To compare cardiac function and systolic dyssynchrony of fetuses not exposed to and those exposed to maternal autoimmune antibodies using two-dimensional speckle tracking echocardiography (2DSTE).An observational study of 52 fetuses, 18 from mothers with autoimmune antibodies  and 34 from healthy mothers without antibodies, was conducted. Maternal baseline characteristics, fetoplacental Doppler parameters, and conventional echocardiographic data were prospectively collected. Systolic global and regional longitudinal strain of left and right ventricle (LV and RV) and the time to peak strain of regional myocardium were measured using 2DSTE. We also calculated the differences in time to peak strain between the LV free wall and RV free wall  and the LV dyssynchrony between the septum and LV free wall .P = 0.042).There were no significant differences in conventional systolic and diastolic functional parameters for the LV and RV. No effect modification was demonstrated in a myocardial deformation analysis. However, 1C-DYS was significantly more prolonged in the maternal autoimmune disease group (19.50 [8.00 to 29.25] vs. 28.50 [13.50 to 39.25], LV systolic mechanical dyssynchrony in fetuses of mothers with autoimmune antibodies suggests in-utero subclinical damage of the cardiac conduction system. Autoimmune diseases (AD), including rheumatoid arthritis, systemic lupus erythematosus, and Sjogren’s syndrome, are more common in women of childbearing age . Intra-uFetal echocardiography remains the mainstay for cardiac evaluation and can assess cardiac structure, heart rhythm, anatomic abnormalities, ventricular function, and valvular function . ConventTwo-dimensional speckle tracking echocardiography (2DSTE) is a recent technology that tracks speckle patterns in the myocardium throughout the cardiac cycle. By calculating the myocardial deformation parameters (strain and time to peak strain), this technology provides a more accurate measure of cardiac function and dyssynchrony in fetuses, children, and adults, in normal and specific disease conditions than previous parameters –11.To the best of our knowledge, cardiac function and systolic dyssynchrony of fetuses have not been well characterized in fetuses exposed to maternal autoantibodies. Therefore, the purpose of this study was to evaluate cardiac function and systolic mechanical dyssynchrony in fetuses of mothers with AD compared to fetuses of healthy mothers, exploring the potential role of deformation analysis and ventricular dyssynchrony using 2DSTE. We assumed that fetuses exposed to maternal autoimmune antibodies suffer ventricular dysfunction and dyssynchrony.An observational study was conducted at our hospital between July 2018 and November 2020. The research protocol was approved by the hospital ethics committee, NO. WZ (2020032). Informed consent was obtained from all participants. Fifty-two singleton pregnancies between 20 and 26 weeks of gestational age were enrolled in our study.The anti-SSA/Ro60, anti-Ro52, and anti-SSB /La antibody tests were performed twice, before pregnancy and at the second trimester respectively. The results of the two tests were consistent. The EUROLINE ANA Profile (IgG)  was adopted, and the operation was carried out strictly in accordance with the reagent instructions. After completion of the tests, the results were categorized into four grades based on the depth of the film strip: −; ±; +, ++; and +++. We divided the pregnant women into two groups according to the test results, which were analyzed by two senior physicians. Moreover, the diagnosis was double-blind. Fetuses of 18 of these women  positive  were randomly selected as the AD group. They were treated regularly with hydroxychloroquine (HCQ) before and during pregnancy, and some also treated with methylprednisolone. The control group fetuses were 34 randomly selected and matched with the cases by gestational age. All women in the control group were healthy with AD antibodies negative (−). Women in both groups had no history of smoking, alcohol abuse, hypertension, diabetes, or heart, liver, or other chronic diseases.The ultrasound examination was performed within 48 h following the antibody tested in the second trimester. Detailed fetal echocardiography was performed by an experienced cardiologist, according to the guidelines , 13. PlaAll echocardiographic parameters were acquired using a Vivid E95 ultrasound scanner  equipped with a S5–1 and a C1–6 transducer. The 2D cine loops were stored at a high frame rate (134 ~ 200 frames/s). Pulsed Doppler parameters were measured with the insonation angle <20. The analysis of deformations and dyssynchrony was performed offline using EchoPAC version 203 (GE Vingmed Ultrasound AS).We used the formula by Hadlock et al.  to estimCardiac morphometric and functional assessment by both conventional echocardiography and 2DSTE were performed. The morphometric measurement has been previously described . CardiacA mechanical PR interval of the fetal heart was obtained by pulsed Doppler as described previously . Left anThe 2D grayscale video clips of basal or apical four-chamber views were chosen. Because of the inability to record a fetal electrocardiograph, the mitral valve was followed to identify the beginning and end of one cardiac cycle, as previously described . One carThe sample size was determined by using the results from our preliminary experiment, in which the 1C-DYS was our primary outcome. We use it for the sample size calculation. The medians of the maternal AD group and the control group were 27.50 and 15.50 respectively, and the standard deviations (SDs) of the maternal AD group and the control group were 17.07 and 12.86, respectively. A two-tailed test was required with an alpha of 0.05, an statistical power of 85%, and the ratio