The mammalian heart, which is one of the first organs to form and function during embryogenesis, develops from a simple tube into a complex organ able to efficiently pump blood towards the rest of the body. The progressive growth of the compact myocardium during embryonic development is accompanied by changes in its structural complexity and organisation. However, how myocardial myoarchitecture develops during embryogenesis remain poorly understood. To date, analysis of heart development has focused mainly on qualitative descriptions using selected 2D histological sections. High resolution episcopic microscopy (HREM) is a novel microscopic imaging technique that enables to obtain high-resolution three-dimensional images of the heart and perform detailed quantitative analyses of heart development. In this work, we performed a detailed characterization of the development of myocardial architecture in wildtype mice, from E14.5 to E18.5, by means of structure tensor analysis applied to HREM images of the heart. Our results shows that even at E14.5, myocytes are already aligned, showing a gradual change in their helical angle from positive angulation in the endocardium towards negative angulation in the epicardium. Moreover, there is gradual increase in the degree of myocardial organisation concomitant with myocardial growth. However, the development of the myoarchitecture is heterogeneous showing regional differences between ventricles, ventricular walls as well as between myocardial layers, with different growth patterning between the endocardium and epicardium. We also found that the percentage of circumferentially arranged myocytes within the LV significantly increases with gestational age. Finally, we found that fractional anisotropy (FA) within the LV gradually increases with gestational age, while the FA within RV remains unchanged. The mammalian heart, which is one of the first organs to form and function during embryogenesis, develops from a simple tube into a complex organ with four chambers and four valves able to efficiently pump blood towards the rest of the body. One of the animal models to investigate the developing heart and related pathologies is the mouse embryo. During embryonic development, there is concomitant development of myocardial architecture and organisation. At early developmental stages, soon after looping, ventricular trabeculations start to develop which, apart from enhancing contractility, are also important in coordinating intraventricular conduction and increase myocardial oxygenation prior to septation and establishment of coronary circulation . With thThe progressive expansion/growth of the compact myocardium is accompanied by changes in its structural complexity and organisation. In the adult heart, myocytes are organised and aligned following a predominant  direction within the ventricular walls, and this predominant arrangement changes with myocardial depth, forming a 3-dimensional (3D) network . However, how myocardial architecture develops during embryogenesis is poorly understood. Most studies on myocardial development have used histology to characterise myocardial structural development . HoweverHigh resolution episcopic microscopy (HREM) is a novel microscopic imaging technique that enables to obtain high-resolution (in the order of microns) 3D images of whole organs, such as the heart , or embrIn the present study, we aimed to perform a detailed quantification of embryonic development of myoarchitecture in wildtype mice, from E14.5 to E18.5, by means of structure tensor analysis applied to HREM images of the heart.Mus musculus) embryos were obtained from NIMR:Parkes . For approximate embryo staging, detection of a vaginal plug was taken as gestation day 0.5 (GA0.5).All specimens were handled in compliance with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health and with the approval of the MRC National Institute of Medical Research Ethical Review Panel. Mouse  was considered as the vector following the orientation of the myocyte aggregates in their longitudinal axis as it corresponded with the lowest intensity variation   was usedtion see .f for each heart as follows: Ra and Rb are the major and minor axis of the LV ellipsoid respectively.The orientation of ventricular myocyte aggregates was assessed by means of two angles: the helical angle (HA) and the intrusion angle (IA). To do that, we performed first a change of coordinate system from Cartesian to prolate spheroidal coordinates . The proThen, the HA was calculated as the angle between the tertiary eigenvector rections . Whereasrections  (Garcia-rections .Distributions of HA and IA within the LV and right ventricle (RV) were computed at three different apico-basal levels . Then, ty = β1·x + β0, was applied to transmural HA and IA profiles to characterise their linearity. Linearity coefficient (R2) and gradient (β1) over the normalised myocardial wall (0: endocardium—1: epicardium) in degrees (°) were computed. Trabeculations were manually removed and therefore not considered in all the different quantitative analyses.Transmural profiles, from endo- to epicardium (or right-side endocardium in the case of the septum) of HA and IA were obtained for each LV and RV wall as illustrated in In order to quantify the organisation of ventricular myocardium, two different parameters were computed: the fractional anisotropy (FA)  and the λ1, λ2, λ3) of the structure tensor as follows , whereas smaller values of MDI denote a great loss of myocytes organisation or, in other words, high degree of myoarchitectural disarray . Mean FA and MDI values within the LV (excluding the septum), septum and RV were plotted as a function of GA for the three apical-basal image slices  and line3D plots of the longitudinal direction of the myocyte aggregates, represented by the tertiary eigenvector Paraview  using a p-value < 0.05 indicated statistical significance. Statistical analysis was performed using SPSS (v28).Continuous variables were expressed as mean ± standard deviation or median [range] based on a normal distribution by Kolmogorov-Smirnov testing. Differences between groups  were analysed for statistical significance using one-way ANOVA followed by Tukey honestly significant difference (HSD) test for all pair-wise comparisons. A Three-dimensional reconstruction showed the detailed anatomy of the embryonic mouse hearts at different stages of development, including four chambers, atrioventricular valves and pectinate muscles . The incp = 0.009) (p = 0.007). In the RV, the percentage of circumferentially arranged myocytes also increases during the entire gestational period studied, in the mid and basal myocardium  . The percentage of longitudinally positive arranged myocytes within the LV and RV decreases with developmental age in particular in the apical and mid myocardium  , at the < 0.001) , similar< 0.001) . The peocardium . On the ocardium .When looking at the distributions of HA in the different LV segments , it is ap < 0.001), while in the RV significantly increases in the basal and mid lateral and posterior walls (p < 0.001)  . We obse< 0.001) . We also< 0.001) . Similar< 0.001) . Neverthp < 0.001), and remains below 10% the rest of gestation (p < 0.001)  . However< 0.001) , as have< 0.001) . When lo< 0.001) , the sepR2) and gradient (β1) coefficients of the linear fitting of the IA transmural profiles for the different LV and RV segments are also provided in Regarding the change in IA along the myocardial wall, In It can be observed that FA in the LV gradually increases throughout the development, particularly from E16.5 to E18.5, potentially due to changes in myocytes size and shape . HoweverRegarding MDI, it increases during gestation as myocytes align and myocardium becomes more organised in all the myocardial walls . This inIn this study, we have shown quantitatively, for the first time, how myocardial architecture develops in the latter gestation mouse embryo and fetus. Our results show that, even at E14.5, around the time of completion of ventricular septation, myocytes are already aligned, following a predominant direction. This main direction changes gradually throughout the wall depth, from positive angulation in the endocardium towards negative angulation in the epicardium, and do not support a three-layered model of the myocardium . If a unOur results provide further evidence that significant proportions of myocytic aggregates deviate markedly from the tangential plane. At early developmental stages, more than 10% of myocytes within the RV exhibited an angle of intrusion or extrusion that exceed ±45°, while this proportion decreased with gestational age by up to ∼5%. However, the proportion of myocytes within the LV with an angle of intrusion higher than ±45° does not change during gestation and is ∼5%. This suggests that, at early developmental stages (E14-5–E15.5), the RV myocardium appear to be less organised than the LV myocardium. Our values agreed with those reported in previous studies . We haveWe have shown that FA gradually increases with developmental age within both ventricles, particularly from E16.5 to E18.5. However, FA in the septum is significantly lower than in the LV and RV. Abdullah et al. reported differences in FA between the RV and LV (including the septum), and he hypothesised it was likely because myocytes in the fetal RV are larger than myocytes in the LV . The incWe have previously demonstrated that MDI, a parameter that quantifies the similarity in the alignment of myocytes within an ROI, is a good descriptor of myocardial disarray/disorganisation . In thisIt is well known that the left and right ventricles are derived from different embryonic origins: the first (LV) and the second or anterior (RV) heart fields . ContribIn conclusion, the present study provided, for the first time, a comprehensive detailed analysis of ventricular myoarchitecture development in mice. This work provides an important basis for the understanding of the how myoarchitecture develops.


