis (RR 1.10; 95% CI 1.02–1.23; p=0.047) and indexed right atrial volume (iRAV; RR 1.22; 95% CI 1.07–1.39; p=0.004), but not indexed left atrial volume were independently correlated with the diagnosis of AF/AT. The same two variables were independently correlated with any degree of AV block (years from SSc diagnosis: RR 1.11; 95% CI 1.01–1.23; p=0.004; iRAV: RR 1.14; 95% CI 1.02–1.27; p=0.019). Due to the low sample size, we were unable to detect any clinical predictors of sudden cardiac death in our population, however those who died experienced a larger worsening in left ventricle GLS values (4.0±1.6 vs. 0.9±0.4, p=0.056). Conclusions Supraventricular arrhythmias and conduction defects are common in patients with SSc. Time from diagnosis and right atrial volumes are able to predict the incidence of such conditions, supporting the hypothesis that a long-lasting disease and the anatomical remodelling of the right atrium could contribute to the developing of tachy- and bradyarrhythmias in this population. Funding Acknowledgement Type of funding source: None

Molecular and Mechanical Mechanisms Regulating Ductus Arteriosus Closure in Preterm Infants.

Failure of ductus arteriosus closure after preterm birth is associated with significant morbidities. Ductal closure requires and is regulated by a complex interplay of molecular and mechanical mechanisms with underlying genetic factors. In utero patency of the ductus is maintained by low oxygen tension, high levels of prostaglandins, nitric oxide and carbon monoxide. After birth, ductal closure occurs first by functional closure, followed by anatomical remodeling. High oxygen tension and decreased prostaglandin levels mediated by numerous factors including potassium channels, endothelin-1, isoprostanes lead to the contraction of the ductus. Bradykinin and corticosteroids also induce ductal constriction by attenuating the sensitivity of the ductus to PGE2. Smooth muscle cells of the ductus can sense oxygen through a mitochondrial network by the role of Rho-kinase pathway which ends up with increased intracellular calcium levels and contraction of myosin light chains. Anatomical closure of the ductus is also complex with various mechanisms such as migration and proliferation of smooth muscle cells, extracellular matrix production, endothelial cell proliferation which mediate cushion formation with the interaction of blood cells. Regulation of vessel walls is affected by retinoic acid, TGF-β1, notch signaling, hyaluronan, fibronectin, chondroitin sulfate, elastin, and vascular endothelial cell growth factor (VEGF). Formation of the platelet plug facilitates luminal remodeling by the obstruction of the constricted ductal lumen. Vasa vasorum are more pronounced in the term ductus but are less active in the preterm ductus. More than 100 genes are effective in the prostaglandin pathway or in vascular smooth muscle development and structure may affect the patency of ductus. Hemodynamic changes after birth including fluid load and flow characteristics as well as shear forces within the ductus also stimulate closure. Current pharmacological treatment for the closure of a patent ductus is based on the blockage of the prostaglandin pathway mainly through COX or POX inhibition, albeit with some limitations and side effects. Further research for new agents aiming ductal closure should focus on a clear understanding of vascular biology of the ductus.

Left atrial diameter and atrial fibrillation, but not elevated NT-proBNP, predict the development of pulmonary hypertension in patients with HFpEF.

BackgroundThe determinants of pulmonary hypertension (PH) due to heart failure with preserved ejection fraction (HFpEF) have been poorly investigated in patients with cardiovascular diseases (CVD).MethodsFrom July 1 2017 to March 31 2019, a total of 149 consecutive HFpEF patients hospitalized with CVD were enrolled in this prospective cross-sectional study. A systolic pulmonary artery pressure (PASP) > 35 mmHg estimated by echocardiography was defined as PH-HFpEF. Logistic regression was performed to establish predictors of PH in HFpEF patients.ResultsOverall, the mean age of participants was 72 ± 11 years, and 74 (49.7%) patients were females. A total of 59 (39.6%) patients were diagnosed with PH-HFpEF by echocardiography. The left atrial diameter (LAD) was related to the ratio of the transmitral flow velocities/mitral annulus tissue velocities in early diastole (E/E') and the left ventricular diameter in systole (LVDs). N-Terminal pro B-type natriuretic peptide (NT-proBNP) was not found to be associated with LAD and impaired diastolic or systolic function of the left ventricle. Multivariable logistic regression showed that atrial fibrillation (AF) increased the risk of PH-HFpEF incidence 3.46-fold with a 95% confidence interval (CI) of 1.44–8.32, P = 0.005. Meanwhile, LAD ≥ 45 mm resulted in a 3.43-fold increased risk, 95% CI: 1.51–7.75, P = 0.003. However, the significance levels of NT-proBNP, age and LVEF were underpowered in the regression model. Two variables, AF and LAD ≥ 45 mm, predicted the PH-HFpEF incidence (C-statistic = 0.773, 95% CI: 0.695–0.852, P < 0.001).ConclusionsTwo parameters associated with electrical and anatomical remodelling of the left atrium were related to the incidence of PH in HFpEF patients with CVD.

