Hypertrophic Cardiomyopathy (HCM) is a pathological condition characterized by an abnormal thickening of the myocardium. When affecting the medio-basal portion of the septum, it is named Hypertrophic Obstructive Cardiomyopathy (HOCM) because it induces a flow obstruction in the left ventricular outflow tract. In any type of HCM, the myocardial function can become compromised, possibly resulting in cardiac death. In this study, we investigated with computational analysis the hemodynamics of patients with different types of HCM. The aim was quantifying the effects of this pathology on the intraventricular blood flow and pressure gradients, and providing information potentially useful to guide the indication and the modality of the surgical treatment . We employed an image-based computational approach, integrating fluid dynamics simulations with geometric and functional data, reconstructed from standard cardiac cine-MRI acquisitions. We showed that with our approach we can better understand the patho-physiological behavior of intraventricular blood flow dynamics due to the abnormal morphological and functional aspect of the left ventricle. The main results of our investigation are: (a) a detailed patient-specific analysis of the blood velocity, pressure and stress distribution associated to HCM; (b) a computation-based classification of patients affected by HCM that can complement the current clinical guidelines for the diagnosis and treatment of HOCM. Hypertrophic Cardiomyopathy (HCM) is a typically congenital cardiac disorder characterized by an abnormal thickening of the myocardium  without additional causes inducing secondary hypertrophy . The preOne of the most frequently employed surgical treatments for a pathologically relevant HOCM is the septal myectomy, namely the resection of a portion of the interventricular septum, to abolish or reduce the obstruction in the LVOT . TherefoTo obtain quantitative indications on velocity patterns, pressure gradients and wall shear stresses associated to the ventricular blood flow dynamics, computational hemodynamics approaches have proved to be extremely helpful, thanks to their flexibility and level of detail . In thisThe goal of this study was to investigate the hemodynamics in the systolic phase and the LVOT obstruction severity and extent in patients with HCM, and also to provide quantitative information useful to potentially guide the design of the possible surgical treatment. To these aims, we used a computational procedure based on cardiac cine-MRI data , and we ad hoc designed hemodynamical indicators, and the identification of the region of the septal wall most suitable for the surgical approach by septal myectomy. The systematic discussion of the outcomes represents a step forward toward the applicability of our computational tools to accompany standard diagnostical procedures, and the definition of a comprehensive severity score for HOCM including hemodynamics indicators.The novelty of this study consists in the quantitative comparison of patients with some types of HCM by means of the extended computational procedure outlined above, based on routinely acquired cardiac cine-MRI data. This results in a CFD-based assessment and classification of the severity of the HCM-induced flow obstruction with In the present section, we describe the imaging data on which this study is based, and we introduce a computational procedure encompassing image processing, surface morphing, and numerical simulations for the study of the hemodynamics in LV and ascending aorta.Cardiac cine-MRI data of three patients were provided by L. Sacco Hospital in Milano, Italy, with the approval of the Ethics Committee and in accordance with the ethics guideline of the institutions involved, including the signed consent of the patient. The main characteristics of the patients are reported in The following are the clinical features of the patients:•Patient 1. The overall contractility of the right ventricle is preserved, despite the hypertrophy involving also the free right ventricular wall, and in contrast with the reduced overall systolic function of the LV. She also presented with a mild pericardial effusion. No valve regurgitation or stenosis were reported.•Patient 2. This patient is a smoker, hypertensive and overweight; he experienced chest pain and incipient dyspnea, and was recently hospitalized for heart failure. Subsequent electrocardiography limited the electrophysiological findings to sporadic extrasystoles. A trivial degree of regurgitation was reported for the aortic and tricuspid valves, but not for the mitral valve. The right ventricle had a significantly reduced systolic function (ejection fraction = 12%) although the values of its walls thickness remained in the normal range.•Patient 3. No effusions, edemas, fibrosis, or other concurrent conditions were reported, except for a prolapse of the anterior leaflet of the mitral valve toward the septum (SAM), without regurgitation.ad hoc acquisitions.For each patient, the data included different views, with different resolution properties: a volumetric short-axis acquisition, with a spacing and a slice thickness of 8 mm along the LV main axis, a space resolution of 1 mm and a time resolution of 1/20 of the heartbeat; a set of single-slice, two-dimensional long-axis acquisitions on the so-called two-chambers, three-chambers, and four-chambers planes, with space resolution of 1 mm and time resolution of 1/20 or 1/30 of the heartbeat. These are standard cardiac cine-MRI data, routinely acquired during diagnostical procedures: the reconstruction algorithm presented in this study does not require the setup of So far, none of these patients underwent surgery yet, based on the indications given by their attending clinicians.Since the only available three-dimensional data was represented by the short-axis views, which, however, has a relatively low resolution along the LV main axis, we developed an algorithm to enhance the short-axis images with the long-axis acquisitions (commonly named as 2/3/4-chambers views) obtaining a high-resolution artificial, time-dependent series of volumetric image. This represents the first step of our reconstruction algorithm, described in the following Algorithm 1 and depicted in Algorithm 1 – Reconstruction procedure.1.Create a high-resolution artificial image merging the information from all the available cine-MRI series. This operation encompasses:1.a.creating an empty artificial image initialized with the short-axis bounding box and with a uniform space resolution of 1 mm in the three cartesian directions;1.b.for each target pixel of this new artificial image, identify the nearest pixel on each slice of the input cine-MRI series;1.c.compute the new gray level as a weighted average of the values of the pixels identified at point b, with the weights depending on their distance from the target pixel;2.for each instant of the artificial image, segment both the endocardium and the epicardium of the LV;3.intersecting the endocardium and epicardium surfaces obtained at the previous step, obtain a volumetric representation of the myocardium as a level-set image;4.choosing the end of systole as a reference configuration, apply a registration algorithm among the level-set images of the myocardium, to obtain a displacement field for each acquisition time. The displacement field is applied to the endocardium surface of the reference configuration to obtain its evolution throughout the heartbeat;5.complete the geometry resorting to a template geometry: from the Zygote solid 3D heart model , a healtSCR_001622). As reconstruction tools, we employed the Medical Image Toolkit (MITK)1 3 and the Vascular Modeling Toolkit 4 (The reconstruction procedure presented above is based on the one we previously reported . The mai (MITK)1  for the 001893)4 .Regarding the mitral valve, the use of a template geometry was motivated by the fact that, usually, standard MRI acquisitions do not provide sufficient details to allow an accurate reconstruction of the valves leaflets. Since we only investigated the systolic phase, and since mitral regurgitation was not present in any of the patients, the valve was maintained closed during the whole systolic phase. However, we believe it was important to include the mitral valve in the domain, since it defines two thirds of the LVOT boundaries and thus influences the blood dynamics. For all the patients we considered the same mitral valve geometry template, adapted to the patient’s annulus as described in point 5 of Algorithm 1. In particular, for Patient 3 we do not consider the SAM of the valve, in order to isolate and analyze only the HCM-induced effects on the blood flow.MV representing the mitral valve leaflets, is displayed in out the outlet section of the ascending aorta and by Σwall the boundary comprising the ventricular endocardium and the aortic wall. Under the common assumption that blood is an incompressible Newtonian fluid, at least in the heart chambers and large vessels, we could model its flow by incompressible Navier-Stokes equations, with density ρ = 1.06 × 103 kg/m3 and viscosity μ = 3.5 × 10–3 Pa × s (MV is modeled as a surface immersed in the fluid dynamics domain by the Resistive Immersed Implicit Surface (RIIS) method. RIIS lays in the class of immersed boundary methods , the end-diastolic/end-systolic volume (EDV/ESV) and ejection fraction (EF), an accurate reconstruction of the LV volume changes occurring throughout the heartbeat was recovered. Then, focusing on the systolic phase, we could assess the possible HCM-induced obstruction in terms of velocity distribution, aortic jet development and pressure gradients. A particularly relevant indicator for the clinical assessment of the obstruction severity is the distribution of pressure along the septum. This information provides a quantitative measure of the spatial location and extension of the obstruction, very useful for the design of the surgical approach for HOCM: septal myectomy. Finally, thanks to the additional functionality offered by CFD with respect to diagnostical tests, we analyzed the Wall Shear Stress (WSS) on the endocardium and the aortic wall, which affects wall cell growth and possible flow-induced damage , and evaIn this section, we present the outcomes of the proposed computational procedure for the data of three patients described above, in terms of geometric, functional, and hemodynamics indicators.From the reconstruction procedure we obtained the displacement fields shown in t = 0.08 s, then followed by a relatively slower deceleration. Patient 2 and 3, instead, present a more progressive development of the aortic jet, with a maximum velocity of 1.31 and 2.2 m/s at times t = 0.23 and 0.20 s, respectively, and persistent high velocity values (>1 m/s) also at later stages of the systolic phase. These two patients also have in common the impingement of the jet on the wall of the aorta just downstream to the Valsalva sinuses , although with different velocity values. In terms of velocity peak, Patients 1 and 2 lay just above the limits of the range of physiological values (1–1.2 m/s), whereas Patient 3 attains a pathological value.Having discussed the reconstruction of the ventricular displacement, we now present the results of the computational hemodynamics simulations under such prescribed motion. As the aim of the present study was to assess the possible obstructions induced on the flow by HCM, we