While mortality in patients with hypertensive emergency has significantly improved over the past decades, the incidence and complications associated with acute hypertension-mediated organ damage have not followed a similar trend. Hypertensive emergency is characterized by an abrupt surge in blood pressure, mostly occurring in people with pre-existing hypertension to result in acute hypertension-mediated organ damage. Acute hypertension-mediated organ damage commonly affects the cardiovascular system, and present as acute heart failure, myocardial infarction, and less commonly, acute aortic syndrome. Elevated cardiac troponin with or without myocardial infarction is one of the major determinants of outcome in hypertensive emergency. Despite being an established entity distinct from myocardial infarction, myocardial injury has not been systematically studied in hypertensive emergency. The current guidelines on the evaluation and management of hypertensive emergencies limit the cardiac troponin assay to patients presenting with features of myocardial ischemia and acute coronary syndrome, resulting in underdiagnosis, especially of atypical myocardial infarction. In this narrative review, we aimed to give an overview of the epidemiology and pathophysiology of hypertensive emergencies, highlight challenges in the evaluation, classification, and treatment of hypertensive emergency, and propose an algorithm for the evaluation and classification of cardiac acute hypertension-mediated organ damage. Systemic hypertension is the most prevalent non-communicable disease and remains the leading preventable cause of premature death globally, accounting for more than 50% of cases of myocardial infarction, heart failure, and stroke . Since 1The most common acute complication of systemic hypertension leading to emergency room visits is hypertensive emergency. Hypertensive emergencies represent a heterogenous group of disorders characterized by (1) acute severe blood pressure (BP) elevation, often ≥180/120 mmHg, (2) acute hypertension-mediated organ damage, and (3) the need for a prompt but contextual, system-specific lowering of the BP to avert catastrophic outcomes . The orgCardiac complications are the most prevalent acute hypertension-mediated organ damage in hypertensive emergencies. The three major cardiac acute hypertension-mediated organ damage syndromes include acute heart failure/cardiogenic pulmonary oedema, acute coronary syndrome (ACS), and less commonly, acute aortic syndrome (primarily acute aortic dissection) ,7,8,9. MDespite numerous studies and reports on cardiac complications of hypertensive emergencies, uncertainties remain. Different studies report varying prevalence rates, reflecting the heterogenous nature of the studies and potentially, selection bias. The use of terminology in the classification and reporting of hypertensive emergency has been inconsistent across studies . Despite the overwhelming evidence of the prognostic implications of elevated cardiac troponin and subclinical cardiac injury, acute myocardial injury is not considered as acute hypertension-mediated organ damage. Presently, no robust system exists for risk stratification to promptly identify subgroups at a high risk of adverse cardiovascular and renal outcomes that could pre-emptively guide future management.In this narrative review, we aimed to: (1) give an overview of the epidemiology and pathophysiologic mechanisms of hypertensive emergency, (2) highlight the prevalence of cardiac complications of hypertensive emergency, (3) identify challenges in the evaluation, identification, classification and reporting of cardiac complications of hypertensive emergency, (4) propose an algorithm for the evaluation and classification of cardiac complications of hypertensive emergency, including the routine assay of cardiac troponin, and (5) make recommendations for the future.Although the availability of effective and well-tolerated antihypertensive medications has significantly improved outcomes in patients with hypertensive emergencies, the incidence remains unchanged ,14. An eStudies report a varying prevalence of cardiac acute hypertension-mediated organ damage, depending on demographics and comorbidities, among others; however, cardiac involvement predominates in most of the studies, with a cumulative prevalence ranging from 3.6 to 91% . ReasonsThe exact pathophysiologic mechanisms of hypertensive emergency remain incompletely understood. However, a sudden rise in BP serves as a common denominator underlying the various forms of acute hypertension-mediated organ damage, and most hypertensive emergencies occur in people with pre-existing hypertension . AlthougThe principal function of vascular autoregulation is to ensure uninterrupted blood flow to vital organs during fluctuations in BP and perfusion pressure, and this is accomplished via the appropriate modification of the peripheral vascular resistance (PVR) ,25. VascHeightened activation of the RAAS and increased levels of angiotensin II is nearly ubiquitous in patients with hypertensive emergency and correlates with the extent of microvascular damage . AngioteFibrinoid necrosis of small muscular arteries and arterioles, characterized by medial smooth muscle cell necrosis and the focal deposition of proteinaceous material occurs in malignant hypertension, a form of hypertensive emergency . This isThe constellation of pathophysiologic events described above does not occur in any preferential order, but rather, evolves concurrently in a variety of sequences with overlaps and widespread involvement of the vascular beds across various organs. The combined effects of autoregulatory failure, endothelial dysfunction and RAAS activation establishes a vicious cycle of BP elevation and progressively worsening acute hypertension-mediated organ damage. A summary of the pathophysiological mechanisms is presented in The different cardiac complications of hypertensive emergency are presented in Acute heart failure (including cardiogenic pulmonary edema) is the most common cardiac complication in hypertensive emergency with a prevalence ranging from 21.1 to 58% . A recenMost patients presenting with hypertensive emergency have preexisting hypertension, and as many as 83% have left ventricular hypertrophy (LVH) and diastolic dysfunction . An acut3 or summation gallop, and bibasilar crackles. Features of pulmonary congestion, cardiomegaly, and a widened mediastinum (due to aortic disease) may be visible on plain chest radiograph. However, subtle forms of cardiomegaly may not be apparent on conventional posterior-to-anterior chest X-ray. Echocardiography (the most frequently used diagnostic tool in heart failure) is useful in demonstrating cardiac morphology, function, and elevated left ventricular filling pressure. Reversible subclinical left ventricular systolic dysfunction has been reported with speckled-tracking echocardiography [Clinical features include a cough with frothy (pinkish) sputum, dyspnea, orthopnea, tachycardia, and elevated BP. Other findings are a heaving (often un-displaced) cardiac apex, Siography .The lowering of BP is associated with a prompt improvement of symptoms and outcomes in patients with acute hypertensive heart failure . The ESCStudies on the outcome of acute hypertensive heart failure are conflicting. While some studies found hypertension to be a predictor of low-risk for 30-day mortality and readmission , reportsAcute coronary syndrome is an umbrella term encompassing ST-elevation myocardial infarction, non-ST-elevation myocardial infarction and unstable angina. The prevalence of myocardial infarction in patients with hypertensive emergency ranges from 1 to 59.5% . These vEndothelial injury and intravascular thrombosis associated with hypertensive emergency could result in Type 1 myocardial infarction, especially in patients with pre-existing coronary artery disease. One study reported a prevalence of 76.5% for coronary artery disease among patients with hypertensive emergency and elevated troponin who underwent coronary angiography . The strDiagnosis of myocardial infarction is established in the presence of an elevated cardiac troponin levels above the 99th percentile of the upper reference limit (URL) with a rising and/or falling pattern, and at least one of the following: (1) symptoms of myocardial ischemia, (2) new ischemic ECG changes, (3) development of pathological Q waves, (4) evidence of new loss of viable myocardium or regional wall motion abnormalities in a coronary distribution, and (5) demonstration of coronary thrombus . SymptomThe aim of BP lowering in hypertensive emergency and ACS is to reduce myocardial oxygen demand by afterload reduction without compromising left ventricular diastolic filling. The ESC Council on hypertension recommends the immediate (within 1 h) lowering of the systolic BP to 140 mmHg or lower using nitroglycerin or labetalol , sublingThe concurrence of acute severe hypertension and myocardial infarction presents a diagnostic and management challenge. Blood pressure increases could either be the consequence, or cause of acute myocardial infarction (and stroke), and spontaneous reduction in BP has been reported in patients presenting with acute myocardial infarction and severe hypertension within 6 h of admission without the use of antihypertensive medications . DemonstThe different subtypes of ACS have varying pathophysiological mechanisms and prognoses, and it is unclear as to what degree unstable angina (without objective evidence of cardiac injury or acute hypertension-mediated organ damage) can be regarded as true hypertensive emergency. Most of the studies reporting ACS did not provide details of the subtypes to allow for appropriate risk stratification and prognostication. Another limitation is the selective application of the cardiac troponin assays, resulting in an underdiagnosis of atypical ACS .The universal definition of myocardial infarction identified myocardial injury separately from myocardial infarction in the ‘continuum’ of acute ischemic heart disease . Acute mFibrinoid necrosis, proliferative endarteritis, and intravascular thrombosis  could result in myocardial injury ,50. HoweThe initial evaluation of patients with myocardial injury is aimed at identifying features of myocardial ischemia and myocardial infarction. Where there are no features of myocardial ischemia, the evaluation is focused on non-cardiovascular causes. Without doing a cardiac troponin assay, myocardial injury could go unrecognized, underscoring the need for a routine cardiac troponin assay in all patients presenting with hypertensive emergency. Presently, there are no guidelines or consensus regarding the management of patients with acute myocardial injury and treatment is tailored to managing the triggers.Differentiating acute myocardial injury from Type 2 myocardial infarction is challenging. Each of the two conditions may represent different points along a single continuum of varying severity of cardiac complications, and they may co-exist in patients with hypertensive emergency ,59. The Most studies looking at the prognostic impact of myocardial injury did not differentiate acute from chronic myocardial injury, and hypertensive emergency was not represented in the cohort. Overall, patients with myocardial injury have a poorer prognosis compared to patients without ,49,59. IThere is increasing interest and awakening towards the identification of high-risk groups among patients with myocardial injury. The troponin assessment for risk stratification of patients without acute coronary atherothrombosis (TARRACO) risk score  was receAcute aortic syndrome comprises of acute aortic dissection, intramural hemorrhage/hematoma, a penetrating atherosclerotic aortic ulcer and aortic rupture. Acute aortic dissection (AAD) is the most prevalent acute aortic syndrome complicating hypertensive emergency. However, it is the least common cardiac complication of hypertensive emergency with a prevalence of 0 to 6.3% . A recenThe true incidence and prevalence of AAD is difficult to determine because of a high out-of-hospital mortality, diverse/overlapping clinical presentations, and misdiagnosis ,65. Pre-Acute