Population Density Modulates the Duration of Reproduction of C. elegans

Population density can modulate the developmental trajectory of Caenorhabditis elegans larvae by promoting entry into dauer diapause, which is characterized by metabolic and anatomical remodeling and stress resistance [1, 2]. Genetic analysis of dauer formation has identified the involvement of evolutionarily conserved endocrine signaling pathways, including the DAF-2/insulin-like receptor signaling pathway [3-7]. Chemical and metabolomic analysis of dauer-inducing pheromone has identified a family of small molecules, ascarosides, which act potently to communicate increased population density and promote dauer formation [1, 8-10]. Here, we show that adult animals respond to ascarosides produced under conditions of increased population density by increasing the duration of reproduction. We observe that the ascarosides that promote dauer entry of larvae also act on adult animals to attenuate expression of the insulin peptide INS-6 from the ASI chemosensory neurons, resulting in diminished neuroendocrine insulin signaling that extends the duration of reproduction. Genetic analysis of ins-6 and corresponding insulin-signaling pathway mutants showed that the effect of increased population density on reproductive span was mimicked by ins-6 loss of function that exerted effects on duration of reproduction through the canonical DAF-2-DAF-16 pathway. We further observed that the effect of population density on reproductive span acted through DAF-16-dependent and DAF-16-independent pathways upstream of DAF-12, paralleling in adults what has been observed for the dauer developmental decision of larvae. Our data suggest that, under conditions of increased population density, C.elegans animals prolong the duration of reproductive egg laying, which may enable the subsequent development of progeny under more favorable conditions.

Navigating Alzheimer's Disease via Chronic Stress: The Role of Glucocorticoids.

Alzheimer's disease (AD) is a chronic intensifying incurable progressive disease leading to neurological deterioration manifested as impairment of memory and executive brain functioning affecting the physical ability like intellectual brilliance, common sense in patients. The recent therapeutic approach in Alzheimer's disease is only the symptomatic relief further emerging the need for therapeutic strategies to be targeted in managing the underlying silent killing progression of dreaded pathology. Therefore, the current research direction is focused on identifying the molecular mechanisms leading to the evolution of the understanding of the neuropathology of Alzheimer's disease. The resultant saturation in the area of current targets (amyloid β, τ Protein, oxidative stress etc.) has led the scientific community to rethink of the mechanistic neurodegenerative pathways and reprogram the current research directions. Although, the role of stress has been recognized for many years and contributing to the development of cognitive impairment, the area of stress has got the much-needed impetus recently and is being recognized as a modifiable menace for AD. Stress is an unavoidable human experience that can be resolved and normalized but chronic activation of stress pathways unsettle the physiological status. Chronic stress mediated activation of neuroendocrine stimulation is generally linked to a high risk of developing AD. Chronic stress-driven physiological dysregulation and hypercortisolemia intermingle at the neuronal level and leads to functional (hypometabolism, excitotoxicity, inflammation) and anatomical remodeling of the brain architecture (senile plaques, τ tangles, hippocampal atrophy, retraction of spines) ending with severe cognitive deterioration. The present review is an effort to collect the most pertinent evidence that support chronic stress as a realistic and modifiable therapeutic earmark for AD and to advocate glucocorticoid receptors as therapeutic interventions.