between AD and control is 0.5. The sample size was calculated as the maternal AD group was 17, and 34 for the control group. Since this was a cross-sectional observational study, we determined a sample size of 18 in the maternal AD group and 34 in the control group.t test or Mann-Whitney U test, if appropriate. The chi-squared test or Fisher’s exact probability test was used for comparison of the classified data if applicable. For 2DSTE measurement, data from 10 random individuals were selected for inter- and intra-observer agreements and analyzed using the intra-class correlation coefficient (ICC) and Bland-Altman plots. We considered an ICC > 0.80 as excellent, 0.60 ≤ ICC ≤ 0.80 as good, 0.40 ≤ ICC ≤ 0.60 as moderate, and ICC < 0.40 as poor. All statistical analyses were performed using SPSS software . P < 0.05 was considered statistically significant.Categorical data were described as counts and proportions, and continuous data were expressed as mean ± SD and the median and interquartile range for skewed distributions. Normal distribution of the continuous data was determined by the Shapiro-Wilk test. Continuous variables were compared with an independent n = 18) and healthy controls (n = 34), were selected. Maternal AD included rheumatoid arthritis , systemic lupus erythematosus , undifferentiated connective tissue disease , Sjogren’s syndrome , and idiopathic thrombocytopenic purpura . All cases were anti-SSA/Ro60 antibody positive, 17% (n = 3) were anti-SSB/La antibody positive, while 50% (n = 9) were anti-Ro52 antibody positive. The enrollment flowchart is presented in Fig. A total of 52 fetuses, including those exposed to maternal AD . However, 1C-DYS was significantly more prolonged in fetuses of the maternal AD group . Nevertheless, 2C-DYS was not significantly prolonged.Deformations and dyssynchrony analyses of the ventricles are reported in Table P < 0.001) for LV GLS and 0.880 (P < 0.001) for 1C-DYS. The ICC for the inter-observed variability were 0.815 (P < 0.001) for LV GLS and 0.843 (P < 0.001) for 1C-DYS. The Bland-Altman plots analyses for intra- and inter-observer variability are shown in Fig. The ICC for LV GLS and 1C-DYS were excellent. The ICC for the intra-observed variability were 0.849 /L0. Where S = strain, L0 = baseline length, and L = instantaneous lengths at the time of measurement. Strain was used to assess cardiac systolic function. Time to peak longitudinal strain was defined as the time from the beginning of the QRS complex on ECG to the negative peak of the longitudinal strain curve during the cardiac cycle. It was used for the quantification of mechanical dyssynchrony of segments myocardium.Sometimes asymptomatic pregnant women with autoantibodies can have fetuses with CHB, and the bradycardia is usually noticed during a routine prenatal examination . HoweverTo the best of our knowledge, the present study is the first to comprehensively analyze the cardiac function and systolic dyssynchrony using 2DSTE in fetuses in maternal AD.Our data suggest that LV and RV function, as measured by conventional echocardiography and 2DSTE, were no significantly different between the fetuses of the two groups. In addition, no significant differences were found between the two groups when comparing the longitudinal strain of the LVFW, IVS, and RVFW. These results demonstrated that both the left and right systolic and diastolic ventricular values were preserved, which differs from our hypothesis. This might be explained by the fact that all mothers of the AD group were treated regularly with HCQ before and during pregnancy, and some also treated with methylprednisolone. HCQ has been suggested as a potential preventive medicine against autoimmune CHB by inhibiting Toll-like receptor signaling . A studyAt present, pulsed Doppler study is used to measure the mechanical PR interval of the fetal heart , 17. ForVentricular systolic dyssynchrony has an important impact on ventricular function and structure . Our stuThe present study has several limitations. First, this was a single-center study and the sample size was small. Second, the serum antibody was detected by the EUROLINE ANA Profile (IgG) , which is a qualitative diagnosis assay and could not measure the anti-Ro/La titer. Hence, we should analyze the association between anti-Ro “level” and echocardiographic parameters in a future study. Third, on account of the small size of the fetal heart, the circumferential and radial strain parameters were not analyzed. The small size of fetal heart might have also led to reduced accuracy and over smoothing due to suboptimal spatial resolution. Fourth, due to infeasible fetal electrocardiograph and lack of knowledge on perfect time of AV closure, only the time to peak strain could be measured. Thus, the exact systolic strain values and time to peak systolic strain might have been overestimated. Finally, this was a cross-sectional study, and regular follow-up should be conducted in future studies.Despite these limitations, the study demonstrated that LV longitudinal strain and mechanical dyssynchrony parameter derived by 2DSTE measurement showed good feasibility and reproducibility, as reported in previous studies , 7.In conclusion, a comprehensive evaluation of fetal cardiac function and dyssynchrony is feasible in maternal AD by 2DSTE. Fetuses exposed to maternal AD with autoimmune antibodies (anti-SSA/Ro or/and anti-SSB /La) showed increased levels of left ventricular dyssynchrony in comparison to fetuses of healthy pregnant women. The 2DSTE could provide additional information over conventional fetal echocardiography in detecting subclinical damage to the left ventricle conduction system of fetal heart in maternal AD, which may help clinicians better understand and manage those pregnant women and their fetuses.