aortic dissection commonly present with an abrupt onset of chest pain (often described as tearing or ripping and radiating to the interscapular region of the back) and severe BP elevation. However, patients with cardiac tamponade  may present with hypotension. Other symptoms of AAD include back pain, abdominal pain, pre-syncope/syncope, lateralizing signs , and loss of consciousness . ExtensiTreatment of AAD is aimed at reducing pulsatile hemodynamic stress on the aortic wall to forestall propagation of the dissection and prevent aortic rupture. The ESC Council on hypertension recommends immediate (within 20 min) lowering of systolic BP to between 100 mmHg and 120 mmHg, and the heart rate to less than 60 beats per minute using short-acting beta-blockers . AlthougDiagnosis of AAD can be elusive, requiring a high index of suspicion. The most common misdiagnosis is acute myocardial infarction . MortaliBased on current guidelines, the measurement of cardiac troponin in patients with hypertensive emergency is recommended only when there are symptoms/features of myocardial ischemia. Asymptomatic/sub-clinical myocardial injury occurs in more than one-third of patients with hypertensive emergency  and therThe nomenclature and classification of cardiac complications of hypertensive have not been consistent. Many studies used acute heart failure and acute pulmonary oedema (or cardiogenic pulmonary oedema) interchangeably, whereas some reported the two separately.The universal definition categorizes myocardial infarction into five types . HoweverThere are no randomized controlled trials to guide treatment in most cases of hypertensive emergencies, and the choice of medications, as well as the rate and magnitude of BP reduction is mainly based on expert opinion . The ESCPresently, there are no well-validated systems for risk stratification or consensus regarding the best management options for high-risk groups, including patients with subclinical target organ damage. Based on the results of the DEMAND MI study, patients with suspected Type 2 myocardial infarction should be subjected to routine assessment of their coronary arteries (invasive or computed tomography) and be given the benefit of evidence-based treatments to improve outcomes . This isCardiac troponin is undoubtedly the best indicator of myocardial injury. However, new biomarkers of myocardial injury are being increasingly identified. Cardiac myosin-binding protein C is a novel biomarker of myocardial injury that is more sensitive and has the advantage of rising and falling more quickly than cardiac troponin . This ali.Subclinical acute hypertensive target organ damage/dysfunction should be actively sought and added to the categories of acute hypertension-mediated organ damage . This shii.There is a need for consistency in the nomenclature and classification of acute hypertension-mediated organ damage. Acute heart failure should be used instead of cardiogenic pulmonary edema. The different types of myocardial infarction should be categorically identified as defined in the universal definition of myocardial infarction and included in studies reporting cardiac complications of hypertensive emergency.iii.There is the need for a properly designed study to: (i) accurately determine the true burden of acute hypertension-mediated organ damage in patients with hypertensive emergencies; (ii) determine the markers and long-term outcomes of subclinical acute hypertension-mediated organ damage; (iii) provide evidence-based strategies for immediate and long-term management of the different forms of acute hypertension-mediated organ damage; (iv) validate the use of oral medications in the treatment of hypertensive emergency; (v) develop well-defined strategies for the evaluation and management of acute myocardial injury and Type 2 myocardial infarction in patients with hypertensive emergencies.The following recommendations are aimed at addressing some of the challenges highlighted above: A proposed algorithm for evaluation and classification of acute severe rise in blood pressure and hypertensive emergency is presented in


This is our second article devoted to the cardiac myoarchitecture considered as a nematic chiral liquid crystal (NCLC). While the first article focused on the myoarchitecture of the left ventricle (LV), this new article extends to the whole ventricular mass and introduces the concept of disclinations and topological singularities, which characterize the differences and relationships between the left and right ventricles (RV). At the level of the ventricular apices, we constantly observed a vortex shape at the LV apex, corresponding, in the terminology of liquid crystals, to a “+1 disclination”; we never observed this at the RV apex. At the level of the interventricular septum (IVS), we identified “−1/2 disclinations” at the anterior and posterior parts. During the perinatal period, there was a significant difference in their distribution, with more “−1/2 disclinations” in the posterior part of the IVS. After birth, concomitant to major physiological changes, the number of “−1/2 disclinations” significantly decreased, both in the anterior and posterior parts of the IVS. Finally, the description of the disclinations must be considered in any attempt to segment the whole ventricular mass, in biomechanical studies, and, more generally, for the characterization of myocardial remodeling. Recent findings show that some biological tissues behave like liquid crystals, opening up a new perspective in understanding the structural mechanisms of living tissues ,2,3,4. TIn the human heart, we recently demonstrated with polarized light imaging (PLI) that the myosin myocardial mesh is a biological analogue of nematic chiral liquid crystals (NCLCs), where cardiomyocytes adopt an orientational order and organize themselves along their long axis  5]. In . In 5]. The term “liquid crystals” was used for the first time in 1900 by F. Reinitzer and O. Lehmann to describe the mesophase between the liquid and solid phases, where molecules have an orientational order  but lack a positional order (like liquids) ,12,13. IInside nematic liquid crystals, molecular arrangements are defined by angular correlations between molecules . An abruGrenoble-Alpes University hospital owns a legally declared collection of embedded tissue sections collected after autopsies of perinatal and early infant death performed for a diagnostic purpose. Perinatal hearts referred to patients who died before birth of within the first week of life, while early infant hearts referred to patients who died after the first week of life (>7 days). This collection was obtained after a written consent from the parents or guardians at the time of the request for autopsy authorization and for research authorization on normal and abnormal development. The institutional review board of the hospital approved the research protocol and the study was conducted in accordance with the 1964 Declaration of Helsinki and its later amendments. The sample dedicated to research purposes were kept anonymous, but past medical history and patient characteristics were collected. For this study, we selected perinatal and early infant hearts from patients without detectable cardiac anomalies.3  and expressed this information by two angles in a Cartesian system: the azimuth angle and the elevation angle. Representation of this orientation information was obtained using streamline maps with an LIC texture  to cancel collagen birefringence, allowing to focus on the birefringence of myosin molecules ,15,20. T texture  or falseDisclinations were identified by a visual analysis of each heart section, using different representation maps to maximize the visual characteristic of each disclination.Eighteen patients were included in our series. Among them, 11 (61%) died during pregnancy (after 22 weeks of gestation) or during the first week of life, and 7 (39%) died after the first week of life. Age at death was missing for two patients, but we were able to classify them reliably as perinatal hearts, given their small heart size. The number of heart sections obtained with the rotary microtome varied from 26 to 51. Section “0” referred to the most basal section, while the highest number referred to the most apical section. Approximately, the higher the number of heart sections, the larger the heart size. We identified on the compact myocardium only two types of disclinations. The first was a disclination of order m = +1 (noted “+ 1 disclination”), identified on the LV apex and illustrated in p = 0.031, and 41.7% vs. 9.4%, p = 0.006, respectively). This is also true in absolute values. While the total number of “−1/2 disclinations” observed among the 11 hearts of the perinatal group was 238 , the total number of “−1/2 disclinations” observed among the 7 hearts of the early infant group was 51 .As described above, the anterior and posterior connections between the left and right ventricles with the IVS were analyzed in each heart section of the patients using streamline maps with an LIC texture. We identified connections with the characteristic of a “−1/2 disclination” in both groups and reported them according to their apico-basal level . After np = 0.009), while there was no difference in early infant hearts . There was no variation in the mean position of “−1/2 disclinations” along the apico-basal axis between perinatal and early infant hearts.In perinatal hearts, the number of “−1/2 disclinations” was higher in the posterior than anterior parts of the IVS (23.8% vs. 41.7%, While for all patients the LV apex distinctly presented a vortex shape, corresponding to a “+1 disclination”, it was evident that the shape of the RV apex was different and not that expected of a vortex. This observation was constant regardless of the perinatal or early postnatal period. After demonstrating that the architecture of the LV behave like a liquid crystal, this second article of our series adds the concept of disclinations to the analysis of the whole compact ventricular mass, especially in the IVS . This woThe pioneering work of the biologist Yves Bouligand in the 1970s described stabilized liquid crystals in biology ,25. SincIn contrast, during the postnatal adaptation, we did not observe variations of the myoarchitecture of the two apices: there is a constant topological singularity at the LV apex whereas there is constantly none at the RV apex.Regarding the LV apex, the vortex appearance is a constant feature of all patients, regardless of size and age, and corresponds to a “+1 disclination”, as illustrated in Regarding the RV apex, we have never observed the appearance of a vortex and other disclinations. While these major differences between the right and left apices are widely acknowledged, to this day, it still lacks a scientifically demonstrated model of the whole myoarchitecture of the RV taking into account these morphological differences ,28,29,30The purpose of this article was to introduce the concept of disclinations in the description of the myoarchitecture of a compact ventricular mass, to promote these physics concepts in the fields of cardiology and anatomy. We gathered all the conditions that allowed us to identify the disclinations in cardiac myoarchitecture: an adequate sample collection and adapted digitized microscopic methods. While this inaugural work is somewhat marginal because of the technical constraints of PLI and being limited to using perinatal and early infant hearts, it must not be limited to that; it concerns the bulk of cardiology. Indeed, promising resolution improvements in routine cardiac imaging modalities, such as cardiac MRI or CT scans, will surely be allowed within a few years, thereby helping to apply these physical concepts to normal and pathological adult hearts. We are reasonably certain that, in the future, comprehensive methods for understanding and managing pathological cardiac conditions will have to integrate studies on the dynamics of disclinations in a ventricular mass. Describing the disclinations in a ventricular mass will become the standard for all future work on the segmentation of different domains of the ventricular mass and subsequent biomechanical analyses.