focus on the systolic phase. t = 0.08 s, and the corresponding large coherent structure visible in t = 0.1 s rapidly splits up into smaller structures that are progressively breaking down along the flow. A similar behavior is shown by Patient 2 , with the breakdown of the jet into disorganized structures being mainly localized in the aortic root. This is consistent with experimental and computational studies that can be found in the literature, e.g.,  corresponding, for each time t, to the maximum blood velocity attained in the aorta, and we report its time evolution in thr the median value of U(t) over the whole systolic phase; then, we can define the duration of the obstruction as the length of the largest time interval in which the maximum velocity remains above Uthr. The results are reported in The velocity field can also be inspected to assess the out between the pressure p and its value pout at the outlet section Σout of the ascending aorta. For all patients and at all times, significant pressure gradients can be appreciated as expected in the LVOT and  in the Valsalva sinuses, whereas pressure is essentially uniform elsewhere. The overall pressure gradient of Patient 1 is always between −3 and 3 mmHg, whereas for the other two cases it is more than double. Regarding time evolution, each patient experiences an increase or a decrease of Δp at different stages of the systole, reflecting the variability that we observed above about the time dependence of the displacements and volume of the LV.One of the main quantities that is inspected in the assessment of the hypertrophy-induced obstruction is the intraventricular pressure gradient, that is the variation of pressure in the LVOT. In order to provide a synthetic evaluation of the severity of the hypertrophy-induced obstruction, and to quantify its localization and extension, ad hoc acquisition series, in order for our procedure to be applicable in virtually any clinical setting. From such data, we could generate a time-dependent, volumetric artificial image with a relatively high resolution in all directions, used to reconstruct the patient-specific geometry and motion of the left ventricle and ascending aorta during a complete heartbeat. The resulting time-dependent displacement was employed as a boundary condition for the computational fluid dynamics description of the blood flow, by Navier-Stokes equations in the ALE form. A resistive method was adopted to immerse the mitral valve leaflets in the domain.We introduced and applied an image-based computational approach for the analysis of the hemodynamics in patients suffering from hypertrophic cardiomyopathy. To reconstruct the geometry and the motion of the LV, we started from cine-MRI data, the gold standard for the clinical assessment of the heart function , especiaThe results of the reconstruction procedure displayed a considerable variability of the ventricle geometry and contractility among three different HCM patients. Different portions of the endocardium can be affected by hypokinesis, leading to different evolutions of the chamber volume and shape. The associated inhomogeneities in the ventricular displacement, as well as the assessment of the end-diastolic and end-systolic volume, showed how the ellipsoid approximation commonly employed in clinical evaluations may be quite inaccurate and yield a non-negligible underestimation of the ejection fraction.In addition to the morphological data that can be extracted from clinical images, CFD simulations provide additional information on the blood flow in terms of velocity, vortical structures, and distribution of pressure and stress. To account for the domain motion, we adopted the approach of prescribed-motion CFD, which differs from the FSI approach in which the displacement of the cardiac muscle is the outcome of a mechanics model. By imposing directly the patient-specific image-based motion reconstructed from cardiac cine-MRI, we eliminated the need of a patient-dependent calibration of the myocardium mechanical model and the additional computational cost of solving the structural equations coupled with hemodynamics. This came at the expense of a more complex reconstruction procedure, described and discussed above. To the best of our knowledge, the present study represents the first comparison of the hemodynamics of HCM patients based on computational hemodynamics with image-based patient-specific endocardial displacement.The hemodynamics results quantified the flow obstruction induced by the hypertrophy of the myocardium. For all the patients, the obstruction lasted for 30% of the duration of systole. On the other hand, the typical systolic jet through the aortic orifice had significantly higher intensity in the case of obstruction than in the other cases, and this is strongly related with the pressure gradient developed in the LVOT and in the Valsalva sinuses.The distribution of pressure on a line along the septum allowed to quantify the intraventricular pressure gradient and to identify its position and extension. The main pressure gradient develops in a very short length, in the order of 10–15 mm, and its location is different among the patients: for Patient 2 the main obstacle to the flow is represented by the aortic annulus, whereas for Patients 1 and 3 the obstruction is within the LVOT. Therefore, for Patients 1 and 3 we can state that the obstruction is directly correlated with the HCM-induced thickening of the basal portion of the septum. Moreover, in Patient 3 a pressure drop concentrates in the subaortic portion of the LVOT: this generates a Venturi effect often acknowledged as the main cause of the SAM of the mitral valve, further obstructing the flow through the LVOT and increasing the intraventricular pressure gradient, as previously reported and discussed .From this assessment, we can also derive clinical indications useful in the design of the possible surgical treatment by septal myectomy. Although this procedure is well-established and typically entails low mortality and an impressive long-term survival rate , it is cOur analysis highlighted also other regions of the patients’ anatomy that should be subject to follow-up examinations, although they are not directly involved by the hypertrophy. From the evaluation of the WSS, we could measure the impingement of the systolic jet on the aortic wall, particularly in the case of Patient 2 and 3, in whom follow-up future monitoring is advisable to reduce the risk of wall damage and possible aneurysm formation .ex post clinical validation is still missing. However, being this a computational study, and not a statistical one, we designed an a priori model, supported by the imaging data and based on the physical principles of fluid dynamics, and not an a posteriori model based only on clinical measurements. As a consequence, our sample is in fact not limited, and it allowed us to provide useful quantitative information about the patients, with the possibility of future utilization for other HCM patients. For sure, investigations involving a larger number of patients will achieve a more comprehensive understanding of the hemodynamics of HCM, confirming our preliminary results, and better accounting for the strong inter-patient variability of this clinical condition. To facilitate this process, an improved automatization of the reconstruction procedure is under development, to reduce the time elapsing between the acquisition of data and the post-processing of computational results.First, the present study analyzed a small number of subjects, and none of them underwent surgery so far, based on the indications given by their attending clinicians. Therefore, our study represents a proof of concept, and for the moment Second, the aortic valve leaflets are not considered in the current settings, since, in the absence of pathological features, they are expected to have a negligible influence on the development of the intraventricular obstruction, which is the main feature of interest to classify HOCM. However, including also that valve in the geometry would allow an accurate assessment of the flow in the ascending aorta.Another limitation consists in the study of the systolic phase solely. To extend the assessment of the effects of HCM over the whole cardiac function, the model can be extended from the systolic phase to the full heartbeat (and possibly multiple heartbeats). This would entail to consider the valves opening and closing dynamics and to introduce a proper reconstruction of the left atrium: since such data is only partially available in standard cardiac cine-MRI data, an extension of the reconstruction algorithm should be envisaged.Finally, alternative management options for HOCM, such as medical treatment with a combination of beta-blockers, calcium channel blockers, and/or antiarrhythmic medications, or other interventional approaches like septal ablation and potential implantation of cardioverter defibrillator, have not been discussed, as all of them are beyond the purpose of our computational study.Regarding our patient population:•The hypertrophy in Patient 1 does not induce an obstruction since little intraventricular pressure gradient is appreciable. Nevertheless, the inhomogeneous displacement partially hinders the effectiveness of the cardiac pump, with an ejection fraction that is just above the limit value of 50%.•About Patient 2, the pressure gradient mainly develops at the aortic annulus, thus it is not directly associated to HCM. Moreover, it is of small magnitude, and it does not induce a pathologically intense aortic jet. However, the relatively large LV volume and rather generalized hypokinesis determine a low ejection fraction.•Patient 3 fits different criterions for the definition of HOCM, with a strong aortic jet accompanied by a significant pressure gradient in the LVOT, and we could also quantify the Venturi effect that may have been at the origin of the development of a SAM of the mitral valve. Moreover, the obstruction has been localized, providing relevant indications for the design of a possible surgical treatment by septal myectomy.These conclusions confirm the suitability and effectiveness of our proposed computational approach to assess the cardiac function and the hemodynamical implications of HCM, as well as to provide clinically relevant indications potentially useful to guide the surgical treatment of the disease.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 the Ethics Committee of L. Sacco Hospital. The patients/participants provided their written informed consent to participate in this study.IF: conception of the study, development of the methods and software, image processing, simulations, analysis of the results, manuscript drafting, figures preparation, and revision of manuscript. PV: image processing, simulations, analysis of the results, figures preparation, and revision of manuscript. CV: conception of the study, analysis of the results, manuscript drafting, revision of manuscript, and supervision of the study. MF: development of the methods and software, and revision of manuscript. AC: clinical relevance of the results, and revision of manuscript. SI: images acquisition. RS: clinical relevance of the results, and revision of manuscript. AQ: funding, coordination of the study, and revision of manuscript. All authors contributed to the article and approved the submitted version.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.