Echocardiography is the first-line imaging modality for assessing cardiac function and morphology. The miniaturisation of ultrasound technology has led to the development of hand-held cardiac ultrasound (HCU) devices. The increasing sophistication of available HCU devices enables clinicians to more comprehensively examine patients at the bedside. HCU can augment clinical exam findings by offering a rapid screening assessment of cardiac dysfunction in both the Emergency Department and in cardiology clinics. Possible implications of implementing HCU into clinical practice are discussed in this review paper. Historically, the cardiovascular history and examination were the primary methods for screening cardiovascular disease. The advent of hand-held cardiac ultrasound (HCU) enables augmentation of the cardiovascular assessment at the bedside. These HCU devices enable subjective and quantitative assessment of cardiac morphology and function with reasonable diagnostic accuracy, even when used by inexperienced operators with basic training –5.Echocardiography remains the first-line imaging test for the assessment of suspected cardiac pathology. Standard transthoracic echocardiogram (TTE) allows the determination of cardiac dysfunction by assessing LV cavity size, wall thickness, valvular appearance, and function, as well as for the presence of abnormal blood flow within the heart . HCU tecIn this comprehensive review, we aim to provide clinicians with a greater understanding of handheld ultrasound probe specifications and discuss the clinical utility of HCU for the augmentation of the physical cardiovascular examination. Devices available at the authors' institution were used to acquire images included in the current review.Multiple HCU devices are currently approved for clinical use and widely available including Clarius wireless scanner , Lumify , Vscan extend  and Butterfly iQ  Fig. . The LumCurrently available HCU devices are designed to be portable and lightweight whilst maintaining high technical specifications. The Butterfly iQ device is manufactured using a complementary metal-oxide semiconductor (CMOS) material which allows mass production at a low cost, making this scanner one of the most affordable. HCU devices are compatible with Android, Android-like and iOS devices. Images can therefore be interpreted remotely by experienced diagnosticians. This includes utilisation in rural areas and low-resource countries where conventional ultrasound is not easily accessible , 8. DeviThe ultrasound technology incorporated into HCU devices is becoming increasingly more sophisticated. GE Vscan and Butterfly iQ have developed technology to automatically calculate left ventricular ejection fraction whilst Clarius ultrasound scanner is the only HCU device able to provide pulsed-wave Doppler technology. Butterfly iQ have introduced an educational view guidance tool that assesses the quality of the images acquired in real-time to enhance scanning technique.Battery life limits the use of HCU and therefore is indicated for quick scans. Vscan has an exchangeable battery which allows for longer scanning times compared to other devices. Continuous imaging can lead to the device freezing to allow for cooling which also limits the length of time they can be used.Spectral Doppler technology causes HCU devices to heat up more rapidly and is one reason for only a few models incorporating these imaging modalities. Clarius is one of the only scanners on the market capable of PWD, permitted by the installation of a liquid heating device which prevents overheating . This feThe availability of HCU varies between departments, institutions and countries. For example, Butterfly is not commercially available in Japan compared to the UK where it occupies a large share of the market. Although this review aims to describe the range of specifications of individual HCU devices, there is little research into the impact of these varying specifications on their diagnostic ability.Point-of-care ultrasound (POCUS) has rapidly transformed over the past two decades beyond the large machines that were initially introduced into emergency medicine and critical care. The advancement of POCUS technology has led to the introduction of more portable, handheld devices which are now also used in obstetrics to confirm intrauterine pregnancies, rheumatology to image for joint and soft tissue injuries and gastroenterology in the diagnosis of appendicitis and gallbladder pathology . One of Physical signs of impaired LV systolic function often only manifest when there is advanced disease. HCU can identify evidence of declining cardiac function in asymptomatic patients allowing for earlier commencement of treatment, thus limiting the development of cardiac failure. HCU permits the assessment of left ventricular morphology and function by estimating LVEF and detecting regional wall motion abnormalities (WMA) , 12–14. Rapid HCU assessment and identification of regional WMAs may help confirm a diagnosis of acute myocardial infarction (MI) in patients with chest pain who have an equivocal or non-localising ECG and/or indeterminate laboratory markers . HCU mayRoutine TTE examination for LV filling pressure involves tissue Doppler imaging (TDI) to measure LV myocardial velocities (eʹ and aʹ), pulse-wave Doppler for mitral inflow velocities (E and A) and continuous-wave Doppler for measuring peak TR velocity. Current probes do not offer all these ultrasound technologies, hence LV diastolic assessment is limited to mitral inflow assessment by some probes which offer pulse-wave Doppler assessment. Nevertheless, left atrial size can be estimated by HCU and this is also routinely advocated for estimating