Pre-(PRE) and post-ejection (POE) velocities by mitral annular tissue Doppler (TD) are biphasic and may be related to myocardial deformations. We investigated the predominance and concordance of TD-PRE and POE velocities and their effect on myocardial functions in controls and in heart failure (HF) patients.Retrospectively, 84 HF patients , 42 normal young controls, and 26 asymptomatic age matched controls were included. Echocardiography was done and from mitral annular tissue Doppler recordings, the biphasic PRE and POE velocity signals were identified and compared between groups.p < 0.001, age controls:r = 0.79, p < 0.001, HFpEF: r = 0.56, p < 0.001, HFrEF: r = 0.42, p = 0.018; PREn vs POEp: young: r = 0.25,p = 0.1, age controls: r = 0.42, p = 0.04, HFpEF: r = 0.43, p = 0.004, HFrEF: r = 0.61, p < 0.001) and the ratios PRE-P/N and POE-N/P correlated significantly with E/e’ in HF only.While controls had almost always predominantly positive PRE and negative POE, HF had more negative PRE and positive POE. Moreover, almost all controls exhibited normal concordance (positive PRE and negative POE). HF exhibited more abnormal concordance which was significantly associated with worse NYHA, and parameters of diastolic and systolic functions. Opposite PRE and POE velocities correlated significantly in all groups (PREp vs POEn: young:r = 0.52, In physiological state, TD signals are predominantly positive during PRE and negative during POE. Opposite PRE and POE velocities corelate, representing the PRE-generation and POE-reversal of shortening–stretch relationships, the attenuation of which in HF may be related to elevated LV filling pressures. In HF, partially or completely reversed concordance of PRE and POE is associated with progressive worsening of clinical and hemodynamic profiles. Heart failure (HF) is a leading cause of death worldwide, the incidence and the prevalence of which is only expected to increase especially in the face of an aging population . SeveralVelocities during pre-ejection (PRE) and post-ejection (POE) recorded by tissue Doppler imaging (TDI) of the mitral annulus are biphasic. Several studies have shown that the positive velocity during PRE (PREp) represents a less load independent state of myocardial contractility and is associated with clinical and hemodynamic variables in patients with systolic dysfunction , 4.Moreover, we have recently reported that PREp is associated with LV filling pressure in systolic dysfunction  and in pIn a retrospective study protocol, patients referred to the echocardiography laboratory on outpatient basis with symptoms suggestive of heart failure were included. In addition, normal young controls (age < 40 years) and patients referred for routine echocardiographic examination who had no symptoms or structural myocardial abnormalities and who were age matched to heart failure patients were also included in the study . Patients were excluded if they had terminal illness, were in atrial fibrillation, had more than mild valvular disease, or had less than acceptable echocardiographic image quality. Demographic, clinical and laboratory variables were compared between groups and, in addition, conventional echocardiographic examination focused on tissue Doppler recording and measurements were also compared between subgroups.All echocardiographic studies were performed with a commercially available echocardiography systems equipped with a 2.5-MHz phased array transducer. Digital routine grayscale 2-dimensional and tissue Doppler cine loops from 3 consecutive beats were obtained at end-expiratory apnea from standard apical views at depths of 12–20 cm. Sector width was optimized to allow for complete myocardial visualization while maximizing the frame rate. Gain settings were adjusted for routine clinical grayscale 2D imaging to optimize endocardial definitions. LV-EF was calculated from the apical 2- and 4-chamber images using the biplane Simpson’s technique. EF was defined as preserved if EF was > 50% and reduced if EF was ≤ 50%. All measurements were made in ≥ 3 consecutive cardiac cycles and average values were used for the final analyses. The pulsed-wave Doppler-derived transmitral velocity and spectral tissue Doppler-derived mitral annular velocity were obtained from the apical 4-chamber view. The early diastolic wave velocity (E) and the late diastolic atrial contraction wave velocity (A) were measured using pulsed-wave Doppler recording, and the early diastolic mitral annular velocity (e’) and systolic velocity (s’) were measured and averaged from the septal and lateral mitral annular positions. The E/e´ ratio was calculated to assess LV filling pressure (LVFP) for all patients.From the mitral annular tissue Doppler recordings, the biphasic pre-ejection (PRE) and post-ejection (POE) velocity signals were identified Fig. . PRE wasp < 0.05. All analyses will be performed with a commercially available software .Categorical data are presented as number (%) and were compared using chi square test. Continuous data are presented as mean ± SD. Data were tested for normality using Kolmogorov–Smirnov and Shapiro–Wilk tests and, accordingly, continuous data were compared using t-test or analysis of variance (ANOVA) if they are normally distributed or the Mann–Whitney U test if they are not normally distributed. The correlations between different variables were done using the Pearson correlation coefficient. Cut-off values for prediction of E/e’ > 13 were tested using receiver-operator-characteristic (ROC) curves. Reproducibly analyses were done using interclass correlation coefficient and absolute differences for inter-observer and intra-observer differences of repeated measures in 15 randomly selected patients. Differences were considered statistically significant at The initial study group included 102 patients. 18(18%) patients were excluded due to atrial fibrillation in 5(5%) patients, and significant mitral valve disease in 13(13%) patients , Accordingly, the final study cohort consisted of 84 heart failure patients . Of these, 52(62%) patients had HFpEF (EF: 65 ± 5%), and 32(38%) patients had HFrEF (EF: 39 ± 9%). The cause of heart failure in patients with HFpEF was related to hypertension in 18 patients, diabetes in 11, both hypeertension and diabetes in 14 patients, and coronary artery disease in 9 patients, and the cause of heart failure in patients with HFrEF was ischemic cardiomyopathy in 9 patients, and non-ischemic cardiomyopathy in 23 patients. In addition, 42 young normal subjects , and 26 age matched controls  were included. Table p < 0.001; POEn: 3.3 ± 1 vs. 2.4 ± 0.7, p < 0.001) while there was no significant difference between PREn and POEp compared to HFpEF  and, similarly, there was no significant difference regarding both ratios . On the other hand, with the exception of a higher POEp in the normal subjects, none of the PRE or POE velocities were different between normal subjects and matched controls. Moreover, it was noted that normal and age matched controls had almost always a predominantly positive PRE and predominantly negative POE, while predominantly negative PRE and predominantly positive POE occurred almost always in HF patients  HFpEF patients and 25(67%) HFrEF patients, (p = 0.003). All types of concordance were observed in patients with HFpEF, however, in patients with HFrEF, almost all patients had abnormal concordance . Importantly, concordance seemed to be significantly associated with NYHA functional class such that the best NYHA was in normal concordance (1.6 ± 1) and the worst was in reversed concordance (2.6 ± 0.5), while reversed PRE and POE was in between normal and reversed . Similar patterns were observed in parameters of diastolic and systolic functions where the highest E/A and E/e’, the lowest average e’, the largest ESV and EDV and the lowest EF were noted in reversed concordance, while all these parameters were noted to be best in normal concordance and were intermediate between both groups in reversed PRE and POE. Importantly, in heart failure patients, bundle branch block was not significantly different between groups, while intraventricular conduction delay was most frequent in patients with totally reversed concordance  patients vs. 4(6%) controls, p < 0.001) and HFpEF , it was slightly weaker in patients with HFrEF . On the other hand, correlations between PREn and POEp were mainly noted in heart failure patients as no correlation was noted in normal subjects , and only a weak correlation was noted in matched controls . The correlation became slightly stronger in HFpEF  and was strongest in HFrEF . As such it was noted that the pattern of correlation was opposite in controls and heart failure between signals associated with normal concordance and signals associated with reversed concordance showing the normal concordance signals correlate better in controls and reversed concordance signals correlate better in HF patients.As suggested by the concordance of the biphasic waves, the main waves in the normal pattern were the positively directed in PRE and negatively directed in POE. Correlations noted in our study between different PRE and POE velocities are summarized in Table Correlation between the ratios PRE-P/N and POE-N/P, however, showed significant strong correlations in normal young subjects, weaker correlations in matched controls and HFpEF, while it was the strongest in HFrEF.p < 0.001, = 0.025), between E/e’ and POEn in patients with HFpEF only , between E/e’ and POEp in patients HFrEF only , while PREn did not correlate with E/e’ in any of the patients. The ratio PRE-P/N was found to correlate the strongest with E/e’ in both HFpEF and HFrEF , while the ratio POE-N/P showed similar however weaker pattern of correlations .Correlations noted in our study against left ventricular filling pressures as expressed by E/e’ are summarized in Table Receiver operator characteristic curves Fig.  showed tp = 0.021). Other than that, PREp, PREn, POEn, and POEp velocities as well as the ratios PRE-P/N and POE-N/P did not correlate with EF in any of the groups of the study patients or control groups.Finally, correlations noted in our study against left ventricular EF are summarized in Table Reproducibility parameters are summarized in Table The main study findings are as follows: first, normally, tissue Doppler-derived biphasic signals are predominantly positive during pre-ejection (PRE) phase and predominantly negative during post-ejection (POE) phase. Second, normal concordance of both velocity signals (positive PRE and negative POE) is associated with the best clinical, hemodynamic, and functional profiles in heart failure patients. Partially reversed concordance  occurs in heart failure patients (both HFpEF and HFrEF) and is associated with an intermediate worsening of clinical and hemodynamic profiles. Completely reversed concordance (negative PRE and positive POE) occurs mostly in patients with HFrEF and is characterized by the worst clinical, hemodynamic, and functional profiles. Third, velocities of opposite directions during the pre-ejection and post-ejection phases exhibit positive correlations, and seem to be related to the LV filling pressures as expressed by E/e’ ratio.The LV mechanical behavior during pre-ejection and post-ejection is a complex and controversial topic –10. Pre-Reportedly, the forces produced during pre-ejection are stored in memory within the myocardial wall until the end of the ejection phase , 14. RevImportantly, the positive predominance of the PRE and the negative predominance of the POE suggests that the magnitude of the active forces (shortening) during PRE and the magnitude of their release during POE exceeds that exerted by the passive fiber stretch and its reversal and further suggest that the active endocardial mechanics are the driving force in all isovolumic mechanical behavior over the passive epicardial mechanics.The coupling of normal predominance of both phases, noted in our study as the normal concordance between both phases, was mostly found in normal young patients and in age matched controls. Moreover, when such normal concordance was encountered in heart failure patients, it was associated with the best clinical and hemodynamic profile. The loss of normal concordance was almost always found in heart failure patients and was characterized by either reversal of one of both phases  or reversal of both phases . The progression from normal concordance to partially reversed and finally to completely reversed concordance in our study was associated with a similar progression in severity of the clinical and hemodynamic profiles in heart failure patients. Importantly, it was uncommon to have an isolated reversal of PRE , while isolated reversal of the POE was not uncommon. Partial reversal of the predominance of the biphasic velocities may be due to failure of normal transmission of the pre-ejection forces (shortening–stretch) in memory into the post-ejection phase which may lead to inappropriate diastolic behaviors (as noted in patients with HFpEF) but may also affect systolic function to a certain degree. Complete reversal, on the other hand, means complete disruption of the presumed PRE-POE relationships and may be due to faulty generation of PRE forces and subsequent faulty transmission of these forces into the POE.The mechanistic explanation of these changes lies in the fact that PRE-POE relationship is based on myocardial electromechanical anisotropic coupling , 16. In This timing and sequence of electrical