Lateral S’ was 36% higher at T3 than at T1 (p < 0.05). Changes in diastolic function were demonstrated by 10% lower E wave and 15% A wave at T1, compared to T4 (p < 0.05). E’ and A’ were 23% and 42% higher at T3 compared to T4 (p < 0.01). Both lateral E/E’ and E’/A’ were 6% and 19% lower at T3 compared to T1 . At T3, MPI was 51% and 34% lower when compared to T1 or T2 (p < 0.05). The echocardiographic evaluation of maternal cardiac function is important, as structural, and functional changes occur throughout pregnancy.This study aimed to evaluate maternal left ventricular (LV) systo-diastolic function using conventional and TDI echocardiography and included 10 healthy Saint-Bernard pregnant bitches. M-mode, peak transmitral flow velocities during early diastole (E) and atrial contraction (A), aortic and pulmonic flow, myocardial performance index (MPI), TDI studies , atrial contraction (A’) and peak systole (S’)), and blood pressure were measured at 21 to 28 (T1), 40 (T2) and 60 (T3) days of gestation and four to eight weeks postpartum (T4). Cardiac output and heart rate were 20% and 9% higher at T3, respectively, compared to T4 ( Appropriate development of the foetuses during pregnancy induces several hemodynamic alterations, with consequent cardiac changes. Echocardiographic and Doppler studies have been widely used to assess heart function during pregnancy in humans ,2,3 and Pulsed wave Doppler transmitral inflow velocity may not truly reflect the left ventricle (LV) diastolic function during pregnancy since it is highly influenced by ventricular loading conditions, which are naturally altered by the pregnancy volume overload state . Tissue Myocardial performance index  is a valuable tool in evaluating systo-diastolic function. This index correlates with the New York Heart Association (NYHA) class and some echocardiographic indices , serving as a prognostic measure . In addiThe cardiac changes in human pregnancy have been widely studied. A primary fall in vascular tone in early pregnancy leads to a rapid decrease in preload and afterload with compensatory increase in heart rate and activation of the volume-restoring mechanisms, with resulting increase in cardiac output . This coIn the bitch, significant changes have been observed by late pregnancy, characterized by an increase in heart rate ,19, stroUnderstanding the physiological adaptations of the heart to the pregnancy is essential for monitoring maternal cardiac function and detecting early signs of cardiac failure in high-risk pregnancies  or obste®, with a 3.5-MHz linear transducer), at the first visit, and the gestational age was calculated from the date of mating. The bitches were evaluated three times during pregnancy at early , mid  and late pregnancy , as well as 4 to 8 weeks postpartum (PP). In each visit, the dogs were evaluated by clinical examination, obstetric ultrasound for monitoring foetal development  × 100 [The aortic (Ao) and left atrium (LA) diameters and the LA/Ao ratio were evaluated by the right parasternal short-axis view at the level of the aortic valve. The fractional shortening (FS) and the ejection fraction (EF) of LV were calculated according to the formulas: FS (%) = [(LVIDd − LVIDs) /LVIDd] × 100 and EF = [ and during atrial contraction (A-wave) were measured.3]/(2.4 + LVDd/10) and ESV is the end systolic volume, calculated by ESV = [7 × (LVDs/10)3]/(2.4 + LVDs/10). Cardiac output (CO) was calculated as the product of SV and HR, and the LV mass was calculated by the formula: 0.8 × [1.04 × (((ISVd/10 + LVDd/10 + LVPWd/10)3) − (LVDd/10)3)] + 0.6  + 0.6 .Left ventricular myocardial performance index (MPI), also known as Tei Index, was calculated from pulsed-wave Doppler, according to the formula: (IVCT+IVRT)/ET, where IVCT, IVRT and ET represent, respectively, isovolumetric contraction time, isovolumetric relaxation time, and left ventricular ejection time . Value fSpectral TDI recordings were made from the apical four-chamber, left parasternal view. Ventricular myocardial velocities were assessed during both contraction and relaxation. The sample volume was placed at the lateral margin  and at the common septal margin  of the mitral annulus, as previously described . From th®) was used to collect five consecutive measurements, after discarding the first one, from which the means for systolic , diastolic  and mean  arterial pressures were calculated.Blood pressures measurement was performed as previously described . The bitp < 0.05 was considered statistically significant.Data were graphed and analysed using the Prism 9.0 software . Data were expressed as mean and standard deviation (SD). Comparisons between groups were analysed by one-way analysis of variance (ANOVA), that compared echocardiographic variables obtained at early, mid and late pregnancy as well as at postpartum. Post hoc evaluation was performed using the Tukey comparison test. Selected echocardiographic variables are listed in p < 0.01). Blood pressure  was higher at T1, T2 or T3 than at postpartum (p < 0.01) and reached maximal values at T1 that progressively decreased until the end of pregnancy (T3).Post hoc testing revealed several statistically significant differences. Body weight was significantly higher on late pregnancy (T3) than at T1, T2 or postpartum (p < 0.05), and the cardiac output was 20% higher at T3 than at postpartum (p = 0.02). The LA/Ao ratio was 7% higher at T2 than at T3 (p = 0.03). Transmitral early diastolic flow (E) was 9% lower at T1 than at T2 or T3 (p < 0.05). At T1, transmitral late diastolic flow (A) was 13%, 16% and 15% lower than at T2, T3 or postpartum, respectively (p < 0.05). Pulmonic flow was 26% and 21% greater at T3 than at T1 or T2, respectively (p < 0.05). Similarly, aortic flow was also 13% higher at T3 than at T1 (p < 0.01).Heart rate was 10% and 9% higher at T3 when compared to T1 or postpartum, respectively (p < 0.05).Even though ejection time did not change throughout pregnancy, both IVRT+IVCT and MPI decreased, with the latter being 56% and 34% lower at T3 when compared to T1 or T2 (p < 0.01). The lateral S’ and A’ were also higher at T3 than at T1 or T2 (p < 0.01). Lateral S’ was 35% and 30% higher at T3, and lateral A’ was 66% and 34% higher at T3 when compared to T1 and T2, respectively. The E’/A’ ratio decreased with gestational age, being 19% lower in T3 when compared to T1 (p < 0.05). The E/E’ ratio of the lateral mitral annulus decreased throughout pregnancy, being 6% lower at T3 compared to T1 (p < 0.01) and was always within normal limits as described for healthy dogs [Changes in TDI variables throughout pregnancy are shown in thy dogs .Blood pressure values were elevated throughout the entire pregnancy (>160 mmHg), opposing a previous study carried out in small pregnant bitches, where systolic blood pressure did not change ; observeOur data suggest that early systemic hypertension possibly triggers the following cardiac events: a pressure overload in canine early pregnancy and consequent increased left ventricular filling pressure  induces an increase in left atrium size by day 40. As the placental-foetal circulation develops , the decIn human gestation, it is well established that an early endocrine mediated fall in vascular tone triggers volume-restoring mechanisms, responsible for the increasing cardiac output seen through pregnancy, primarily caused by an increased stroke volume, but later on also due to increased heart rate . This naIn the current study, no cardiac hypertrophy was observed, despite the tendency of some variables to increase at the end of gestation . Previous studies reported contradictory results, with some reporting no increase of LV end-diastolic dimension or volume ,8, whilsIn bitches, several cardiac indices of systolic function increase in late pregnancy ,5. In thThere are few studies that evaluated diastolic function in pregnant bitches. In human pregnancy, studies on mitral inflow velocities showed an increase in E wave on the first trimester of pregnancy ,18, follThe compensatory increase in preload (increased plasma volume) observed in pregnancy  induces The MPI is a valuable tool in evaluating LV systo-diastolic function. MPI seems to be independent of ventricular geometry, preload and heart rate ,15. In tOne potential limitation of the current study would be the sample size, since serial evaluation of cardiac function during pregnancy was often not feasible; however, we may assume that it is minimized as we have only included Saint Bernard bitches. As previously referred, we intended to characterize the cardiac adaptations during pregnancy in a large breed dog prone to develop cardiac diseases. However, the obtained results may not be representative of the large breed dog population.The present work demonstrated an elevation of blood pressure throughout pregnancy, with the highest values observed in early pregnancy. Cardiac output increased during pregnancy, probably due to increased heart rate. Pregnancy, as a chronic, natural volume-overload state, also caused alterations on TDI parameters, where S’, E’ and A’ values increased with advanced gestation. On the other hand, the values obtained for MPI, in conjunction with other systolic function parameters, suggested an improvement of cardiac function throughout gestation in a large breed dog such as the Saint Bernard. In the future, increasing the sample size, or even including different breeds of the same size, would help to better describe these cardiac adaptations. It would also be interesting to study animals with different obstetric complications, to deepen the knowledge already published ; also, t