LV filling pressures.Left atrial assessment can be made easily by apical 4-chamber and 2-chamber views. These views are relatively simple to acquire by HCU. These views allow us to quantify both the left atrial area and volume. HCU can more sensitively detect left atrial enlargement compared with auscultation of S4 on clinical examination , 22–25. Quantitative assessment of valvular heart disease (VHD) using HCU is limited because pulse-wave and continuous-wave Doppler modalities are not available with the majority of probes. Imaging for valvular insufficiencies or morphological abnormalities of stenotic valves, therefore, relies on qualitative colour-Doppler and B-mode assessment. Initial assessment following a clinical suspicion of VHD can determine whether the patient requires further investigation. Repeat imaging can also provide complementary information to clinical examination regarding disease progression, which can support a decision to refer for more complex imaging.Early detection of right ventricular (RV) enlargement and hypokinesis can improve the prognosis of acutely unwell patients such as those admitted with an undiagnosed pulmonary embolism (PE). The majority of fatal PEs occur within the first few hours of developing symptoms, with 30–50% remaining undiagnosed until autopsy , 27. RapThe presence of an anechoic space within the pericardium, right atrial inversion or right ventricular diastolic collapse indicates pericardial effusion. These measurements using HCU can specifically predict pericardial effusions , 18, 33.Ultrasound examination of jugular venous pressure (U-JVP) can be used to estimate a patient’s fluid status by identifying the collapse point of the internal jugular vein (IJV). The collapse point is viewed in the longitudinal axis with the patient positioned in a semi-upright position Fig. . The locMinimal training is required to gain basic competency in image acquisition using HCU . AlthougThe lack of a designated HCU training pathway, certification and hospital service poses a barrier to the implementation of bedside imaging in clinical practice. Levels of competence cannot be standardised and the absence of HCU services means clinicians cannot gain the experience necessary to acquire and interpret images with consistently high accuracy. Ultrasound education has been implemented in American medical school curriculums for more than a decade which is currently not available in the UK . Such trHCU has been associated with reduced costs when compared with standard echocardiography , 44, 45.The increasing sophistication of available HCU devices enables clinicians to more comprehensively examine patients at the bedside. HCU can augment clinical exam findings by offering a rapid screening assessment of cardiac dysfunction in both the Emergency Department and in cardiology clinics. Possible implications of implementing HCU into clinical practice are earlier detection of cardiac pathology and a reduction in unnecessary TTE referrals.


Conclusions: Human cells affected by FD may respond differently to ERT: while cardiomyocytes retain their GL3 content after 2 years of treatment, gastro-intestinal cells show GL3 removal with recovery of function. This divergent response may be related to differences in cellular turnover, as well as tissue IGF-II-R expression.Background: The impact of enzyme replacement therapy (ERT) on cardiomyocytes and intestinal cells, affected by Fabry disease (FD), is still unclear. Methods: Six patients with FD, including five family members with GLA mutation c.666delC and one with GLA mutation c.658C > T, manifesting cardiomyopathy and intestinal symptoms  were included in the study. Clinical outcome, cardiac magnetic resonance (CMR), endomyocardial and gastro-intestinal biopsies were evaluated before and after 2 years of treatment with agalsidase-α (0.2 mg/kg every other week). Immunohistochemistry and Western blot assessments of mannose-6-phosphate receptors (IGF-II-R) on intestinal and myocardial frozen tissue were obtained at diagnosis and after 2 years of ERT. Results: After ERT left ventricular maximal wall thickness, ranging from pre (<10.5 mm) to mild (<15 mm) and moderate hypertrophy (16 mm), was not associated with significant changes at CMR. Degree of dyspnea, mean cardiomyocyte diameter and % vacuolated areas of cardiomyocytes, representing intracellular GL3, remained unmodified. In contrast, intestinal symptoms improved with disappearance of diarrhea, recovery of anemia and weight gain, correlating with near complete clearance of the enterocytes from GL3 inclusions. IGF-II-R expression was remarkably higher even at histochemistry in intestinal tissue compared with myocardium ( Fabry disease (FD) is an X-linked inborn error of glycosphingolipid catabolism that is caused by deleterious mutations in the GLA gene encoding the lysosomal hydrolase, alpha-galactosidase A  ,2. The mCurrently, available treatments for FD are limited and include ERT  and chaperone therapy  of the patients, age 21–72 years, were relatives with GLA gene mutation c.666delC. The sixth patient was a 35-year-old non-related man with GLA mutation c.658C > T. All patients presented with cardiomyopathy and palpitation and/or dyspnea, abdominal pain and diarrhea, and 2 patients had intestinal malabsorption (weight loss and iron-deficiency anemia).Six out of 88 patients with Fabry disease, with endomyocardial and intestinal biopsies, clinical and imaging studies before and 2 years after initiation of agalsidase-α were enrolled into this study. Clinical, imaging and biopsy findings of the patients are summarized in In all patients, cardiac investigations included non-invasive  studies. In particular, ECG, Holter