excitation influenced by the His-Purkinje system and the anistropic nature of myocardium , both ofThe study suffered from the following limitations: first, the sample size is small and larger studies should be conducted before the findings can be adopted to clinical practice. Second, mitral annular velocities are the result of the tethering of the fibrous structure of the mitral annulus, and as such represents only an indirect measure of myocardial mechanics. Better representation of the myocardial mechanics can be obtained using myocardial deformation imaging techniques such as speckle tracking echocardiography. Strain rate imaging would be an appropriate alternative, however, due to the lower frame rate and higher signal to noise ratio, deformations during PRE and POE can either be missed or recorded with high noise, making it less reproducible than spectral tissue Doppler of the mitral annulus. Third, mitral annular velocities represent mainly deformations in the longitudinal directions, however deformations during pre- and post-ejection phases occur in all other directions of contraction, namely, circumferential, radial, as well as rotational (twist). Further studies should focus and compare the relationships of deformation in other directions of myocardial contraction in PRE and POE both in health and disease. Forth, reduced EF in our study was defined as EF ≤ 50% according to the American society of echocardiography guidelines for chamber quantification . It is iTissue Doppler-derived biphasic velocities during the pre- and post-ejection phases can be related to the active endocardial shortening and passive epicardial stretch forces that occur during PRE and their reversal during POE. In normal physiological state, biphasic signals are predominantly positive during PRE and predominantly negative during POE highlighting the prevalence of the active endocardial shortening over the passive epicardial stretch forces. A positive correlation between the opposite velocities of PRE and POE represent the PRE-generation and POE-reversal of shortening–stretch relationships, the attenuation of which may be related to elevated LV filling pressures in patients with heart failure as expressed by E/e’ ratio. In heart failure patients, a normal concordance of both velocity signals is associated with the best clinical, hemodynamic profiles, while partially reversed (either PRE or POE), and completely reversed concordance are associated with progressive worsening of clinical and hemodynamic profiles. Reversal of concordance can be explained by faulty generation and/or propagation of shortening–stretch forces due to mechanical barriers such as fibrosis or electrical abnormalities such as loss of gap junctions that occur in the myocardium of patients with heart failure. The relationships noted in our study can aid in the prediction of the prognosis in heart failure patients and may aid therapeutic selection and dosing, however larger studies are needed to test the clinical implications of such findings.


Compared to controls, LA reservoir strain and strain rate, conduit strain and strain rate, booster pump strain rate, total EF and passive EF were significantly lower ; the patients with preserved but lower RVEF(<50%) had lower reservoir strain, reservoir strain rate and pump strain rate  than the patients with higher RVEF (≥50%). (4) Conclusions: In patients with rPA/VSD, LA function was altered when biventricular EF was preserved, which may provide an early indication of left ventricular diastolic dysfunction. CMR can detect LA dysfunction at an early stage, even before LA enlargement.(1) Background: The left atrium (LA) is much more than a reservoir for left ventricular filling. The aim of this study was to assess the LA volume and function in patients with repaired pulmonary artery atresia with ventricular septal defect (rPA/VSD) using CMR. (2) Methods: 31 pediatric patients with rPA/VSD and 30 healthy controls were prospectively recruited. Left atrial ejection fraction (EF), strain and strain rate of three phases  and left atrial volume were measured with cardiac function analysis software. (3) Results: Patients with rPA/VSD had decreased maximal volume index ( Congenital heart diseases (CHD) is the most common birth defect, with approximately 122.7 per 100,000 live births affected by a CHD of the right heart structures. ,4,5. TheThe role of left atrium (LA) in cardiac function is receiving increased attention . LA is nCardiac Magnetic Resonance Imaging (CMR) is considered as the gold standard for assessing atrial function compared with echocardiography ,13. TherThirty-one consecutive patients with rPA/VSD were recruited with CMR examination between August 2017 and February 2022. The inclusion criteria were as follows: (1) patients who had undergone repair with no residual shunting and no more than mild and moderate right ventricular outflow tract and pulmonary obstruction, (2) patients with preserved biventricular ejection fraction . The patients with (1) residual VSD, (2) decreased ventricular ejection fraction , (3) inadequate CMR image quality for assessment, and (4) CMR contraindications were excluded.The control group of 30 gender- and age-matched children were selected from healthy volunteers. They had no abnormalities in cardiac function by echocardiography and no known history of cardiovascular diseases. In the healthy group, no contrast agent was used. The study was consistent with the Declaration of Helsinki and was approved by the institutional ethics committee. Informed consent was obtained from the guardians of all children involved in the study.All patients underwent cardiac MRI performed with a 3.0 T MRI scanner  or 1.5-Tesla  with an 8-channel phased array cardiac coil. Use of sedation depended on the patients’ status. If subjects were younger than five years old or could not be cooperative during the examination, sedation was carried out. Two-dimensional cine b-SSFP images were obtained with retrospective electrocardiograhic gating during free breathing or breath holding if they were able to cooperate, including short-axis views that cover both ventricles, two- and four-chamber views. Imaging parameters: echo time/repetition time 1.5–2.0/3.1–3.9 ms, slice thickness/interslice gap = 5–8/0 mm, temporal resolution/spatial resolution 25–32 ms/1.3–1.6 mm, and 20–30 reconstructed cardiac phases per cardiac cycle.PR fractions of the main pulmonary artery (MPA) were calculated on two-dimensional phase contrast cine. Anatomical location of scanning was perpendicular to the MPA and slightly above the pulmonary valve with parameters including repetition time/ECG time 3.6–4.6 ms/3.3–4.6 ms, slice thickness 4–5 mm, and encoding velocity 120–300 cm/s.We used the commercial cardiovascular post-processing CVI 5.9.1 software  for assessing ventricular function and PR. Ventricular parameters were measured and indexed to the body surface area (BSA), including end-diastolic volume index (EDVi), end-systolic volume index (ESVi), stroke volume index (SVi), ejection fraction (EF), and cardiac output index (CI) of the left and right ventricle. PR fractions = regurgitant volume/forward flow volumeThe assessment was performed on QMass 8.2 software  on the basic four-chamber and two-chamber cine views by biplane area-length method, including maximal LA volume at LV end-systole (LAVmax), LA volume at LV diastole before LA contraction (LAVpreA), and minimal LA volume at LV end-diastole (LAVmin) . All LA With the measured volumes above, we then calculated the LA ejection fraction (LAEF) at three phases. Total LAEF, passive LAEF, and active LAEF represented atrial reservoir, conduit, and pump function, respectively. The corresponding formulas were as follows:LA deformation analysis was performed with QStrain software , using two-and four-chamber views a. LA endt-test. If the continuous variables were not normally distributed, the Mann-Whitney U test was used. Correlations between left atrial volume and strain parameters were assessed using Pearson’s correlation coefficient for normally distributed variables and Spearman’s correlation coefficient for non-normally variables. Correlations can be classified as weak, moderate, and strong, depending on the range of coefficients . Based on 20 randomly selected subjects (10 controls and 10 patients with rPA/VSD), reproducibility was assessed by the intraclass correlation coefficient. A p value of ≤0.05 was considered statistically significant.All statistical analyses were performed using commercially available SPSS 26.0 Statistics software . The Kolmogorov-Smirnov test was used to assess the normal distribution of the data. Continuous variables were presented as mean ± standard deviation or median and interquartile range as appropriate. Categorical variables were stated as frequencies or percentages. If the continuous variables were normally distributed, comparisons between the two groups were performed using an independent-samples Thirty-one consecutive patients with rPA/VSD and 30 volunteers were finally enrolled in the study. Baseline characteristics are showed in p < 0.001). Both LVEF and RVEF were lower in patients with rPA/VSD but in the normal range. All subjects with rPA/VSD presented pulmonary regurgitation and the mean value was 36.27%.Left and right ventricular volume and function parameters in the two groups are presented in p = 0.008). Compared to controls, the reservoir strain and strain rate, conduit strain and strain rate, total EF, and passive EF were significantly lower in rPA/VSD . As for LA booster pump function parameters, only booster pump strain rate showed significant differences (p = 0.03). The details of the values for left atrial volume and function parameters were summarized in Among three LA volume indexes, there were no statistically significant differences in LAVIpreA and LAVImin between the two groups. However, patients with rPA/VSD had significantly smaller LAVImax  had lower reservoir strain and SR and pump SR  than the patients with higher RVEF .As showed in The ICC of left atrial strain and SR were listed in The present CMR study demonstrated the alteration of LA size and function in patients with rPA/VSD, characterized by diminished strain and strain rates at reservoir and conduit phase, and reduced booster pump SR before LA dilation. Furthermore, patients showed no increased left atrial volume but had decreased maximal volume index. An additional interesting finding was that the LA performed better in patients with higher RVEF (≥50%).In our study, we found that rPA/VSD group with preserved ventricular EF had significantly impaired RV performance with higher RVEDVi, ESVi, SVi and CI compared with controls. On the other hand, all patients demonstrated pulmonary regurgitation, which is a common condition in postoperative right-sided malformations of congenital heart diseases. In the long run, it could cause irreversible ventricular remodeling and cardiac dysfunction . These fEmerging data suggested that the LA is much more than a reservoir for LV filling. As previously mentioned, it has three phasic functions: (1) reservoir, (2) conduit, and (3) contractile function. Its structure and function are expected to be useful indicators for evaluating cardiac function and prognosis in multiple disease states, including CHD . MoreoveTo the best of our knowledge, this is the first study about the assessment of left atrial volume and function in rPA/VSD by CMR. In this group with the patients with preserved biventricular EF, we demonstrated significantly lower LA reservoir strain, reservoir SR, total EF, conduit strain, passive EF, and lower pump SR than those in healthy controls, indicating impaired reservoir, conduit and pump function. It is suggested that abnormal LA function might precede LV dysfunction, which may be an early indicator of LV dysfunction. Our findings were consistent with a previous echocardiographic study by Hou et al.  in patieOn the other hand, in the presence of abnormal LA function, children with rPA/VSD showed no increase in LA volume, but a decrease in LAVImax. This may be due to the reduced pulmonary blood flow secondary to PR, leading to a decrease in the preload and thus inadequate filling of the left atrium. Above all, it is suggested that abnormalities in left atrial function had already have occurred in children with rPA/VSD before the enlargement of the left atrium.In addition, we also found moderate to good correlations between the strain parameters and total EF, which corresponds to the reservoir function of LA and can be simply calculated by LAVmax and LAVmin. This was consistent with previous studies in HCM  and non-The left atrium is one component of the whole heart, which should not be separated from the other chambers. It interacts with the LV through the atrioventricular junction and manifests a dynamic adaptation in its size and function for left ventricular compliance alterations . When LVThere were some limitations to this study. First, this was not a multi-center study and the number of the rPA/VSD is limited; thus, the data should be considered preliminary. Second, interactions between the atria have been reported , and theIn patients with rPA/VSD, left atrial function has been altered when left ventricular ejection fraction was preserved, which may provide an early indication of left ventricular diastolic dysfunction. In addition, CMR can detect abnormalities of left atrial function at an early stage, even before left atrial enlargement.