MicroRNAs Contribute to Angiotensin II‐Mediated Regulation of Transmural Electrical Remodeling in the Heart

Activation of the local renin angiotensin system (RAS) by Angiotensin II (Ang II) in the heart induces electrical remodeling, including inhibition of transient outward potassium current Ito, prolongation of the action potential, and increased contractility. Moreover, the long‐term, persistent action of Ang II causes cardiac hypertrophy and heart failure (anatomic remodeling). The transmural gradient of multiple ionic currents, including Ito, is involved in Ang II‐mediated electrical remodeling. Differential expression of miRNAs may play a critical role in the signaling cascade for Ang II‐induced electrical remodeling. To investigate this hypothesis, a detailed analysis of potential miRNAs involved in Ang II‐mediated modulation was undertaken using miRNA microarray analysis of endocardium and epicardium tissue from the left ventricle of a Sprague‐Dawley rat. The left ventricular tissue samples were treated with either Ang II (2mM) or Losartan (2mM) to further screen for differences in miRNA expression between EPI and ENDO. Although forty‐nine miRNAs were expressed in a significant gradient between EPI and ENDO, only miR‐385‐5p and miR‐301a‐3p were found to exhibit similar expression patterns as Ito when modulated by Ang II. Taken together, these data suggest that miR‐382‐5p and miR‐301a‐3p could contribute to Ang II‐mediated transmural electrical remodeling and may provide a potential target for the study of heart failure mechanisms and therapeutic application.Expression of miR‐382‐5p and miR‐301a‐3p in EPI and ENDO.A. Left: miR‐382‐5p is upregulated in EPI compared to ENDO. Middle: miR‐382‐5p is upregulated in EPI compared to EPI with Ang II. Right: miR‐382‐5p is downregulated in ENDO compared to ENDO with Losartan.B. Left: miR‐301a‐3p is downregulated in EPI compared to ENDO. Middle: miR‐301a‐3p is downregulated in EPI compared to EPI with Ang II. Right: miR‐301a‐3p is upregulated in ENDO compared to ENDO with Losartan.Figure 1Schematic diagram of Ang II‐mediated anatomic and electrical remodeling in the heart. The transmural distribution of Ang II causes the transmural gradient of ionic currents including Ito, Ip, ICaL and ICaTL (electrical remodeling). Under long term imbalances between volume load and maximum contractile strength, the heart undergoes hypertrophy and heart failure (anatomic remodeling). We hypothesize that miR‐382‐5p and miR‐301a‐3p contribute to Ang‐II mediated remodeling of the heart.Figure 2

Atrial premature activity detected after an ischaemic stroke unveils atrial myopathy

Recent publications suggest that left atrial (LA) myopathy is a potential source of thromboembolism, independent of atrial fibrillation. We sought to investigate whether the presence of atrial premature activity after an ischaemic stroke is associated with LA remodelling and dysfunction, and might be a surrogate marker of LA myopathy. After an ischaemic stroke or a transient ischaemic attack, patients without known atrial fibrillation or overt heart disease were included prospectively in the study. All patients had a standard workup, including ambulatory Holter electrocardiogram monitoring and transthoracic echocardiography. In some patients, transoesophageal echocardiography was also performed. Anatomical and functional LA remodelling were assessed using minimal and maximal volumes and LA emptying fraction in two-dimensional and three-dimensional echocardiography. Patients were separated into two groups according to the burden of atrial premature complexes (APCs), measured by Holter electrocardiography. Among 148 eligible patients recruited from October 2015 to May 2016, 93 were included in the group with non-frequent APCs (nf-APC:<100 APCs/24hours) and 43 in the group with frequent APCs (f-APC:>100 APCs/24hours). Twelve patients had paroxysmal atrial fibrillation, and were not included in the statistical analysis. Maximal and minimal indexed LA volumes were significantly higher in the f-APC group than in the nf-APC group (P<0.01). LA emptying fraction was worse in the f-APC group than in the nf-APC group. In addition, LA appendage emptying velocity was impaired in the f-APC group, and was correlated with LA remodelling variables, especially LA emptying fraction (r=0.621). After an ischaemic stroke or a transient ischaemic attack, excessive APCs are associated with LA remodelling. Thus, LA dilatation and dysfunction reflect early LA myopathy, which might itself be responsible for cardioembolic stroke.

Explainable Anatomical Shape Analysis Through Deep Hierarchical Generative Models.