and 2D-echo were obtained every three months, while CMR and left ventricular endomyocardial biopsy were undertaken, after written informed consent, before and after 2 years of ERT  administration.Gastric and duodenal biopsies were performed before and after 2 years of ERT.Laboratory tests, including hemoglobin and serum iron determination were acquired in addition to the assessment of body weight before and after ERT as part of evaluations for intestinal malabsorption.CMR exams were performed on a 1.5 Tesla scanner. Standard cardiac magnetic resonance protocol included (1) cine magnetic resonance images acquired during breath-holds in the short-axis, 2-chamber and 4-chamber; (2) black blood T2-weighted short tau inversion recovery images on short-axis planes covering the entire left ventricle during 6 to 8 consecutive breath-holds for myocardial edema detection; and (3) late gadolinium-enhanced imaging performed 15 min after injection of 0.2 nmol/kg of gadoteratemeglumine and signal intensity value 2 SDs above the mean signal intensity of the remote normal myocardium was considered suggestive for myocardial fibrosis. .Cardiac catheterization with left ventricular and coronary angiography was obtained in all patients. Endomyocardial biopsy (four to 8 samples each patient) was performed in the septal-apical region of left ventricle. For histological analysis, the endomyocardial and gastric and duodenal biopsy samples were fixed in 10% buffered formalin and paraffin embedded. Five microns–thick sections were stained with hematoxylin and eosin and Masson trichrome. For electron microscopy studies, additional biopsy samples were fixed in 2% glutaraldehyde in a 0.1 M phosphate buffer, at pH 7.3, post-fixed in osmium tetroxide and processed by following a standard protocol for embedding in Epon resin. Ultrathin sections were stained with uranyl acetate substitute and lead hydroxide and analyzed by a JEOL-1400-plus electron microscope.Assessment and comparison of mannose-6-phosphate receptors in the myocardial and intestinal tissues in Fabry disease patients:To evaluate a possible receptor-mediated different ERT delivery in the myocardium and intestine, we determined the expression of mannose-6-phosphate receptor in frozen intestinal and myocardial tissue in all six patients before and after 2 years on ERT. Results were compared with values from normal myocardium and intestine.The expression of mannose-6-phosphate receptors was evaluated by immunoperoxidase using IGF2R Recombinant Rabbit Monoclonal Antibody (SR45-09) . Intensity of immunostaining was semi-quantitatively evaluated as absent (grade 0), weak (grade 1), mild (grade 2) moderate (grade 3) or strong (grade 4). For each patient, the grading was calculated on 10 different histological sections, and the average value was computed.Heart tissue samples were treated as previously described . The expCardiomyocyte’s cross-sectional area was computed by measuring the cardiomyocyte diameter across the nucleus in 50 to 100 cells cut transversely. At that level, the total area of glycolipid bodies was measured, and the percent of cardiomyocyte total area occupied by glycolipid bodies was calculated. These measurements were analyzed by using Nis-Elements BR software.Common morphological (OM and TEM) features in Fabry disease’s myocardial, gastric and duodenal biopsy samples before and after ERT.see .OM shows perinuclear and intracardiomyocyte bodies, which, at TEM, appeared as osmiophilic myelin-like glycolipid bodies (MLGLBs), typically observed in Fabry diseases.Myelin-like glycolipid storage bodies are membrane-bound vacuoles containing electron-dense membranaceous material, which, at higher magnification, appear organized similarly to the myelin membranes.Before and after ERT, as evaluated by morphometry, there are no significant differences in the glycolipid bodies content. See Before ERT, mucosal epithelium is apparently unaffected at OM. At TEM occasional typical osmiophilic myelin-like glycolipid bodies of limited extend may be observed in muciparous cells of the epithelium. Endocrine cells are also unaffected.ML-GLBs are mostly observed in sub epithelial mesenchymal cells, mostly fibroblasts, macrophages and endothelial cells. After ERT, in all patients studied, glycolipid bodies are absent, both at OM in thick sections and at TEM in ultrathin sections. The limitation of this evaluation resides in the dimensional characteristics of samples which have a small surface area and a limited thickness, excluding the deep layers of the submucosa. See Before ERT, mucosal epithelium is apparently unaffected both at OM and TEM. Endocrine cells are also unaffected. See Subepithelial mesenchimal  frequently contains typical osmiophilic myelin-like glycolipid bodies of limited extend.After ERT, glycolipid bodies are no more visible. However, a number of autophagocytic vacuoles are present. They may contain mitochondria, membrane debris and small myelin-like glycolipid bodies; sometimes they are devoid of dense structures (ghost bodies), suggesting a previous digestion of GB3.The clinical and pathologic characteristics of our 6 patients are summarized in p = 0.002 (p  <  0.001), and a normal expression in control intestinal tissue versus FD intestine (p= 0.1455 (NS).Semi-quantitative evaluation of immunostaining (grades from 0 to 4) for mannose-6-phosphate receptors showed an intense positive cytoplasmic immunostaining cardiomyocyte expression in normal heart A comparep < 0.01). Of note, in Fabry disease, intestinal tissue expression was 1.7-fold higher compared to normal bowel , while FD myocardial expression was 7-fold lower than in normal heart . Thus, FD intestinal expression was 19-fold higher than FD myocardium . After 2 years of ERT, there was no statistically significant difference in intestinal and myocardial receptors compared with baseline values. . The comparison between groups was performed with Mann–Whitney non-parametric test was used. A A 72-year-old normotensive lady presented with a long history of palpitation, dyspnea on effort, abdominal pain and diarrhea. Routine laboratory tests were unremarkable. In the past, she had undergone multiple negative gastric and intestinal endoscopy and received a diagnosis of irritable colon. She was normotensive with sinus rhythm and a heart rate of 68 bts/min; PR was 140 ms, and QRS voltages were in the normal limits. Holter registered 8300 VEBs with polymorphic couplets and triplets. 