Compared with traditional right ventricular apical pacing, His-bundle pacing (HBP) provides more physiologic pacing by activating the normal conduction system. However, HBP has some limitations including higher pacing thresholds. In addition, disease in the distal His-Purkinje system may prevent the correction of abnormal conduction. Left bundle branch pacing (LBBP) may overcome these disadvantages by providing lower pacing thresholds and relatively narrow QRS duration that improve cardiac function. Here, we describe a rare case of a transient loss of ventricular capture due to acute anterior wall myocardial infarction in an LBB-paced patient. With the improvement of the ischemia, the function of the pacemaker partly recovered. We review the adaptations, advantages, and limitations, and long-term safety of LBBP. A computed tomography (CT) scan of the lung revealed bilateral pneumonia and hydrothorax that was related to the heart failure. Echocardiography revealed a left ventricular end-diastolic diameter of 56 mm, ejection fraction of 42%, interventricular septal thickness of 11.8 mm, and decreased diastolic function. The second day after AMI, the ST segments on his ECG declined toward the baseline value with inverted T waves in the anterior leads (An 82-year-old man who was treated with LBBP in 2018 for atrioventricular (AV) conduction disorder was admitted to the Chest Pain Center of the 980th Hospital of the Joint Logistic Support Force of the People's Liberation Army (PLA) in 2021. Based on typical acute chest pain, the elevation of the ST segment in leads V1–V4 of the electrocardiogram (ECG) , and posor leads .via a transventricular septal approach  was advanced and positioned approach ,B. The papproach , 3C. Theapproach . Compareapproach ; Table 1approach –F. A rouapproach , Table 1The patient recovered well and was discharged. After more than 1.4 years of follow-up, the patient showed good recovery with no complications and a septal thickness of 9 mm. The ventricular pacing threshold remained relatively steady with a slight decrease to 1.75 V/0.4 ms .To overcome the limitations of right ventricular apical pacing (RVAP) such as electrical and mechanical dysynchrony and a high risk of heart failure , two phyIn this report, we described a patient with AV block and a high percentage of right ventricular pacing rate that was successfully treated with LBBP. After the implantation in 2018, the threshold of the pacemaker remained stable and was similar to that observed at the time of implantation, and the patient was asymptomatic without heart failure for more than 2 years till the year 2021.Many articles and systematic reviews have demonstrated the effectiveness of LBBP , which wCompared with RVAP and HBP, LBBP has technical advantages, especially in terms of physiologic pacing, but there are still some aspects that warrant consideration . First, Short-term clinical outcomes of physiologic pacing, especially LBBP, have been promising , 12. NonThe IVS ischemia may occur more frequently than with RVAP in patients with LBBP, making them more prone to loss of capture, which should be taken into account when selecting the mode of pacing.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.The studies involving human participants were reviewed and approved by the Ethics Committee of 980th Hospital of the Joint Logistic Support Force of PLA, Hebei Medical University. Written informed consent to participate in this study was provided by the In review participants' legal guardian/next of kin. Written informed consent was obtained from the minor(s)' legal guardian/next of kin for the publication of any potentially identifiable images or data included in this article.XZ, SQ, and DW were responsible for study design and manuscript preparation. XZ, YM, and JL performed clinical data acquisition. LR contributed to the operation of PCI. XZ wrote the manuscript. All the authors contributed to the article and approved the submitted version.This work was supported by the Key Project of Medical Science Research in the Hebei Province (grant no. 20200232).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Hence, BAV patients need lifelong evaluations to prevent severe clinical sequelae. We applied 4D-flow magnetic resonance imaging (MRI) for in detail visualization and quantification of A total of 51 BAV patients with mild regurgitation and 24 healthy controls were recruited to undergo routine cardiac MRI followed by 4D-flow MRI using 3T MRI scanners. A dedicated 4D-flow module was utilized to pre-process and then analyze the LV flow components  and left-sided [left atrium (LA) and LV] local pressure drop. To elucidate significant diastolic dysfunction in our population, transmitral early and late diastolic 4D flow peak velocity , as well as E/A ratio variable, were acquired.p > 0.05). In terms of pressure analysis , maximum and mean as well as pressure at E-wave and A-wave timepoints at the mitral valve (MV) plane were significantly different between BAV and control groups . Furthermore, maximum pressure and pressure difference at the A-wave timepoint at left ventricle mid and left ventricle apex planes were significant. Although we could not find any correlation between LV diastolic function and flow components, Low but statistically significant correlations were observed with local pressure at LA mid, MV and LV apex planes at E-wave timepoint .The significant means differences of each LV flow component  were not observed between the two groups  can be a more reliable biomarker to reveal the early stage of diastolic dysfunction. The beating heart’s ultimate function is to continuously and efficiently pump blood to supply body organs constantly. Many cardiac abnormalities can perturb normal intricate intra-cardiac hemodynamics flow patterns and local pressure, triggering higher energy dissipation and pumping deficiency , 2. BicuApproaches for intra-cardiac left ventricular (LV) four flow components including direct flow (DF), retained inflow (RI), delayed ejection (DE), and residual volume (RV) under healthy and abnormal conditions, have been proposed using 4-dimensional time-resolved blood flow velocities (4D-flow) , 12. Mulin vivo pressure gradients in clinical practice, diagnostic catheterization is used as the gold standard. Although this method is reliable with a low risk  phase-contrast magnetic resonance imaging , shows an excellent agreement to pressure drop acquired from heart catheterization , 24. LatIntegration of morphological data and 3D cine phase-contrast cardiovascular magnetic resonance (PC-CMR) flow data has allowed addressing unresolved physiological and clinical questions of BAV mediated hemodynamics on the surrounding environment such as LV and thoracic aorta clinically –32. Howen: 51 BAV patients with mild regurgitation  and n: 24 healthy controls  with negligible mean age difference (p = 0.65). A minimum sample size of 11 subjects per cohort was estimated based on Engineering’s sample size estimation  approved this study at our institution. All research procedures were performed in agreement with the Declaration of Helsinki.in vivo volumetric blood flow assessment. The parameters were set as follows: velocity encoding range in all direction (venc): 150–200 cm/s, flip angle: 15°, spatial resolution: 2.0–3.6 mm × 2.0–3.0 mm × 2.5–3.5 mm, temporal resolution: 25–35 ms, phases: 30, bandwidth: 455–495 Hz/Pixel, echo time: 2.01–2.35 ms, pulse repetition time: 4.53–5.07 ms. The overall scan times varied between 8 and 12 min, depending on the physiologically based factors, defined scan parameters and respiratory gating efficiency.All subjects underwent a standardized imaging protocol consistently using 3T MRI scanners . Multi-planar segmented ECG gated, time-resolved balanced steady-state free precession (SSFP) cine imaging in 4-chamber, 3-chamber, 2-chamber, and short-axis views were achieved covering the whole heart at end-expiration for functional assessment of LV. Moreover, for volumetric assessment, 3D magnetic resonance angiography (MRA) of the whole heart was acquired by administrating 0.2 mmol/kg gadolinium contrast . Then, whole-heart 4D flow MRI was performed 5–10 min following contrast administration, using free-breathing retrospective ECG-gated for comprehensive intracardiac 3D Standard clinical reading was performed using cvi42 v5.11.5 . We derived functional parameters of LV from cardiac MR images. Left ventricular end-systolic volume (LVESV) and left ventricular end-diastolic volume (LVEDV) obtained and indexed to body surface area (BSA). The cvi42 v5.11.5 4D-flow module was used to analyze the left ventricular flow components  and left-sided [left atrium (LA) and LV] pressure drop during a cardiac cycle. Moreover, to elucidate significant diastolic dysfunction in the pEF, transmitral early and late diastolic 4D flow peak velocity , as well as E/A ratio variable, were acquired. The schematic workflows are provided in Intracavitary LV blood flow was divided into four components over the cardiac cycle, namely: (I) DF, the blood volume that enters and leaves the LV during the same cardiac cycle; (II) RI, blood volume that enters the LV during the diastolic phase and does not eject in systolic phase in the same cardiac cycle; (III) DE flow, blood volume that retained into the LV and ejected in the next systole and; (IV) RV, the amount of blood that remains in LV for two cardiac cycles or more.The left ventricular flow components analysis starts with selecting the long-axis three-chamber SSFP cine image preferably to automatically localize static AV and MV planes on each frame . An autoRendered phase-contrast magnetic resonance angiography (PC-MRA) acquisitions of the whole heart were used for LA and LV 3D segmentation. Then, five static planes, including a reference plane, were accurately positioned orthogonal to the segmented LA and LV longitudinal axis, and contoured manually in succession at the segmented left side of the heart as follows: upper part of the LA (reference plane), LA middle part, MV, LV middle part, LV apex. For each