Quantification of anatomical shape changes currently relies on scalar global indexes which are largely insensitive to regional or asymmetric modifications. Accurate assessment of pathology-driven anatomical remodeling is a crucial step for the diagnosis and treatment of many conditions. Deep learning approaches have recently achieved wide success in the analysis of medical images, but they lack interpretability in the feature extraction and decision processes. In this work, we propose a new interpretable deep learning model for shape analysis. In particular, we exploit deep generative networks to model a population of anatomical segmentations through a hierarchy of conditional latent variables. At the highest level of this hierarchy, a two-dimensional latent space is simultaneously optimised to discriminate distinct clinical conditions, enabling the direct visualisation of the classification space. Moreover, the anatomical variability encoded by this discriminative latent space can be visualised in the segmentation space thanks to the generative properties of the model, making the classification task transparent. This approach yielded high accuracy in the categorisation of healthy and remodelled left ventricles when tested on unseen segmentations from our own multi-centre dataset as well as in an external validation set, and on hippocampi from healthy controls and patients with Alzheimer's disease when tested on ADNI data. More importantly, it enabled the visualisation in three-dimensions of both global and regional anatomical features which better discriminate between the conditions under exam. The proposed approach scales effectively to large populations, facilitating high-throughput analysis of normal anatomy and pathology in large-scale studies of volumetric imaging.

Radiological evaluation of anatomical changes in implant and adjacent segments after rigid fusion

Aim: We aimed to determine the anatomical remodeling seen after lumbar spine stabilization in detail. Using magnetic resonance images, it is also aimed to reveal this remodeling is not only limited to the adjacent segment and also happens in the upper instrumented vertebra region. At the end of this study, it is suggested to develop new radiological parameters to predict the changes in the adjacent segment and upper instrumented vertebra regions.Materials and Methods: Twenty cases operated for degenerative lumbar stenosis were included in our study. Quantitative data were obtained by radiological measurements by a radiologist and neurosurgeon. On magnetic resonance images, the anatomical structures changed by remodeling were compared before and after the operation during (6-26 months) postoperative period. Unlike previous studies, anterior, middle and posterior disc heights; Cobb angle in the adjacent segment, spinal canal area, bilateral neural foramen, facet joint areas and flavum thicknesses were evaluated.Results: From the sixth month after lumbar fusion, it was observed that angles and anatomical structures were changed in adjacent segment. Also, it was observed that the areas with neural structures expanded in the upper instrumented vertebra region. The degeneration in adjacent segment and relaxation in the upper instrumented vertebra region were found to be statistically significant. A statistically strong positive correlation was found between the number of vertebrae included in the lumbar fusion and the mean height of the adjacent segment disc (r: 0.526, p: 0.017).Conclusion: After comparing the measurements in adjacent segment and upper instrumented vertebra regions before and after the operation, it was concluded that the remodeling was statistically significant. We suggest that the parameters in our study can be used as a scoring method for early detection of adjacent segment degeneration and/or disease. Thus, it will be possible to create follow-up indicators findings after fusion.

Aging of the Hematopoietic Stem Cell Niche: An Unnerving Matter.

The drivers of aging in the hematopoietic system remain incompletely understood. In this issue of Cell Stem Cell, Ho etal. (2019) report that functional switching of β-adrenergic nerve signaling underlies remodeling of stem cell niches, driving age-associated alterations in hematopoiesis.

Balance of Active, Passive, and Anatomical Cardiac Properties in Doxorubicin-Induced Heart Failure

Late-onset heart failure (HF) is a known side effect of doxorubicin chemotherapy. Typically, patients are diagnosed when already at an irreversible stage of HF, which allows few or no treatment options. Identifying the causes of compromised cardiac function in this patient group may improve early patient diagnosis and support treatment selection. To link doxorubicin-induced changes in cardiac cellular and tissue mechanical properties to overall cardiac function, we apply a multiscale biophysical biomechanics model of the heart to measure the plausibility of changes in model parameters representing the passive, active, or anatomical properties of the left ventricle for reproducing measured patient phenotypes. We create representative models of healthy controls (N = 10) and patients with HF induced by (N = 22) or unrelated to (N = 25) doxorubicin therapy. The model predicts that HF in the absence of doxorubicin is characterized by a 2- to 3-fold stiffness increase, decreased tension (0–20%), and ventricular dilation (of order 10–30%). HF due to doxorubicin was similar but showed stronger bias toward reduced active contraction (10–30%) and less dilation (0–20%). We find that changes in active, passive, and anatomical properties all play a role in doxorubicin-induced cardiotoxicity phenotypes. Differences in parameter changes between patient groups are consistent with doxorubicin cardiotoxicity having a greater dependence on reduced cellular contraction and less anatomical remodeling than HF not caused by doxorubicin.