2D-echo showed mild LV hypertrophy  13.5 mm) with preserved end-diastolic diameter (48 mm) and Ejection Fraction (53%) and normal valves. CMR indicated an area of LGE in the LV lateral free wall and a reduced T1 mapping (873–896 ms) suggesting glycolipids accumulation. She underwent a coronary angiography, which showed normal vessels and a left ventricular endomyocardial biopsy. Her histology showed large cardiomyocytes with perinuclear vacuoles that, on frozen sections, were positive for GL3 A–C. TEM A 54-year-old normotensive female from same family, with GLA gene mutation (c.666delC) and increased Lyso-Gb3 , presented with asymptomatic mild LV hypertrophy by 2D-echo (LV-MWT 13 mm) and recurrent abdominal pain and diarrhea. ECG showed sinus rhythm with short PR (116 ms) and negative T wave in D1, aVL and V3-V6 leads. Her CMR was characterized by reduced T1 Mapping (875–897 ms) and a mild LGE area in the LV posterior wall. Coronary angiography was normal. The LV endomyocardial biopsy showed moderately hypertrophied cardiomyocytes  with intracellular vacuoles A and unaVacuoles were positive for GL3 by immunofluorescence microscopy C and preGLA mutation (c.666delC), 0% α-Gal-A activity and elevated Lyso-Gb3 , presented with ECG sinus rhythm, but short PR interval (110 ms), increased QRS voltages and moderate LV hypertrophy (MWT 16 mm at 2-D echo) with preserved end-diastolic diameter (50 mm) and EF (60%), associated with effort dyspnea. The major symptoms were, however, related to gastrointestinal tract consisting of diarrhea and weight loss: lately he reached the weight of 40 kg and developed iron-deficiency anemia . He had a sinus rhythm of 74 bts/min with short PR (115 ms) and increased QRS voltages at ECG. CMR showed a reduced T1 Mapping (T1 874–883 ms) indicating glycolipid accumulation and LGE positive areas in the LV lateral wall denoting fibrosis. The patient underwent a coronary angiography that showed normal arteries. An LV endomyocardial biopsy documented hypertrophied cardiomyocytes with large intracellular vacuoles on H&E stain that were positive for GL3 by immunofluorescence microscopy and contained myelin-like glycolipid bodies at TEM , 0% α-Gal activity and elevated plasma Lyso-Gb3 , was admitted because of palpitations, abdominal pain, diarrhea and weight loss (body weight 41 kg on admission). His blood pressure and ECG were normal, including PR duration (182 ms) and QRS voltages. Holter monitoring registered 7621 ventricular ectopic beats with 48 couplets and 2 triplets. The 2D-echo documented normal cardiac dimensions (LV end-diastolic diameter 45 mm), contractility (LVEF 59%) and wall thickness (LV-MWT 9 mm). The CMR showed , with normal α-Gal-A activity and plasma Lyso-Gb3 concentration , was admitted because of palpitations and severe diarrhea (up to 12 bowel movements per day), causing hypotension and syncope. Routine laboratory tests, including serum electrolytes (K + 3.7 Meq/L), iron and Hb, were within normal limits. ECG was normal, but Holter registered 4200 ventricular ectopic beats with 32 couplets and 5 triplets. The echocardiogram showed normal cardiac dimensions (LV end-diastolic diameter 49 mm), contractility (LVEF 62%) and left ventricular wall thickness (LV-MWT 8 mm). The CMR showed normal T1 mapping (1020 ms) and absence of LGE areas. Coronary angiography and LV endomyocardial biopsy were performed after informed consent to investigate the origin of electrical instability. Coronary arteries were normal, but the myocardial histology showed mildly hypertrophied cardiomyocytes (20-micron transverse diameter at nuclear level) containing perinuclear vacuoles on H&E stain that were positive for GL3 by immunofluorescence microscopy and were composed of enlarged lysosomes filled with myelin-like glycolipid bodies by TEM. Gastric and duodenal biopsies showed extensive GL3 accumulation in the intestinal cells. The patient started on agalsidase alpha at a dosage of 0.2 mg/kg every other week. After a few infusions, her diarrhea, palpitations and syncope disappeared. Holter registered 280 ventricular ectopic beats in 24 h with no repetitive activity. After 2 years of ERT, she had control CMR, endomyocardial and intestinal biopsies. The CMR findings were normal; however, the biopsy studies did not reveal any significant change in cardiomyocyte diameter or vacuolization by light microscopy, or GL3 accumulation by immunofluorescence or electron-microscopy. In contrast, the intestinal biopsy after 2 years of ERT showed no residual GL3 accumulation by light microscopy, IF or TEM.A 21-year-old normotensive girl from same family as above, , short PR interval at ECG and concomitant abdominal pain with diarrhea. The patient underwent CMR, denoting reduced values of T1 mapping to 950 ms in the absence of abnormal LGE signals.A 35-year-old normotensive man with c.658C > T mutation of The patient, after informed consent, underwent coronary angiography, LV endomyocardial