plane, the maximum and average pressure and pressure at four cardiac time points were measured, including peak systole, end-systole at the time of IVR, early and late diastolic transmitral pressure . The four cardiac time points locations were determined using acquired flow-time curves for each assigned plane to measure pressure according to the pressure-time diagram . The dedAlthough cardiac catheterization is the gold standard method and echocardiography has been suggested as a reliable imaging technique to assess diastolic function, we have employed 4D flow MRI capability to measure this parameter. Early and late transmitral diastolic peak velocity  were measured by dynamic mitral plane obtained by MV contouring throughout all phases of the cardiac cycle in the ventricle flow components analysis by 4D flow MRI. E-wave and A-wave timepoints were obtained by the mitral flow-time curve, and then flow-time curve turned into a peak velocity-time curve to measure the maximum velocities at E-wave and A-wave timepoints. Consequently, we attained the E/A variable to uncover any significant diastolic dysfunction as per available normal and abnormal clinically used E/A ranges. In this study, 4D flow MRI-derived mitral filling patterns have been graded as follows: E/A ≤ 1 as impaired relaxation, 1 < E/A < 2 as normal/pseudonormal, and 2 ≤ E/A as restrictive filling  39)..39).t-test and Mann–Whitney U test were used to detect any significant difference between BAV and control subjects for flow components, pressure drop and LV diastolic dysfunction. In addition, Pearson’s product-moment correlation coefficient and Spearman’s rank correlation coefficient were used depending on the type of variables. p-values less than 0.05 are considered statistically significant.Statistical analyses were conducted using IBM SPSS (Version 27). Initially, the Shapiro–Wilk’s test was used to evaluate the type of distribution, whether they are normally distributed or not. Based on the distribution, unpaired two-tailed equal variance student’s p: 0.02).Our study population encompassed a wide age range from 17 to 62 years old, with the prevalence of male sex. Baseline characteristics and the left ventricular functions of BAV and control cohorts have been provided in p > 0.05). There were negligible associations between LV mass and DE and LV mass with RI .Planes were positioned, and pressure was remeasured randomly for 25 subjects by the same observer. All data are available in p: 0.005, p: 0.02, and p: 0.007, respectively). As such, the pressure differences were significant at the three planes at A-wave timepoints . The average pressure difference, as well as pressure difference at the E-wave timepoint at the MV plane , were significant in addition to maximum and A-wave timepoint pressure. Consequently, we could differentiate BAV with mild regurgitation and control groups by measuring local pressure  in healthy control is different from BAV patients with mild regurgitation severity at the different assigned planes. A BAV patient in grade III (restrictive filling) stage of diastolic dysfunction (E/A > 2) that is associated with reduced LV diastolic compliance, although the ejection fraction is preserved, has been compared with a healthy control in We have provided an additional pressure comparison in the four timepoints between a healthy control and a BAV patient in the R: 0.322, p: 0.03), pressure at LA middle part at A-wave timepoint and LV mass , pressure at MV plane, at A-wave timepoint and LV mass and LV mass index . In terms of the association between pressure and LV function variables, pressures at the LV middle part and LV apex at E-wave timepoint have correlations with LV mass and LV mass index. In addition, LVEF did not show any association with the measured local pressures because EF is a global parameter while pressure is a local parameter.We found some low correlations between LV function variables and local pressure as follows: between maximum pressure at LA middle part plane and LVCO .We could not find any correlation between LV flow components and diastolic dysfunction. Correlations just were found between E-wave peak velocity acquired by dynamic plane at MV location in the 4D flow LV analysis with MV total volume and with MV peak velocity . However, separately investigating those cohorts indicates that the slope of the line of best fit is negative and far higher for control compared to BAV  shows negative and low but statistically significant correlations with pressure at LA middle part, MV, LV middle part and LV apex planes at E-wave timepoint . Note that the slope of the line of best fit is positive and higher for BAV compared to healthy controls , and E-wave peak velocity has a low association with pressure at LV middle part and LV apex planes with maximum pressure .A-wave peak velocity correlates with pressure at MV plane at A-wave timepoint , while it was not statistically significant between E/A and healthy control , indicating E/A degrade faster by aging in our BAV subjects compare to healthy individuals  as well. Therefore, the negative and statistically significant correlation between E/A and all subjects  is because of the BAV cohort, and the healthy cohort mitigates the negative slope of the line of best fit.We also could find a moderate and negative correlation between E/A and age in our BAV cohorts . CO was preserved in our study cohorts, indicating that diastolic dysfunction may be developed as a compensatory mechanism by achieving some degrees of correlations between LV and LA function parameters and pressure at some planes and some timepoints.Precise pressure gradient exchange in the healthy condition between LV and LA in the relaxation phase of LV leads to MV opening. Consequently, on-time starting and finishing of the rapid filling of the LV chamber will occur. Any deviation from the standard, optimized pressure exchange and equilibrium in the presence of morphological and hemodynamic abnormalities can lead to diastolic dysfunction. Interestingly, although there was no systolic dysfunction, we could observe diastolic dysfunction in BAV with mild regurgitation according to acquired flow and peak velocity ratio during the rapid filling pressure (RFP) (E-wave) and atrial systole (A-wave) achieved by 4D flow MRI analysis. LV filling pressure valuation has been proved reliable for evaluating HF patients with pEF . OptimizBicuspid aortic valve with mild regurgitation and pEF may result in diastolic dysfunction uncovering by cardiac magnetic resonance feature tracking (CMR-FT) strain imaging as a Whilst we observed different degrees of diastolic impairment based upon the recommendations of the updated American Society of Echocardiography and European Association of Cardiovascular Imaging  in our all-included age groups of BAV population, this phenomenon can be a normal process of aging . Note thConsidering that BAV is accompanied by different secondary complications including LV afterload, AV defects, dilatation and dissection of thoracic aorta, local pressure drop and any clue indicating diastolic dysfunction could be the initial clinical alerts to hinder the progressive process and consequent HF with pEF.4D flow MRI studies increasingly demonstrate the potential of this imaging technique, facilitating quantification and visualization of complex intracardiac blood flow in three orthogonal directions over time. Thus, 4D flow MRI can provide valuable and additional indices in the cases of AV abnormalities and their effects on the heart cavities, which are still poorly uncovered , 31, 49.This exploratory study can provide a new insight by applying 4D flow MRI capabilities for further studies to uncover early and reliable medical imaging markers in asymptomatic and silent BAV patients with regurgitation to prognose disease development, hamper serious clinical outcomes and cardiac failure.Bicuspid aortic valve phenotypes and regurgitation jet direction were not classified in our groups with a wide range of age, which is beyond the scope of this study. In some cases, the same healthy control matched several BAV subjects. Thus, this study did not use 1:1 matching. A propensity score matching with 1:1 population ratio could be an alternative strategy for subject matching. Echocardiography and CMR-FT technique could be applied to supplement diastolic dysfunction measurement. Because of the data limitation, we did not follow up the BAV cohorts to assess any progression in terms of left ventricular remodeling, functional degradation, and surgery referral. Since this exploratory study aimed to prove the validity or accuracy of local and global measurements, all the limitations will be considered in future studies to verify the role of local pressure and its associated indices in clinical applications for disease development.In conclusion, the findings of this study propose that pressure  can be a promising imaging biomarker compared to flow components to prognose left ventricular dysfunction in the BAV-induced regurgitation cases with pEF that may stay clinically asymptomatic for years. The role of local pressure by applying 4D flow MRI deserves more scrutiny in future studies to be validated as an early and reliable subclinical biomarker of LV diastolic dysfunction and remodeling in asymptomatic BAV patients in clinical practice for better risk stratification and disease management.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by University of Calgary Conjoint Health Research Ethics Board. The patients/participants provided their written informed consent to participate in this study.SA and JG performed the data analysis and data collection, drafted the initial manuscript, and performed and reviewed statistical analysis. AS developed the 4D-flow prototype module and reviewed data outputs. MFB, MSB, CL, PF, and JW monitored the patients, supervised the cardiac scan exam, and supervised and performed the clinical reading. JG designed the study, supervised the students and data analysis, and drafted manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.