Myocardial biomechanics, intracardiac hemodynamics and endothelial function in patients before and after various types of pacemakers implantation

This review presents 31 sources from 1995 to 2019. Atrioventricular blockades (AVB) 2-3 degrees occupy a special place among the causes of death from cardiovascular disease. The above AVB lead to a significant slowing of the heart rate and predispose to the development and progression of heart failure (HF) and the occurrence of acute hypoxia of the brain and attacks Morgagni-Adams-Stokes. The main method of treatment of hemodynamically significant AB-conduction disorders is electrocardiostimulation (ES), which is the basic method of treatment. A single chamber pacemaker is the most often implanted with using isolated ventricular stimulation in clinical practice in the Russian Federation. Implantation of a dual chamber pacemaker is less frequent. This type of stimulation allows to maintain atrioventricular synchronization constantly. Stimulation of the apex of the right ventricle leads to a decrease in left ventricle (LV) function and structural changes that are a consequence of the occurrence of electric and mechanical dyssynchrony of the myocardium. There is a large number of works devoted to the comparison of different methods of ES leading to the conclusion that a powerful alternative to the stimulation of the apex of the right ventricle can be a dual ventricular stimulation. It is noted that implantation of single-and dual-chamber pacemaker with fixation of the electrode in the region of the right ventricle apex leads to the fact that both modes of stimulation can not cancel the electrical and anatomical remodeling of the myocardium of left atrium and LV. It may be necessary to use a more physiological site of stimulation with using optimal AB-delay to minimize the frequency of ventricular stimulation. Endothelium plays an important and independent role in the development of cardiovascular diseases. The effect of AB conduction impairment on endothelial function (EF) has not been described to date. There were few studies which are discussed the influence of constant pacemaker on endothelial function in patients with AVB 2-3 degrees in recent years. It should be noted that the studies were conducted on a small sample of patients and had a different design.

The development of the serotonergic and dopaminergic systems during chicken mid-late embryogenesis

Serotonin (5-HT) acts as a morphogen influencing embryonic brain development, and as a neurotransmitter regulating multiple biological functions with lifelong effects on animal physical, physiological and mental health, especially during the rapid growth phase prior to birth when embryos face many challenges to reach structural and functional completion. In this study, the development of the serotoninergic (5-HTergic) system and its modulatory effect on the dopaminergic (DAergic) system and related neural circuits were investigated during the mid-late embryogenesis, embryonic day (E)12-E20, in the chicken's brain. During 5-HTergic neuronal maturation, a growth-related anatomical and functional remodeling was highlighted: the 5-HT neurons continuously grew during E12-E20 except for a remarkable regression during E14-E16. Correspondingly, there was a time-dependent change in the 5-HT synthetic capacity. Specifically, 5-HT concentrations in the raphe nuclei increased from E12 to E14, reaching a first plateau during E14-E16, then continuously increased up to E19, and reaching a second plateau between E19-E20. The second plateau of the 5-HT concentration was in correspondence with the establishment of the 5-HTergic autoregulatory loop during E19-E20 and the development of the DAergic system. The DA concentrations remained unchanged from E12 to E16, then started to increase at E16, reaching a maximum at E19, and diminished before hatching. The unique developing time sequence between the 5-HTergic and DAergic systems suggests that the 5-HTergic system may play a critical role in forming the 5-HT – DA neural circuit during chicken embryogenesis. These results provide new insights for understanding the functional organization of the 5-HTergic system during embryonic development and raise the possibility that prenatally modulating the 5-HTergic system may lead to long-lasting brain structural and functional alterations.

Improving performance of 3D speckle tracking in arterial hypertension and paroxysmal atrial fibrillation by using novel strain parameters