We aimed to functionally characterize the arrhythmogenic substrate using left ventricular (LV) global longitudinal strain (GLS) and heart-to-mediastinum (H/M) ratio on 123I-MIBG scintigraphy. An event was defined as appropriate ICD therapy.We included patients with heart failure with reduced LVEF who received an ICD for primary prevention. To functionally characterize the arrhythmogenic substrate, we measured the LV GLS with two-dimensional speckle tracking echocardiography and cardiac innervation measured as the H/M ratio on p = 0.276). However, LV GLS was significantly more impaired in the group that experienced an event compared to patients that did not . The innervation, measured as the H/M ratio on 123I-MIBG scintigraphy was also significantly more impaired in the patients that experienced and event compared to patients that did not . Multivariable Cox regression analysis showed LV GLS and H/M ratio independently associated with appropriate ICD therapy with a hazard ratio of 1.24  and 5.71 , respectively. LV GLS and H/M ratio were significantly correlated .A total of 155 patients were included, 74% were male and the mean age was 72 ± 9 years. During a median follow-up of 10 (6–12) years, 43 patients (28%) experienced appropriate ICD therapy. Patients that experienced an event were more often male, had more often ischaemic cardiomyopathy and were more likely to have worse renal function. There was no difference in the left ventricular ejection fraction (LVEF) between the two groups (25 ± 6.4% vs 26 ± 6.0%, Functionally characterizing the arrhythmogenic substrate using different imaging techniques defines the risk for appropriate ICD therapy, whereas LVEF did not. Evaluation of heart failure patients who may benefit from implantable cardioverter defibrillator (ICD) remains challenging. Current guidelines recommend an ICD implantation as primary prevention in symptomatic heart failure patients with a left ventricular ejection fraction (LVEF) ≤ 35% treated with optimal medical therapy  scintigraphy. This radiotracer is an analogue of norepinephrine up taken by the sympathetic nerve terminals of the heart, without being metabolized. In heart failure patients, the uptake of 123I-MIBG by the heart is reduced, indicating myocardial denervation. A reduced heart-to-mediastinum (H/M) ratio of the 123I-MIBG uptake on planar imaging has been associated with increased risk of ventricular arrhythmic events  were retrospectively evaluated. Demographic and clinical characteristics were collected using the departmental cardiology information system  and electronic medical records  and retrospectively analysed. Echocardiographic data were stored in the echocardiographic database and the planar 123I-MIBG scintigraphy data in the department of nuclear medicine database. Clinical, echocardiographic and 123I-MIBG scintigraphy data were analysed retrospectively. The association between clinical, conventional and advanced (2D speckle tracking imaging) echocardiographic variables and 123I-MIBG variables and ventricular arrhythmic events was investigated. For retrospective analysis of clinically acquired data anonymously handled, the institutional review board waived the need for written patient informed consent.Heart failure patients who received an ICD for primary prevention, according to prevailing guidelines . Bimodal, M-mode, colour, continuous and pulsed wave Doppler data were acquired with 3.5 MHz or M5S transducers and digitally stored in cine-loop format. Offline analysis was performed using the EchoPac system . Left ventricular end-diastolic volume (LVEDV) and left ventricular end-systolic volume (LVESV) were measured on the apical two- and four-chamber views according to the Simpson biplane method and the LVEF was calculated  were automatically created and adjusted to the thickness of the myocardium. The software automatically tracks the myocardium throughout the cardiac cycle and the quality of the tracking is evaluated. The LV GLS was calculated as the average of the peak systolic longitudinal strain of the three apical views and the results were displayed in a 17-segment “bull’s-eye” plot.123I-MIBG  was injected intravenously, after thyroid blockage with sodium iodide. Using a dual-head gamma camera  equipped with a low-energy high-resolution collimators, planar anterior images of the thorax were obtained 4 h (late) after tracer injection. Images were obtained with a 15% energy window centred at the 159 keV energy peak of 123I and were subsequently stored in a 256 × 256 matrix.For assessment of myocardial innervation, 185 MBq of A ROI was manually drawn over the entire heart to measure the counts in the LV myocardial region. To measure the counts in the mediastinal region, a rectangular ROI was placed on the upper half of the mediastinum using the lung apex, upper cardiac border and medial contours of the lungs as borders. The late H/M ratio was calculated by dividing the mean counts in the cardiac ROI by the mean counts in the mediastinal ROI. The analysis was performed using dedicated post-processing software on a Syngo-MI workstation .Patients were followed up at the heart failure outpatient clinic and the ICD devices were interrogated on 6-monthly visits. The ICD ventricular tachyarrhythmia detection criteria and therapy were programmed conventionally. The occurrence of appropriate ICD therapy was the primary endpoint. Appropriate ICD therapy was defined as anti-tachycardia pacing or shock for ventricular tachycardia or ventricular fibrillation.t test or the Mann-Whitney U test. Categorical data were compared with the χ2 test. Cox proportional hazard regression analyses were used to evaluate the variables that were significantly associated with appropriate ICD therapy. The relationship between LV GLS and H/M ratio was investigated using the Pearson correlation. A p value < 0.05 was considered statistically significant. All statistical analyses were performed using the SPSS software package .Continuous variables are reported as mean ± standard deviation if normally distributed, and as median and 25–75% interquartile range (IQR) if non-normally distributed. Categorical data are presented as frequencies and percentages. Patients were divided in two groups according to the occurrence of an event, appropriate ICD therapy or not. Continuous data were compared between patients presenting with event and patients without event using the Student’s 123I-MIBG scintigraphy and echocardiography with LV GLS data were included . During a median follow-up of 10 years (25–75% IQR 6–12 years), appropriate ICD therapy occurred in 43 patients (28%). An ICD shock was the first appropriate ICD therapy in 70% of the cases. Table A total of 155 patients with p = 0.276). In contrast, patients who presented with an event showed significantly more impaired LV GLS compared to their counterparts  for LV GLS and 5.71  for H/M ratio when corrected for LVEDV and LVEF.The imaging characteristics are shown in Table r = 0.30, p < 0.001, Fig. r = − 0.21, p = 0.027) and was stronger in the group that did experience an event   are not per se pro-arrhythmic since they are electrically inert tissue. However, the areas where the fibrous/scar tissue intermingles with viable myocytes create a substrate where re-entry circuits may form and lead to ventricular arrhythmias , the border zone shows intermediate signal intensity between normal myocardium and dense myocardial scar. Applying specific thresholds, the amount of border zone can be quantified. In 91 patients with ischaemic heart disease and indication for ICD implantation as primary prevention, Roes et al. demonstrated that each 10-g increase in the mass of border zone was associated with 51% increased risk of ventricular arrhythmias and appropriate ICD shocks  study, the largest study so far including 964 heart failure patients followed for 2 years, showed that patients with an H/M ratio between 1.2 and 1.6 had more frequent ventricular arrhythmic events as compared to patients with an H/M ratio ≥ 1.6  (Bax et al. The correlation between LV GLS and H/M ratio was moderate, indicating the distinct differences between both modalities. Our findings are in agreement with previously published studies, reporting similar correlations between LV GLS and H/M ratio (Bulten et al. There are several limitations that should be acknowledged. First, this was a retrospective, single-centre study. Furthermore, since 2D speckle tracking echocardiography requires good image quality for reliable analysis, selection bias might have been introduced. The patient population was heterogeneous, with ischaemic and non-ischaemic cardiomyopathy patients. Also, ischaemia might have risen during the long follow-up of the study and have influenced the results. Finally, the event rate for appropriate ICD therapy in our population was relatively low compared to previous study (Moss et al. 123I-MIBG SPECT were significantly more impaired in patients who experienced an appropriate ICD therapy compared to patients that did not. In contrast, no differences were observed between groups of patients in terms of LVEF. Multivariate Cox regression analysis showed LV GLS and H/M ratio to be independent predictors of appropriate ICD therapy. These results underscore the importance of multimodality imaging for the characterization of the arrhythmogenic substrate and the identification of patients who will benefit from an ICD.In conclusion, LV GLS measured by 2D speckle tracking echocardiography and H/M ratio measured by planar


Aims: The aim of the study is to investigate the association between the degree of ischemia due to coronary microvascular dysfunction (CMD) and the left ventricular (LV) tissue characteristics, systolic performance, and clinical manifestations in hypertrophic cardiomyopathy (HCM).Methods and Results: This prospective study enrolled 75 patients with HCM without obstructive epicardial coronary artery disease. Each patient underwent cardiovascular magnetic resonance (CMR) including parametric mapping, perfusion imaging during regadenoson-induced hyperemia, late gadolinium enhancement (LGE) and three-dimensional longitudinal, circumferential, and radial strains analysis. Electrocardiogram, 24-h Holter recording, and cardiopulmonary exercise testing (CPET) were performed to assess arrhythmias and functional capacity. In total, 47 (63%) patients were men with the mean age of 54.6 (14.8) years, 51 (68%) patients had non-obstructive HCM, maximum wall thickness (MWT) was 20.2 (4.6) mm, LV ejection fraction (LVEF) was 71.6 (8.3%), and ischemic burden was 22.5 (16.9%) of LV. Greater MWT was associated with the severity of ischemia . Ischemic burden was strongly associated with higher values of native T1 . The association between ischemia and LGE was significant in following subgroup analyses: MWT 15–20 mm , non-obstructive HCM , women  and age <40 years . Ischemia in ≥21% of LV was associated with LGE >15% . Ischemia was also associated with atrial fibrillation or flutter (AF/AFL) , but no association was seen for non-sustained ventricular tachycardia. Ischemia was associated with shorter time to anaerobic threshold .Conclusion: In HCM, ischemia associates with morphological markers of severity of disease, fibrosis, arrhythmia, and functional capacity. Hypertrophic cardiomyopathy (HCM) is defined by unexplained left ventricular (LV) hypertrophy in the absence of abnormal loading conditions . In HCM,Myocardial fibrosis is a cardinal feature in HCM, with two patterns identified: replacement fibrosis and diffuse interstitial fibrosis , 5. MyocIncreased myocardial fibrosis is frequently interpreted as a consequence of long-standing disease, including ischemia due to microvascular abnormalities. However, the association between fibrosis and small vessel disease is not completely established . DespiteWe prospectively assessed CMD in patients with HCM by assessing myocardial perfusion defects using stress CMR and hypothesized that CMD impacts on tissues abnormalities, arrhythmias, and functional capacity. We also aimed to identify clinical and imaging characteristics associated with ischemic burden.Multicenter prospective study with recruitment performed in Hospital de Santa Marta, Centro Hospital Universitário de Lisboa Central and Hospital Garcia de Orta, Almada, between December 2017 and August 2020. The CMR studies were performed at Heart Center, Hospital da Cruz Vermelha Portuguesa, and the remaining investigations took place in Hospital de Santa Marta.The study included consecutive adult patients with HCM seen in a cardiomyopathy clinic who fulfilled the inclusion criteria and gave informed consent. The diagnosis of HCM was performed according to published guidelines ; more spPatients with LV ejection fraction (LVEF) <50%, prior septal reduction therapy , and epicardial coronary artery disease were excluded. Obstructive epicardial coronary artery disease was excluded by invasive coronary angiography or coronary computerized tomography in symptomatic patients or asymptomatic patients older than 40 years. In asymptomatic patients younger than 40 years and without cardiovascular risk factors, it was assumed a low likelihood of obstructive coronary artery disease. The investigation followed the principles outlined in the Declaration of Helsinki. The institutional ethics committee of the NOVA Medical School, Lisbon and Centro Hospital Universitário de Lisboa Central approved the study protocol. All patients provided written informed consent.At baseline clinical visit, all patients were evaluated regarding symptoms and physical examination and underwent a 12-lead electrocardiogram and a comprehensive echocardiogram., following current guidelines . Obstruc2), CO2 production (VCO2), and ventilation (VE) were measured. Peak VO2 was analyzed as the percentage of predicted peak VO2 according to age and gender. Minute VE/CO2 production (VE/VCO2) slope was calculated, and peak circulatory power was determined as peak VO2 x peak systolic blood pressure. Arrhythmic response to exercise was defined as the presence of repetitive premature ventricular beats, non-sustained or sustained ventricular tachycardia. Abnormal blood pressure response to exercise was defined as a failure to increase systolic pressure by at least 20 mmHg from rest to peak exercise or a fall of >20 mmHg from peak pressure.Maximal symptom-limited treadmill cardiopulmonary exercise testing (CPET) was performed using a modified Bruce protocol. Oxygen uptake  or atrial flutter (AFL)] and ventricular tachycardia.All subjects underwent CMR performed on a 1.5T system  and abstained from caffeine for at least 24 h. Using compressed sensing-based sequence, cine images in three long-axis planes and sequential short-axis slices spanning the entire left ventricle from the base to the apex were acquired. Basal, mid, and apical precontrast and postcontrast short axis T1 maps were generated using a modified look locker inversion sequence in a 5(3)3 configuration. Basal, mid, and apical precontrast short axis T2 maps were generated, using a single shot TrueFISP acquisition. The same three slices were used for stress perfusion CMR 90 s after hyperemia induced by regadenoson. Images were acquired apex to base during breath-hold at the first pass of contrast (60 measurements). A gradient echo sequence was used. LGE images were acquired using a breath-held segmented inversion-recovery steady-state-free precession sequence.Microvascular dysfunction was considered present if a visual perfusion defect was observed. Perfusion defects were considered surrogates for ischemia. For perfusion assessment and semi-quantification, the myocardium was divided into 32 subsegments (16 American Heart Association (AHA) segments subdivided into an endocardial and epicardial layer). Ischemic burden for each patient was calculated based on the number of involved subsegments, assigning 3% of myocardium to each subsegment, as assessed in previous landmark studies , 12. EacNative T1 and postcontrast T1 values of myocardium were measured from the three slices generating T1 maps. ECV was calculated according to the previous published formula  using paThree-dimensional longitudinal, circumferential, and radial strains were obtained using an automatic feature-tracking algorithm.An exploratory analysis of the variables under study was carried out with categorical variables being described by frequencies (percentages) and quantitative variables by the mean (standard deviation). Locally weighted scatterplot smoothers were used to study the association between MWT and ischemia and between ischemia and LGE.(MWT), LV mass, the presence of LVOT obstruction, and other CMR findings.To identify factors contributing to ischemia (dependent variable) and to study the association between ischemia (independent variable) and tissue characteristics, LV performance, and clinical manifestations, generalized linear regression models for continuous and binary response were applied. Univariable and multivariable models were included patients' characteristics which might potentially influence these outcomes, including age, gender, cardiovascular risk factors, maximum wall thickness p ≤ 0.25 were selected for the multivariable models. Crude and adjusted odds ratios (OR), and crude and adjusted regression coefficients (β) were estimated with corresponding 95% confidence intervals (95% CI). For the linear regression models, the normality assumption of the residuals was verified using Shapiro–Wilk test. To check the assumption of linearity to the logit for the continuous independent variables in the logistic regression analyses, generalized additive regression models for binary response were used.All variables that in the univariable analysis attained a Considering the outcome LGE as a binary variable , a cutoff point was determined for ischemia using the criterion that maximizes sensitivity and specificity.For LGE, a stratified analysis by some groups  was also performed using linear regression models.p-values greater than 0.05 and lower than 0.1 (weak evidence of the difference or association) were still considered.The level of significance α = 0.05 was considered, although http://www.R-project.org.).Data were analyzed using the Statistical Package for the Social Science for Windows, version 25.0  and R  years, 47 (63%) of whom were male. The pattern of hypertrophy was asymmetric septal in 48 (64%), apical in 22 (29%), and concentric in 5 (7%). Fifty-one patients (68%) had non-obstructive HCM and MWT was 20.2 (4.6) mm. An apical aneurysm was noted in four patients, perfusion defect in at least one segment was noted in 68 (91%) patients, ischemic burden was, on average, 22.5 (16.9%) of LV in the overall population, and LGE was detected in 70 (93%) patients. Baseline characteristics are shown in Stress perfusion images were interpretable in all patients. LGE images were not interpretable in one patient due to artifact. Also, in one patient, it was not possible to interpret CPET parameters due to intolerance to the face mask leading to inaccurate analysis of expired gases; four patients refused to do CPET.Clinically relevant baseline characteristics, potentially linked with CMD, were tested for the association with ischemia in patients with HCM .p < 0.001; LV mass β-estimate:0.241, 95% CI: 0.124; 0.358, p < 0.001). No difference in ischemic burden was found between patients with non-obstructive and obstructive HCM. Demographic factors or cardiovascular risk factors such as diabetes and hypertension were not associated with ischemia. In the multivariable analysis, only MWT is associated with ischemia with a mean increase in LV ischemia of 1.79% for each 1 mm increase in MWT. The association between MWT and ischemia is approximately linear and is graphically represented in In univariable analysis, the severity of LV hypertrophy, measured by MWT and LV mass, was associated with more extensive ischemia .Ischemia had a weak evidence of association with ECV in univariable analysis , and no p < 0.001) (p = 0.074)  . Discret< 0.001) . At the = 0.074) .Because LGE is an important prognostic marker of the disease, a subgroup analysis was further performed to clarify the association between ischemia and LGE. This association was found in individuals with MWT 15–20 mm, non-obstructive HCM, women and age <40 years .p = 0.061)  .Among the other imaging findings, MWT was most prominently related to tissue characteristics, associated with increased values of native T1, ECV, and LGE .p = 0.011) and global radial strain . In multivariable analysis, only LV mass and MWT were independently associated with impairment in myocardial deformation parameters  of whom 6 had permanent AF, 8 paroxysmal AF, and 2 paroxysmal AFL on ECG or Holter monitoring. NSVT was reported in 17 patients (23%), on Holter monitoring.During CPET, two patients had NSVT and 12 had premature ventricular beats during exercise or recovery phase; four patients presented abnormal BP response.p = 0.017)  .p = 0.021) and left atrial volume  were independently associated with supraventricular arrhythmias, mainly AF. No association was verified between ischemia and NSVT .Regarding CPET parameters, ischemia was associated with shorter time to anaerobic threshold  and female gender  were the characteristics associated with lower peak VO2 and lower VO2 at anaerobic threshold, whereas LVEF  and LGE  were independently associated with predicted peak VO2.Older age  MR/T005181/1.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.