Novel biomarkers of heart failure are the subject of numerous studies. Biomarkers of heart failure can be determined in the blood and in the urine. Seven groups of biomarkers of heart failure based on pathophysiological mechanisms are presented in this review, namely biomarkers of myocardial stretch, myocyte injury, myocardial remodeling, biomarkers of inflammation, renal dysfunction, neurohumoral activation, and oxidative stress. Studies of biomarkers in the pediatric population are scarce, therefore, further investigation is needed for reliable prognostic and therapeutic implications. The future of biomarker use is in multimarker panels that include a combination of biomarkers with different pathophysiological mechanisms in order to improve their diagnostic and prognostic predictive value. Despite advances in medicine, heart failure is still an important cause of morbidity and mortality in the modern world. Consequently, there is a considerable need to find new ways of predicting, screening, and prognosticating heart failure, especially in pediatrics . LaboratVarious novel biomarkers of heart failure have been studied in adults. However, reliable novel biomarkers of heart failure in pediatrics have not been sufficiently studied for everyday clinical practice yet, therefore, additional knowledge is very welcome. In this review, we try to classify biomarkers according to the pathophysiological mechanisms that contribute to the development of heart failure. Several biomarkers of heart failure are still under evaluation and a detailed review of all of them is beyond the scope of this narrative review.In pediatrics, biomarkers of heart failure are particularly important for the early identification and risk stratification of patients with systemic diseases and associated risk for early development of heart failure. Good biomarkers have the following characteristics: high sensitivity and specificity, the possibility of simultaneous processing of many samples, short analysis time, low cost, and good clinical applications, thus predicting the risk of heart failure and the associated prognosis as well as the adequacy of monitoring .Two strategies are currently in place to detect newer biomarkers of heart failure, the first is based on proteomics and metabolomics, which means comparing blood and tissue samples from patients with heart failure with healthy individuals. It provides data on the expression of proteins and their breakdown products . This fiHeart failure is a condition in which the heart is not able to pump enough blood to meet the needs of all tissues . This caMid-regional proatrial natriuretic peptide (MR-proANP) is an atrial natriuretic peptide that is determined in the form of a prohormone because of its longer half-life and greater plasma stability. Recent research has identified the middle region of prohormone or MR-proANP . N-termiNumerous studies have already been conducted in the field of biomarkers of myocardial damage, as the process of cell death of cardiomyocytes due to apoptosis or necrosis is at the forefront of heart failure. Various mechanisms lead to cell death, such as poorer tissue perfusion, poorer oxygen supply, increased heart muscle load, circulating neurohormones, adrenergic system activation, inflammation, and oxidative stress .Troponins are regulatory proteins involved in the contractions of the heart muscle and skeletal muscle. Cardiac troponins are organized as a troponin complex consisting of different subunits. Troponin C binds calcium, troponin I inhibits contraction, and troponin T promotes contraction through the binding of the troponin complex to tropomyosin . CardiacHeart-type fatty acid-binding proteins (H-FABPs) are small intracellular proteins that bind lipids. They are located in tissues with intensive fatty acid metabolism, such as the heart, liver, and intestines . After mGlutathione transferase P1 (GSTP1) is the most widespread isoenzyme among glutathione transferases and plays a significant role in antioxidant defense , it may Remodeling of the matrix leading to cardiac fibrosis is a crucial factor in the progression of heart failure, as evidenced by impaired systolic and diastolic ventricular function .Galectin-3 belongs to the group of lectins and allows specific binding of β-galactosides. Galectin-3 is involved in cell adhesion, activation, proliferation, apoptosis, and also in cell migration . In addiThe soluble isoform of tumor suppression 2 or sST2 has become an interesting biomarker of heart failure due to its involvement in the processes of inflammation, fibrosis, and strain on the heart muscle. There are two isoforms of ST2 protein, namely the transmembrane isoform ST2L and the soluble isoform sST2. The transmembrane isoform has an immunomodulatory function via the interleukin-33 (IL-33) signaling pathway . MechaniMicroRNAs are small non-coding RNAs that are part of myocardial remodeling processes resulting in cardiac hypertrophy and fibrosis, therefore, they are involved in the development and progression of heart failure . ConsequChronic inflammation is one of the pivotal mechanisms in developing heart failure and is related to the progression and prognosis of heart failure. Inflammatory mediators have a direct impact on the heart muscle as well as on the adrenergic system, which leads to hypertrophy, fibrosis, and impaired cardiac function . In the Growth differentiation factor-15 (GDF-15) is a multifunctional cytokine that is a part of transforming growth factors β and also has anti-hypertrophic effects . IncreasEndothelial microparticles (EMPs) and endothelial progenitor cells (EPCs) are related to impaired endothelial function and systemic inflammation . ClinicaCardiovascular and renal diseases are strongly related, as impaired function of one organ often leads to deterioration of function of the other. In patients with cardiorenal syndrome, i.e., with the involvement of both organ systems, morbidity and mortality are greatly increased. Many biomarkers are already used in the field of renal impairment, such as cystatin C, NGAL , KIM-1 (kidney injury molecule-1), interleukin-18, L-FABP (liver-type fatty acid-binding protein), NAG (N-acetyl-β-D-glucosaminidase), β-2 microglobulin, and glutathione-S-transferase . In the Neutrophil gelatinase-associated lipocalin (NGAL) is also known as lipocalin-2 and is one of the lipocalins that are small extracellular proteins associated with inflammation, the transport of small hydrophobic ligands such as steroids and lipids, and prostaglandin synthesis . NGAL alKidney injury molecule-1 (KIM-1) is a transmembrane glycoprotein found on the apical membrane of proximal tubules in patients with renal impairment, on the other hand, in the case of healthy kidneys, KIM-1 gene expression is not found . KIM-1 aCardiac failure is characterized by the activation of the neurohumoral system, namely the sympathetic nervous system. At the initial stage of heart failure, the body tries to provide adequate tissue perfusion through compensatory mechanisms, including activation of the sympathetic nervous system, renin-angiotensin-aldosterone system, decreased activity of the parasympathetic system, and dysregulation of the signaling pathway with nitric oxide (NO), and synthesis of inflammatory cytokines . In addiAdrenomedullin (ADM) is a peptide found in the highest concentrations in the adrenal medulla, ventricles, kidneys, and lungs . EndotheCopeptin is a quantitative biomarker of endogenous biomechanical stress and plays a significant role in body water homeostasis through renal reabsorption, blood volume regulation, osmolality, and vasoconstriction. It is also important in myocardial contractility, cell proliferation, and antidiuretic hormone activity . AlthougMatrix metalloproteinases (MMPs) are part of neurohormonal modulation and act also as an activator of the inflammatory system. They have a significant role in the accumulation of extracellular collagen and in the development of fibrosis. The imbalance between expression of MMPs and suppression of their tissue inhibitors may lead to impaired cardiac function and progression of heart failure . MetalloHeart failure relates to oxidative stress due to circulating neurohormones, hemodynamic changes, inflammation, and poor oxygen supply. Then, disorders of redox balance even further impair vital structures and affect signaling pathways of cell renewal and cell death, additionally deteriorating heart failure . There aCeruloplasmin is a plasma glycoprotein synthesized in the liver. It is considered as an acute phase protein, and it is also involved in copper transport. Ceruloplasmin has a pro-oxidative and antioxidative role . ElevateMyeloperoxidase (MPO) is one of the enzymes found in neutrophils that allows the synthesis of chloric acid and free radicals involved in the destruction of phagocytic pathogens . MPO is With the development of extended research on biomarkers in patients with heart failure and cardiovascular risk, the possibility to determine biomarkers in urine has emerged, which further simplifies investigation and improves the compliance of patients and healthy individuals in clinical trials, even more so in pediatrics. Biomarkers of renal dysfunction associated with heart failure, such as neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1), may be determined in urine. NGAL is a good independent prognostic factor in patients with heart failure . KIM-1 iWith the development of medicine and bioinformatics, attempts have been made to determine which combination of biomarkers has the best predictive value in the diagnosis, prognosis, and monitoring of patients with heart failure. The future use of biomarkers is reflected in multimarker panels, which include biomarkers with different pathophysiological mechanisms that contribute to the development of heart failure, thereby increasing their diagnostic and prognostic predictive value . ResponsThe number of potential biomarkers of heart failure is increasing over recent years and is a current subject of ongoing research. Biomarkers reflect different pathophysiological mechanisms that are present in heart failure. Due to the high prevalence of heart failure and many systemic diseases that can indirectly affect the heart muscle, research in the field of biomarkers has been underway for many years to identify as accurately as possible the risk of disease development and progression, cardiovascular events, and the associated need for close monitoring of risk groups. Newer biomarkers have certain prognostic advantages, but also some limitations, especially in pediatrics due to poor specificity and insufficient data on long-term monitoring. Therefore, the predictive value of these biomarkers is not fully confirmed and requires further investigation for widespread clinical use. Multimarker panels are becoming increasingly promising, however, more clinical trials are required to improve the understanding of individualized therapy of heart failure under biomarker control. Hopefully, the discoveries of novel biomarkers and their treatment target may lead to improved care for patients with heart failure.