The function of left atrium (LA) is closely related to LA remodeling and one of the most important mechanisms is an increased deposition of fibrous tissue that often is the basis for LA electro-mechanical changes before the onset of atrial fibrillation (AF). This study evaluated LA shape and function, by investigating standard and novel strain parameters calculated by a new approach based on homologous times derived from 3D speckle tracking echocardiography (3DSTE) in hypertensive (HT) and paroxysmal atrial fibrillation (PAF) patients with or without left ventricular hypertrophy (LVH), compared to control (C) subjects. LA function was assessed using homologous times to compare strain variables among different individuals, acquired at different physiological time periods. Standard global longitudinal (GLS) and circumferential (GCS) strains were measured at peak of atrial diastole, while longitudinal and circumferential strains (GLSh, GCSh), strain rate (GLSr, GCSr), volume (Vh) and volume rate (Vr) were measured during the atrial telediastolic phase (fifth homologous time) and atrial pre-active phase (tenth homologous time). Using ANOVA, we found an impaired LA deformation detected by standard, interpolated strains and strain rates in both HT and PAF groups compared to C. We also performed ROC analysis to identify different performances of each parameter to discriminate groups (GLSr10 + GCSr10: C vs PAF 0.935; C vs PAF_LVH 0.924; C vs HT_LVH 0.844; C vs HT 0.756). Our study showed anatomical and functional LA remodeling in patients with PAF and HT. 3D strains and strain rates derived from the homologous times approach provide more functional information with improved performance to identify among the explored groups, in particular PAF patients.

The association between left atrial stiffness and low-voltage areas of left atrium in patients with atrial fibrillation.

The low-voltage areas of left atrium (LA-LVA) have recently been of significant focus. However, very few studies have focused on the association between LA function and LA-LVA, and the mechanism of appearance of LA-LVA remains unclear. We investigated the marker for the existence of LA-LVA using automated 3-D mapping system. We studied 92 patients (75 males, 68 ± 9years, 47 non-paroxysmal AF) who received CA for AF and 40 control patients without AF. Echocardiography was performed before the CA, and high-density voltage mapping during sinus rhythm after pulmonary isolation was performed in AF patients. LA-LVA was defined as < 0.5mV, and LA stiffness index (LASI) was defined as the ratio of E/e' to LA peak strain. LA-LVA (LVA burden > 10%) was detected in 19/92 AF patients (21%). Patients with LA-LVA were associated with higher LASI (1.64 ± 1.70 vs. 0.61 ± 0.46, p < 0.0001), larger LA volume, non-paroxysmal AF, higher brain natriuretic peptide, structural heart disease, and older age. On multivariate analysis, LASI, LA volume, and age were independently associated with the existence of LA-LVA. Of these markers, the highest area under curve was obtained with LASI. The rate of high LASI (≥ 0.552) was highest in AF patients with LA-LVA. Moreover, the existence of LVA in anterior LA wall was associated with higher LASI. High LA stiffness index was associated with the presence of LA-LVA. The LA-LVA might be attributed to LA functional remodeling rather than LA anatomical remodeling.

Electrical activation of phrenic afferent neurons evokes phrenic motor plasticity following cervical spinal cord injury

Anatomical data from our laboratory indicate that phrenic afferent fibers can project across the spinal midline and neurophysiological data indicate that electrical activation of phrenic afferents can increase contralateral phrenic motor output. We have also observed that following chronic unilateral C2 hemisection (C2Hx) phrenic nerve afferent fibers undergo significant anatomical remodeling. Here we tested the hypothesis that following chronic C2Hx, activation of ipsilateral (same side as injury) phrenic afferent neurons would induce contralateral (opposite to injury) phrenic motor plasticity. Twelve weeks after unilateral C2Hx (n=9) or C2 laminectomy (n=8), adult Sprague‐Dawley rats were anesthetized, vagotomized, and ventilated to enable phrenic motor output to be studied under controlled conditions. The phrenic nerve ipsilateral to C2Hx or laminectomy was electrically stimulated using a bipolar electrode while contralateral phrenic motor output was recorded. Rats received 30 minutes of inspiratory triggered stimulation (90μA, 40pps, 1ms pulse width) and contralateral phrenic motor output was recorded for one hour. Analysis of contralateral burst amplitude using a two‐way repeated measures ANOVA revealed a significant effect of time (F3,45=9.505, P&lt;0.0001), but not treatment (C2Hx vs. laminectomy, F1,15=0.1577, P=0.6969). Thus, phrenic burst amplitude was significantly changing over the 60 minute post‐stimulation, and both experimental groups had increased phrenic burst amplitude during this period (P&lt;0.05 vs. pre‐stimulation baseline). These results indicate that electrical activation of phrenic nerve afferent fibers can induce a sustained increased (facilitation) of contralateral phrenic motor output after spinal cord injury. The response was not statistically different in the laminectomy group, which indicates that the phrenic afferent‐induced facilitation does not require conditions induced by the spinal cord injury. The ability of phrenic afferent neurons to evoke phrenic motor plasticity after spinal cord injury suggests that these afferent pathways could be important to rehabilitation of the diaphragm motor system post‐injury.Support or Funding InformationK99HL143207‐01 (KS), F32NS095620‐01 (KS), T32HL134621‐01A1 (LBW), SPARC OT2 OD023854 (DDF)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