Despite a shared hemodynamic profile, characterized by severe diastolic dysfunction and restrictive ventricular filling, with normal ventricle ejection fraction and wall thickness, RCM recognizes a broad etiological spectrum, consisting of genetic/familial and acquired causes, each of which has a distinct pathophysiology and natural course. Hence, the aim of this review is to cover the causes, clinical presentation, diagnostic evaluation, treatment, and prognosis of pediatric RCM.Restrictive cardiomyopathy (RCM) is the least frequent phenotype among pediatric heart muscle diseases, representing only 2.5–3% of all cardiomyopathies diagnosed during childhood. Pediatric RCM has a poor prognosis, high incidence of pulmonary hypertension (PH), thromboembolic events, and sudden death, is less amenable to medical or surgical treatment with high mortality rates. In this  Restrictive cardiomyopathy (RCM) is a heart muscle disease characterized by abnormal diastolic function with restrictive filling and normal ventricular size, wall thickness, and ejection fraction. Differently from hypertrophic, dilatated and right ventricle arrhythmogenic cardiomyopathy, where definition is based on morphology, RCM is defined based on physiology. However, under this common denominator, a wide spectrum of diseases are enclosed, with different causes, natural history, prognosis, and management. Furthermore, a restrictive hemodynamic profile can appear during the natural course of dilated and hypertrophic cardiomyopathy (HCM), being predictor of poor prognosis.Among pediatric cardiomyopathies, RCM is the least common phenotype, representing only 2.5–3% of cardiomyopathies diagnosed during childhood . UnfortuPurpose of the present review is to summarize the causes of pediatric RCMs, their pathophysiology, clinical presentation and management.According to European Society of Cardiology position statement, RCM is defined as a myocardial disease characterized by impaired ventricular filling and normal/reduced diastolic volumes in the presence of (near) normal ejection fraction and myocardial thickness . DecreasRestrictive cardiomyopathies represent a heterogeneous group of cardiomyopathies which recognize several etiologies, including inherited and acquired causes. The term of idiopathic RCM is probably no longer appropriate in a large group of patients: in fact, genetics has identified mutations in various genes, above all sarcomeric genes. Although in the past decades pediatric RCMs were most commonly considered idiopathic in origin, the technical progress in genetics and the introduction and diffusion of next-generation sequencing technology into clinical practice have broadened the genetic spectrum of RCMs, discovering disease-causing genes among affected children. The Pediatric Cardiomyopathy Registry Investigators, through whole-exome sequencing of 36 genes involved in cardiomyopathies, reported pathogenic or likely pathogenic variants in 50% of children with RCM . FurtherMYBPC3), β-myosin heavy chain (MYH7), myosin light chain genes, titin (TTN), troponin I (TNNI3), troponin T (TNNT2), and α-cardiac actin (ACTC)  –13.2+ sensitivity for force development, impair the inhibitory properties of troponin, activate thin-filament-mediated sarcomeric contraction at submaximal calcium concentrations, resulting in increased muscle tension during diastole and in abnormalities of cardiac relaxation . Th. Th2+ selaxation . This suDesmin, lamin, and filamin C mutations share a wide heterogeneity in clinical presentation and, particularly, the possibility to determine a RCM, sometimes associated with skeletal muscle involvement and atrio-ventricular conduction disturbances early in the course of disease.DES gene (2q35). Notably, the spectrum of cardiac phenotypes associated with DES mutations ranges from dilated, arrhythmogenic, non-compaction, hypertrophic and, in rare cases, restrictive cardiomyopathies , is member of a family of cross-link actin filaments expressed in cardiac and skeletal muscle, whose main role is to anchor membrane proteins to the cytoskeleton. Furthermore, filamin C is involved in protein degradation and autophagy control. The first association between RCM and FLNC mutations was described by Brodehl et al. in two unrelated Caucasian families with autosomal-dominant transmission, associated to atrial fibrillation and conduction disorders needing PM implantation , coded by the antation . Cardiachildhood . Differehythmias .LMNA gene (1q22), coding the nuclear envelope proteins lamin A and C, via alternate splicing. The spectrum of cardiac involvement ranges from supraventricular tachyarrhythmias and/or conduction system disease to DCM and ventricular tachyarrhythmias. Rarely LMNA can present as RCM in second decade of life, associated with atrio-ventricular blocks and requiring heart transplantation , Danon disease, and PRKAG2 are the most frequently associated with cardiac involvement, generally presenting as HCM.GLA gene, mapping on X-chromosome (Xq22). This results in progressive globotriaosylceramide accumulation, in different cytotypes and tissues, with consequent organs dysfunction. Overt heart involvement is rare in childhood and may determine ECG abnormalities and initial diastolic dysfunction  gene (Xq24), encoding the LAMP2 protein, leading to progressive accumulation of autophagic material. Clinical phenotype is characterized by heart and skeletal myopathy, cardiac conduction abnormalities, mild intellectual difficulties, and retinal disease. Men are typically affected earlier and more severely than women. Cardiomyopathy had classically a hypertrophic phenotype, with high risk of end stage evolution and need for heart transplantation at early age (Danon disease is an X-linked multisystemic disorder caused by a defect in the lysosome-associated membrane protein 2 (arly age .PRKAG2 gene mutation (7q36.1), coding for the c subunit of the AMP-activated protein kinase. It is characterized by ventricular pre-excitation, supraventricular arrhythmias, and cardiac hypertrophy. It is frequently accompanied by chronotropic incompetence and advanced heart blocks, leading to premature PM implantation  the earliest to occur in life, having been reported in the third decade of life .Sarcoidosis is a multisystem, granulomatous disease of unknown etiology, characterized by non-caseating granulomas. Pediatric sarcoidosis is an extremely rare disease, with an estimated incidence of 0.6–1.02/100,000 children and a mean age at diagnosis of 11–13 years . PediatrHFE2 gene mutation, encoding hemojuvelin, a protein that interacts with hepcidin (subtype 1A) or HAMP gene, codying for hepcidin, a key regulator of circulating iron (subtype 2B). Regardless of its origin, IOC is characterized by a RCM with prominent early diastolic dysfunction which progressively evolute to an end-stage DCM . Inside the cardiomyocytes, free iron induces the formation of reactive oxygen species, hence causing peroxidative damage of cellular structures , cellular apoptosis, and finally cardiac dysfunction  results from iron accumulation as a consequence of excessive iron intake or absorption. Increased iron intake is generally caused by multiple red blood cell transfusions for chronic anemia  or less commonly by infusions of iron-containing products used to treat certain porphyrias. Increased iron absorption is mainly caused by hereditary hemochromatosis (HH), due to mutations in genes involved in iron metabolism, increasing gastro-intestinal absorption. Among the known four HH subtypes, type 2  typically presents by the second decade with a more severe phenotype accompanied, in addition to cardiomyopathy, by hypogonadotropic hypogonadism, arthropathy, and liver fibrosis or cirrhosis. Type 2 HH can be caused by two different genes: tage DCM . Althougfunction . Furtherfunction . The bes failure .Tropical EMF is the most common cause of RCM, affecting more than 12 million people worldwide. Initially described in Uganda, EMF is commonly reported in rural populations of equatorial developing countries, where exhibits a bimodal distribution, peaking at 10 and 30 years of age. Many etiological hypotheses, not mutually exclusive, have been proposed: malnutrition, parasitic infections, environmental factors, and genetics. Due to regional differences in disease prevalence, a geochemical basis has been advanced as unifying hypothesis . Despiteacute necrotic stage is characterized by infiltration of eosinophils and release of their granules' contents in the myocardium (eosinophilic myocarditis). Thereafter, an intermediate phase follows, with thrombus formation along the damaged endocardium (more often in the apex of the left ventricle) and finally a fibrotic stage characterized by reduced ventricular compliance and RMC. At this stage, entrapment of the chordae tendineae can lead to mitral and tricuspid regurgitation . Although the causes for eosinophilic infiltration of myocardium are various , pediatric HES is commonly associated with chromosomal abnormalities, and in 40% of the cases, it has been associated with acute leukemia . Eosinopgitation .Endocardial fibroelastosis is a congenital disease characterized by diffuse thickening of the LV endocardium secondary to proliferation of fibrous and elastic tissue, leading to early death. It manifests with a DCM phenotype or with a RCM phenotype with a small LV cavity. Most forms of endocardial fibroelastosis are associated with congenital heart diseases, first of all hypoplastic left heart syndrome and aortic stenosis/atresia, but also coarctation of the aorta, patent ductus arteriosus and, mitral regurgitation. In the minority of cases, a familial recurrence is seen, with all possible pattern of inheritance reported . DespiteABCC6 (ATP binding cassette subtype C number 6) gene  gene . Histolo 6) gene . Restric 6) gene .Progress in cancer therapeutics over the past years has significantly improved survival rates for most childhood malignancies. Unfortunately, the developing cardiovascular system of children and adolescents is particularly vulnerable to most pediatric cancer protocols, relying on cytotoxic chemotherapy and radiation. Indeed, cardiac-specific disease is the most common non-cancer cause of death among long-term childhood cancer survivors, only second to the recurrence of primary cancer and the development of second cancers .2 was identified as significant risk factor for late-occurring anthracycline-induced cardiotoxicity, adverse effects were reported also with lower cumulative doses , used to treat hematologic cancers and solid tumors, are among the most used chemotherapeutic agents causing cardiotoxicity. Although the typical manifestation of cancer drug induced cardiomyopathy is a DCM, with LV dilation and thinning of myocardial wall, with “restrictive” physiology in the more advanced stages, a not negligible proportion of long-term survivors will eventually develop a RCM. Importantly, patients may present cardiotoxicity many years after treatment completion, needing carefully monitoring for years by echocardiography. However, despite the adverse cardiac effects of anthracyclines, these drugs are fundamental components and standard of care for many types of cancer. Risk factors identified for cardiotoxicity include: female sex, younger age at diagnosis, black race, trisomy 21, and certain lifestyle behaviors , in patients with RCM there is not enhanced ventricular interdependence, with concordant left and right ventricular pressures during the respiratory cycle and parallel changes in their pressure curve areas. Moreover, atria progressively enlarge, due to high intracavitary pressures and thin and distensible walls, predisposing to atrial arrhythmias and thromboembolic episodes. A relevant proportion of patients develop pulmonary hypertension (PH) with elevated pulmonary vascular resistances, unresponsive to vasodilator testing, precluding them form orthotopic heart transplantation  and to the increased myocardial stiffness due to the myocardial cells  and the interstitial matrix (fibrosis) alterations, determining elevated left and right-sided filling pressure. Although left ventricular ejection fraction is typically preserved, systolic contractility is often impaired as showed by tissue Doppler imaging and speckle tracking. Systo-diastolic dysfunction leads to reduced stroke volume. In the protodiastole—despite delayed active relaxation—there is an unusually early rapid filling of the ventricles, due to high atrial pressures, halted by incompliant ventricular walls from the end of the first third of diastole onward—reflecting myocardial stiffness. This results in a prominent “y” descent on the atrial pressure curves and, sometimes, in the antation .The clinical presentation of RCM can be highly variable in children population, ranging from asymptomatic to right and/or left heart failure with PH.Biventricular systolic function is typically normal until advanced stages of the disease, leading to heart failure with preserved ejection fraction (HFpEF). Consequently, clinical presentation is characterized by dyspnoea, poor appetite, ascites, peripheral edema, and hepatomegaly. However, while in adults with RCM symptoms and signs of heart failure are easy to detect, clinical evaluation in children is challenging because of the non-specific findings, resulting in some delay in correct diagnosis. Besides, children with RCM may have a history of frequent respiratory infections. Progressive atrial enlargement can also lead to atrial arrhythmias such as atrial fibrillation and thromboembolic complications, with mitral and tricuspid functional regurgitation frequently associated, due to anulus dilatation. Wolff Parkinson-White syndrome with supraventricular tachycardia has also been reported.Sudden death occurs in ≈25% of pediatric RCM patients, with an annual mortality rate reported of 7%, being cardiac ischemia, arrhythmias, and thromboembolic events the main responsible. Various risk factors for sudden death in pediatric RCM have been identified in previous studies: cardiomegaly, thromboembolism, raised pulmonary vascular resistance, pulmonary venous congestion, syncope, chest pain, left atrial size, PR and QRS duration. Albeit inconsistently sometimes, the main limitation of these studies is their retrospective nature and the intrinsic bias associated. Rivenes et al. evaluated a cohort of 18 pediatric patients with RCM who had sudden, unanticipated cardiac arrests, identifying chest pain, and syncope as risk factors for sudden death . HistopaApproximately 98% of RCM patients have an abnormal electrocardiogram (ECG) . The mosChest X-ray is abnormal in nearly 90% of cases and usually show cardiomegaly and pulmonary venous congestion .annulus reversus”)  . This fiversus”) , 56. Theversus”) . Moreoveversus”) . Ancillaversus”) . Indeed,versus”) . In anotversus”) .*-weighted CMR is the diagnostic gold standard to detect and quantify myocardial iron content in IOC (Cardiac magnetic resonance (CMR) offers a better spatial resolution than echocardiography, providing detailed information about anatomic structures, ventricular function, perfusion, and tissue characterization . For inst in IOC . Late gat in IOC . In cardt in IOC . When pet in IOC .18F] FDG can detect inflammatory cells in some pathological processes such as cardiac sarcoidosis. However, due to the rarity of the aforementioned diseases and due to the concern for radiation exposure in childhood, nuclear imaging has very limited applications in the diagnostic work-up of pediatric RCMs.Whole-body scintigraphy or SPECT with bone-seeking tracers  can reveal amyloid deposits  in the heart, as well as PET with [Cardiac catheterization is usually not necessary for RCM diagnosis, but it can be useful to distinguish between restrictive and constrictive physiology and to determine the severity of the diastolic dysfunction by directly measuring the filling pressures of both ventricles . In RCM P = 0.001)  showed that median plasma NT-proBNP was 1,775  pg/ml in those with RCM vs. 124 (68–718) pg/ml in those with CP (= 0.001) . SpecifiThe endomyocardial biopsy can be valuable in doubtful cases, when non-invasive tests are inconclusive. Unfortunately, in idiopathic RCM it often demonstrates non-specific findings such as myocyte hypertrophy, interstitial and/or endocardial fibrosis. Furthermore, periprocedural risks in fragile affected children should be considered .Restrictive cardiomyopathy should be distinguished from CP, since the two diseases have different treatments and outcomes. In some cases—namely, radiation induced cardiac disease—restriction and constriction may coexist in the same patient, making final diagnosis even more challenging. In Current medical therapy for RCM is primarily supportive and is in large part limited to diuretics in patients with signs and symptoms of systemic or pulmonary venous congestion. The International Society for Heart and Lung Transplantation (ISHLT) guidelines for the management of pediatric heart failure published in 2014 recommend in class I the diuretic therapy to establish a clinically euvolemic state, with a close monitoring of renal function and blood pressure during initiation and up-titration . DiuretiAlthough atrial thrombosis has been linked to atrial fibrillation, abnormal hemodynamics, and to a possible hypercoagulable state in adults with RCM, dedicated studies in pediatric populations are lacking . The incConduction system disease recognize different etiologies, such as ischemic injury of the atrio-ventricular node and His-Purkinje system, mechanical stretching due to atrial and ventricular dilation or genetically determined mechanisms –73. In ap = 0.17)  . In anot = 0.17) .® Berlin Heart, with a variety of pump sizes, covering almost all pediatric patients, and the only long-term device for neonates and infants approved in Europe and USA. Few case series of successful bridging to cardiac transplantation with the Berlin EXCOR® left ventricular assist device (LVAD) have been described (® Berlin Heart) is therefore an interesting option in patient with small ventricular cavity, preserved systolic function, and enlarged atria  , as bridge to transplantation or candidacy, may be a precious weapon. At the moment the experience with MCS in children is quite limited, and this is particularly true for RCM. The most used pediatric long-term support device, is the pneumatically driven, pulsatile EXCORescribed , 79. Coned atria . A recenon (75%) . PrimaryConsidering all these major concerns about the poor efficacy of medical treatment, the identification of the right time to list for heart transplantation a patient affected by RCM during the clinical follow-up becomes both challenging and crucial. Although some clinical and instrumental factors such as pulmonary congestion at diagnosis, severe left atrial dilation, or increased ventricular wall thickness have been identified as potential predictors of poor prognosis, there are no established criteria for listing and the decision is often dependent on individual experienced centers . A multiPediatric RCM is a rare disorder, due to a large heterogeneous group of causes. As a result of its poor prognosis, RCM contributes disproportionately to mortality in children with cardiomyopathy, being heart transplantation the only effective treatment. Therefore, early referral to a third-level cardiomyopathy center is warranted for careful observation, to avoid the development of irreversible PH and to avoid a delay in listing for heart transplantation when indicated.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.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.