biopsy, gastrointestinal endoscopy with gastric and duodenal biopsies. Histology and electron-microscopy confirmed Fabry cardiomyopathy with GL3 deposition in the intestinal cells. He received ERT in the form of agalsidase alpha at the dosage of 0.2 mg/kg intravenously every other week. His intestinal symptoms stopped after the second infusion, while his chest symptoms persisted. After 2 years, the patient was re-evaluated with CMR and intestinal and cardiac biopsy. While the CMR and cardiac pathologic findings were unmodified, the intestinal biopsy showed the absence of intracellular MLBs accumulation.This study, for the first time, provided a detailed histologic assessment of paired pre- and post-ERT intestinal and cardiac biopsies after 2 years of treatment with 0.2 mg/kg EOW agalsidase-α. In fact, to our knowledge, this is the first report of the effect of ERT on intestinal tissue GL3 accumulation in Fabry disease. Gastrointestinal symptoms, including abdominal pain, bloating, diarrhea, constipation, recurrent nausea and vomiting, are common among patients with Fabry disease and have been reported in up to 70% of males . These sLong-term follow-up studies and registry data suggest that ERT, especially if started early, may reduce the occurrence of cardiac events ,26,27,28Our study, for the first time, compares endomyocardial and intestinal biopsies obtained before and after 2 years of agalsidase-α administration and provides correlations with clinical evolution and non-invasive studies. Thus, while the clearance of GL3 inclusions was clearly visible in the intestinal epithelial cells, it could not be readily documented in cardiomyocytes that instead remain hypertrophied with prominent glycosphingolipid accumulation. Importantly, GL3 clearance from cardiomyocytes was not demonstrable even in patients with mild (Patients 1 and 2 and 6 with MWT < 15 mm) or pre-hypertrophic  cardiomyopathy where interstitial fibrosis was absent or very limited to interfere with access of infused enzyme to the cells. This novel observation raises important questions on the mechanism of action of ERT and on the opportunity to increase ERT dosage for the treatment of FD.On the other hand, we did not observe any significant increase in cardiomyocyte diameter or vacuolated surface area during the two years of treatment; while our study did not include any untreated controls, these findings suggest that ERT may stabilize the cardiomyopathy at least in its early phase. The general belief is that ERT provides its major clinical benefits in early stages of Fabry disease and may prevent or attenuate disease progression, concepts that would advocate for early diagnosis and initiation of treatment. In our study, disease stabilization, while failing to affect dyspnea, was associated with attenuation of arrhythmia. Thus, the frequency and complexity of ventricular ectopic beats were reduced and repetitive activities were disappeared in our patients after ERT. We do not have, at the moment, a clear explanation for arrhythmias improvement despite persistence of intracellular Gb3. We can speculate that reduced interstitial glycolipids, particularly those around cells of conduction tissue, might have had a beneficial role.Our study clearly demonstrates a heterogeneous response to ERT on human cardiomyocyte and enterocyte. This divergent response appears to be more cell dependent rather than organ dependent. Podocytes and arterial smooth muscle cells are more resistant to ERT compared with endothelial cells, mesangial cells or fibroblasts in the kidney. Arterial smooth muscle cells in the skin and cardiomyocytes in the heart show more resistance to ERT compared to endothelial cells in the same tissues. One could speculate different reasons for these differences. IGF-II-R is the major intracellular carrier of α-Gal A, and, thereby, it is likely to have a response to ERT and the removal of GL3 in Fabry cells. The current study documented that IGF-II-R expression in enterocytes, which exhibit complete GL3 clearance after ERT, is overexpressed, while it is remarkably reduced in cardiomyocytes presenting values 7-fold lower than normal controls . InteresThese results are supportive of a role for IGF-II-R expression in heterogeneous response of different cell types to ERT. Understanding pathways involved in IGF-II-R expression may offer insights for novel therapies targeting ERT-resistant cells, such as cardiomyocytes. In addition, the exogenous enzyme may not be easily accessible to podocytes, cardiomyocytes or smooth muscle cells, due to the barrier created by the extracellular matrix between these cells and the blood, as opposed to the endothelial cells. Cellular turn over may play a significant role in the observed clearance from GL3 following ERT, a concept that has not been examined. Cardiomyocytes and podocytes are both post-mitotic cells, and vascular smooth muscle cells have a longer lifespan than endothelial cells. The turnover of cardiomyocytes is estimated to be about 1% per year at age 20 year and 0.3% at age 75 . NajafiaGLA mutations  were represented in our study, both of which had been reported to cause classic Fabry phenotype [Our study had several limitations. Only two henotype ,34. The The study suggests a different impact of ERT on human tissues affected by classic FD. A total of 0.2 mg/kg EOW of agalsidase-α for 2 years clears intestinal enterocytes from GL-3 inclusions, paralleled by improvement of gastrointestinal symptoms. In contrast, cardiomyocytes remain hypertrophic and retain their GL-3 content. This divergent response may be related to different cellular turnovers and different expression of IGF-II-R, which is the major intracellular carrier of α-Gal A.