ROS Play a Role in Long‐term Gamma Radiation‐induced Heart Damage

Cardiovascular problems are common side effects of cancer therapy, and the heart is one of the major organs that are of concern for potential damage following radiation exposure. Radiation directly affects biological molecules. However, the most impact of radiation‐mediated cell death derives from the generated free radicals, which increase oxidative stress. Reactive oxygen species (ROS) are a hallmark in cardiovascular diseases (CVD), mainly because of its interplay with nitric oxide (NO). NO offers cardioprotection against ROS‐induced damage and ROS, in turn, limits the beneficial effects of NO. Furthermore, radiation induces adaptive alterations in the vasculature leading to vascular dysfunction. Although pathways triggering cardiovascular damage following radiation exposure involve vascular damage in humans, the long‐term mechanisms by which radiation‐induced oxidative stress affects the heart have not yet been clearly defined. We hypothesized that increased ROS contribute to long‐term heart damage following radiation exposure. Flash frozen heart (apex) samples from male C5BL/6J mice (5 months) sacrificed nine months' post radiation was provided by the Department of Surgery at Duke University. Briefly, live animals were subjected to whole body radiation (dose: 200 cGy) at the Brookhaven National Lab. Control animals received Sham treatment. Transverse sections (10 μm) of heart from irradiated and non‐irradiated mice were obtained in a cryostat. Representative images of cardiac fibers were revealed with H&amp;E staining. Additionally, ROS and NO production were evaluated by confocal microscopy. Briefly, the fluorescent probes, Dihydroethidium (DHE) and DAF‐FM Diacetate, were diluted in PBS (5 μM) and the samples were incubated in a humidified chamber at 37° C for 30 minutes. Slides were imaged using a 20x objective and analyzed using ImageJ software (NIH, Bethesda, MD, USA). Protein expression for NOS isoforms was also assessed using a standard Western blotting technique. Our histological analysis indicates loss of cardiac tissue (heart ‐ apex) in irradiated animals compared to Sham animals, suggestive of anatomical remodeling. Confocal microscopy showed an increase in intracellular ROS in irradiated tissue (n=5; p≤0.05), but no significant difference was observed in NO production (n=5; p&gt;0.05). Different NOS isoforms evaluation showed elevated iNOS protein expression levels in irradiated animals. In conclusion, gamma radiation stimulates sustained ROS production in heart tissue and activation of iNOS might be a mechanism for counterbalancing the disruption in the heart antioxidant response system.Support or Funding InformationNASA Florida space Grant Consortium 2018This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Left ventricular hypertrophy in world class elite athletes is associated with signs of improved cardiac autonomic regulation.

In this study we sought to assess whether in elite athletes the physiological increase in cardiac mass attending severe long-term training leading to athlete's heart is accompanied by an improvement of autonomic performance, as assessed by post exercise vagal indices and a novel unitary Autonomic Nervous System Index for sports (ANSIs). The study involved 500 elite athletes (23.9 ± 6.4 years) participating in a screening organised by the National Italian Olympic Committee. All subjects underwent a complete medical examination, rest and stand autonomic assessment (heart rate variability) as well as bicycle exercise. ANSIs was also derived as radar plot from rest, stand and heart rate recovery individual proxies of autonomic nervous system regulation. All subjects were grouped into those with left ventricular hypertrophy present (LVH(+)), or not (LVH(-)), according to recognised thresholds. We observed that LVH(+) athletes (24.8%) showed a marked increase of post-exercise vagal indices (p < 0.001) and of ANSIs (p < 0.001), while no difference was observed for heart-rate variability indices. These changes were contingent upon sport intensity categories. Elite athletes with physiological cardiac hypertrophy (LVH(+)) present a selective profile of indices of autonomic nervous system performance, characterised by increases of markers of vagal recovery and of the novel unitary autonomic index for sports while RR variance and spectral indices seem to be unmodified. Athlete's heart may be characterised by a specific combination of anatomical and neurocardiac remodeling. This approach might furnish potential warning signs differentiating normal training induced physiology from pathological adaptation.