Coronary artery disease is the primary cause of death and is responsible for a high number of hospitalizations worldwide. Ventricular remodeling is associated with worse prognosis following ST-segment elevation myocardial infarction (STEMI) and is a risk factor for ventricular dysfunction and heart failure. This study aimed to identify the predictors of ventricular remodeling following STEMI. Additionally, we evaluated the clinical, laboratory, and echocardiographic characteristics of patients with anterior wall STEMI who underwent primary percutaneous intervention in the acute phase and at 6 months after the infarction.This prospective, observational, and longitudinal study included 50 patients with anterior wall STEMI who were admitted to the coronary care unit (CCU) of a tertiary hospital in Brazil between July 2017 and August 2018. During the CCU stay, patients were evaluated daily and underwent echocardiogram within the first three days following STEMI. After six months, the patients underwent clinical evaluation and echocardiogram according to the local protocol.p=0.008) and the median and interquartile range of E/E’ ratio . This difference was also observed in multivariate logistic regression.Differences were noted between those who developed ventricular remodeling and those who did not in the mean±standard deviation levels of creatine phosphokinase MB isoenzyme (CKMB) peak (no remodeling group: 323.7±228.2 U/L; remodeling group: 522.4±201.6 U/L; Diastolic dysfunction and CKMB peak in the acute phase of STEMI can be predictors of ventricular remodeling following STEMI. Acute myocardial infarction (AMI) is diagnosed when there is evidence of myocardial necrosis along with clinical signs and symptoms consistent with myocardial ischemia .A majority of AMIs occur because of coronary artery atherosclerosis, usually, with overlapping thrombosis. Non-atherosclerotic causes of AMI include vasculitis, trauma, coronary spasm, cocaine, imbalance between oxygen supply and demand, and congenital coronary anomalies .e.g., troponin); ischemic symptoms; ST deviation and T-wave inversion, new left bundle branch block, or pathological Q-wave on electrocardiogram (ECG); loss of viable myocardium or new alterations in segmental contractility on imaging; detection of intracoronary thrombus on angiogram or autopsy; and cardiac arrest with ischemia-like symptoms and ECG alterations (Some of the established criteria for AMI diagnosis are the following: increased cardiac biomarkers (erations .ST-elevation AMI (STEMI) is identified when the previously described AMI criteria are met along with ST elevation or new left bundle branch block .Coronary artery disease is the leading cause of death worldwide . In the Following STEMI, the heart undergoes a remodeling process that occurs at genetic, molecular, cellular, and interstitial levels . The maiAmong the manifestations of ventricular remodeling following STEMI, left ventricular (LV) aneurism  and venti.e., alterations in segmental contractility that is commonly seen in STEMI) is better evaluated based on LV ejection fraction (EF) using the Simpson method , E/E’ ratio (E’ represents tissue Doppler early ventricular filling), or an increase in the left atrial diameter, which indicates an increase in LV end-diastolic pressure. In contrast, systolic dysfunction , also called primary angioplasty, with or without coronary stenting ,15. PCI In addition to PCI, drugs are also important in the treatment of STEMI. Some studies suggest early administration of drugs prior to any intervention , and somChen et al. reported that patients with STEMI presented with diastolic dysfunction in early evaluations irrespective of the duration between STEMI and PCI . ShachamIt is known that ventricular remodeling is associated with worse prognosis following myocardial infarction. Therefore, the hypothesis of the present study was that additional prognostic information may help identify patients at a greater risk of ventricular remodeling. The aim of this study was to identify predictors of ventricular remodeling following AMI.This prospective, observational, and longitudinal study was performed in the coronary care unit (CCU) of the Clinics Hospital of Botucatu Medical School (HC-FMB-UNESP) and included patients with left anterior wall STEMI.All procedures were approved by the Research Ethics Committee (CEP) of Botucatu Medical School (n° 2.102.000), and all patients were informed about the procedures and signed a consent form before they were included in the study.All eligible patients in the CCU of the Clinics Hospital of the Botucatu Medical School between July 2017 and October 2018 were included; overall, 50 patients were included. Five of these patients died, and four were lost to follow-up at 6 months. Enrolled patients included consecutive patients of both sexes who were over 18 years of age, were diagnosed with LV anterior wall STEMI, and underwent primary angioplasty between July 2017 and October 2018.Anterior wall STEMI was diagnosed based on history of chest pain of 20 minutes to 12 hours and ST elevation ≥2 mm in at least two precordial leads or the presence of an assumingly new left bundle branch block. AMI diagnosis was confirmed by an increase in cardiac enzyme levels to at least twice the upper limit , coexisting comorbidities, cardiovascular risk factors , continuous use of medications prior to admission, heart rate, systemic blood pressure, and signs of systemic and pulmonary congestion.Possible in-hospital clinical complications following AMI included post-infarction angina, heart failure, pericarditis, arrhythmias, cardiogenic shock, and death.Clinical examination at 6 months included evaluation of dyspnea and chest pain, continuous use of drugs after discharge, heart rate, systemic arterial pressure, and signs of congestion.Blood samples were collected according to the routine protocol of the CCU. Upon admission, electrolytes, urea, creatinine, and blood counts were assessed. Total creatine phosphokinase (CPK) and MB isoenzyme (CKMB) were evaluated upon arrival and every 6h until early decline in their levels. Troponin I level was evaluated upon arrival and at 90 min later. Blood levels of glucose and glycosylated hemoglobin, low-density lipoprotein (LDL), high-density lipoprotein (HDL), total cholesterol, and triglycerides were also assessed during the in-hospital stay.Thrombolysis in Myocardial Infarction (TIMI) classification ; infarction-related artery (IRA) flow after the intervention as determined by mal flow ); myocarmal flow ).®  with a multifrequency ultrasonic transducer of 2.0-3.5 MHz and an image recording system. Images were obtained and analyzed according to the recommendations of the American Society of Echocardiography  and at 6 months using GE Vivid S6iography .Morphometric variables included the following:Left atrial maximum diameter (mm): LA;Left atrial volume , obtained using the Simpson method;2): LAV normalized according to body surface area (BSA);Left atrial volume index : LVDD and LVSD, respectively;Interventricular septum and LV posterior wall diastolic thickness (mm): IVS and PW, respectively;Relative wall thickness (RWT)=(2 x PW)/LVDD;3- LVDD3]}+0.6; andLV mass =0.8×{1.04×[(IVS+PW+LVDD)2)=MVE/BSA.LVM index =[(LVDD-LVSD)/LVDD]x100.Diastolic function variables included the following:Ventricular early filling phase peak velocity : obtained using spectral Doppler of transmitral diastolic flow;Atrial contraction phase peak velocity : obtained using spectral Doppler of transmitral diastolic flow;E/A ratio;LV isovolumetric relaxation time , corresponding to the period between the end of ventricular ejection and the beginning of diastolic transmitral diastolic flow;E wave deceleration time , corresponding to the time between the initial transmitral flow peak velocity and its extrapolation to baseline;Velocity of mitral annular diastolic excursion on tissue Doppler in the early filling phase was obtained from the mean of septal and lateral sites (E’) ;E/E’ ratio.3)/(2.4+D)] based on LV systolic and diastolic diameters (D).LV remodeling was defined as an increase in LV systolic and/or diastolic volume of at least 15% within 6 months of follow-up . The volth and 75th percentiles and were compared using the Student’s t-test and Mann-Whitney test, respectively. Categorical variables were analyzed using the chi-squared test or Fisher’s exact test.Continuous variables with normal and non-normal distributions are presented as mean and standard deviation or median and 25To evaluate the association of variables with remodeling outcomes within 6 months, we used multivariate logistic regression . The varFor continuous variables that presented differences in multivariate logistic regression, receiver-operating characteristics (ROC) curves were designed to define the thresholds.We evaluated 50 patients with anterior wall STEMI who underwent primary angioplasty. The overall mean age was 61.2±9.8 years, and 84% were male. Four patients were lost to follow-up, and five (10%) died within the 6-month follow-up period. Therefore, 41 patients were re-evaluated clinically and underwent a second echocardiography at 6 months after AMI. Of these, 36.6% presented with ventricular remodeling.p=0.008).p=0.004).The aim of our study was to compare the parameters of patients with STEMI in the acute phase and after 6 months of follow-up to identify predictors of ventricular remodeling.Data from the acute phase provided valuable information about these patients. For instance, Chen et al. found diastolic dysfunction even after early reperfusion . BarberaHellawell et al. findings on reverse remodeling reinforce the idea that the benefit of early reperfusion lies in fighting an unfavorable metabolism, showing positive effects in both primary angioplasty and thrombolysis . There aThe CKMB peak level was closely related to the infarction size and was related to ventricular remodeling  as previIn our study, there was no relationship between the remaining variables and ventricular remodeling. We found in the literature that neutrophils might be altered once the inflammatory reaction following AMI increases the tissue damage. In contrast, there are experimental findings that point to the importance of neutrophils in the repair processes following infarction since their absence in knockout rats is related to worsening in ventricular function, increase in fibrosis, and heart failure .Our study highlights the importance of delay in forwarding patients to our hospital, which can surpass the recommended 12 hours for primary angioplasty. This setback may be due to the patients themselves who are often deprived of health education and neglect the initial AMI symptoms or the regional emergency health assistance, which often surpassed the 10 minutes recommended for STEMI diagnosis. There were also cases of patients who were referred in a timely manner but had already received thrombolytic therapy and were candidates for rescue angioplasty, which was considered an exclusion criterion. These factors limited the sample size, which was initially estimated to be 65 people per year. The economic status of the national health system should also be noted because it limited some biochemical examinations during some periods, notably that of troponin, which is essential in the characterization of these patients.Some previously established concepts were reinforced, such as the correlation of the infarction size, defined in this study by CKMB peak, and diastolic dysfunction in the acute phase, defined as an increase in the E/E’ ratio, with ventricular remodeling as well as the efficacy of primary angioplasty within 12 hours to avoid cardiac dilatation. It was then possible to contextualize the literature findings in the real-life situation of a university hospital. Once we have established values for E/E’ ratio and CKMB peak with good sensitivity and specificity in predicting ventricular remodeling, we can identify patients who should be re-evaluated earlier.It is noteworthy that the people within the region still require health education so that patients can seek help earlier and hospitals can begin medications and forward them to our center as soon as possible for the gold-standard treatment.The results of the present study allowed us to identify diastolic dysfunction and CKMB peak in the acute phase of STEMI as predictors of subsequent ventricular.Silveira CFSMP contributed to the literature search, study design, data collection, analysis and interpretation, and manuscript drafting. Malagutte KNDS, Nogueira BF and Reis FM contributed to the literature search, data collection, data analysis and interpretation, and manuscript drafting. Rodrigues CSA, Rossi DAA, Okoshi K, Bazan R and Martin LC contributed to the literature search, data analysis and interpretation, and manuscript drafting. Minicucci MF, and Bazan SGZ contributed to the literature search, study design, data analysis and interpretation, and manuscript drafting.