Saturated and unsaturated pyrrolizidine alkaloids (PAs) are present in more than 6000 plant species growing in countries all over the world. They have a typical heterocyclic structure in common, but differ in their potential toxicity, depending on the presence or absence of a double bond between C1 and C2. Fortunately, most plants contain saturated PAs without this double bond and are therefore not toxic for consumption by humans or animals. In a minority of plants, however, PAs with this double bond between C1 and C2 exhibit strong hepatotoxic, genotoxic, cytotoxic, neurotoxic, and tumorigenic potentials. If consumed in error and in large emouns, plants with 1,2-unsaturated PAs induce metabolic breaking-off of the double bonds of the unsaturated PAs, generating PA radicals that may trigger severe liver injury through a process involving microsomal P450 (CYP), with preference of its isoforms CYP 2A6, CYP 3A4, and CYP 3A5. This toxifying CYP-dependent conversion occurs primarily in the endoplasmic reticulum of the hepatocytes equivalent to the microsomal fraction. Toxified PAs injure the protein membranes of hepatocytes, and after passing their plasma membranes, more so the liver sinusoidal endothelial cells (LSECs), leading to life-threatening hepatic sinusoidal obstruction syndrome (HSOS). This injury is easily diagnosed by blood pyrrolizidine protein adducts, which are perfect diagnostic biomarkers, supporting causality evaluation using the updated RUCAM . HSOS is clinically characterized by weight gain due to fluid accumulation , and may lead to acute liver failure, liver transplantation, or death. In conclusion, plant-derived PAs with a double bond between C1 and C2 are potentially hepatotoxic after metabolic removal of the double bond, and may cause PA-HSOS with a potential lethal outcome, even if PA consumption is stopped. Patients with acute or chronic liver diseases represent a clinical challenge if toxins are suspected, as possible causes are diverse, such as plant-derived 1,2-unsaturated pyrrolizidine alkaloids (PAs) ,4,5,6, vMuch progress has been made within the last years regarding 1,2-unsaturated PAs metabolic conversion in liver cells via the microsomal cytochrome P450 (CYP) isoforms to toxic intermediates, injurious, mainly, to liver sinusoidal endothelial cells (LSECs) as the target cells of HSOS, differing thereby from other toxins attacking primarily liver parenchymal cells rather than the LSECs. In the past, HSOS was difficult to diagnose, an issue now solved by diagnostic advances in new biomarkers, evidence based diagnostic criteria, and the use of robust causality assessment methods such as the RUCAM  as part of artificial intelligence (AI) principles.In the present review article, we focus on recent developments on the molecular and metabolic events leading to PA-induced HSOS and its worldwide occurrence as sporadic cases or major disease clusters. Finally, the most important clinical features will be discussed.The PubMed database was searched for articles published preferentially during the last 5 years, in line with requirements of the editorial office by using the following key terms: herb-induced liver injury (HILI); hepatic sinusoidal obstruction syndrome (HSOS); pyrrolizidine alkaloids (PAs); Roussel Uclaf Causality Assessment Method (RUCAM). Only reports in English were selected and incorporated in this review article, containing the most relevant and recent publications, with the limitation that some important earlier publications could, regretfully, not be included.Based on compelling evidence that 1,2-unsaturated PAs may cause toxicity, including liver injury dependent on the dose and duration of uptake, attempts to define the risk for humans exposed to PAs have been made in 2016 by the German Federal Institute for Risk Assessments (BfR in short for Bundesinstitut für Risikobewertung) , in 202010 (Bench Mark Dose Lower Confidence Limit), risk assessment by the EFSA deduced a BMDL10 of 237 μg/kg for all 1,2-unsaturated PAs, assuming equal potency , si, si23], n salads . A cautiThere is also a long tradition in Germany, particularly in and around Frankfurt am Main, to consume the so called “Frankfurt green sauce” prepared from seven herbs: borage, burnet, chervil, chives, cress, parsley, and sorrel . The leaBread may contain PAs if grain was used contaminated with PA-producing seeds that are co-harvested with grain ,23. UndeTussilago farfara), comfrey , borage , climbing groundsel (Senecio scandens), and sunn hemp  ..37].It seems that PA toxicity of extrahepatic organs is triggered by PA-related events in the liver cells, as shown at least in experimental PA studies on lung injury, which depends on the metabolism by hepatic CYPs and the blood transport of reactive metabolites . HoweverN atom of the methyl substituent of the otonecine-type PAs, but this step is only a defined precursor step of the formation pathway of toxic DHPAs and does not cause the toxic potential of 1,2-unsaturated PAs , a, a211], Much progress was achieved with the establishment of diagnostic biomarkers using blood pyrrole-protein adducts (PPAs) ,223,224,Diagnostic options include ultrasonography, Doppler ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), and digital subtraction angiography ,229,230.Partially confirming results by ultrasonography and Doppler sonography, typical signs obtained by CT are ascites, liver enlargement syn. hepatomegaly, and thickening of the gallbladder wall, while splenomegaly is a rare finding. MRI provides different information with focus on liver hypointensity or hypoattenuation during the hepatobiliary phase and enhancement around the portal veins during the portal venous phase . For spePrevious invasive diagnostic approaches, like biopsies of the liver in patients with suspected PA-HSOS, were helpful and clinically indicated to assist define the liver injury, using specific typical histological features to confirm the diagnosis  Yet, todPrevious results on liver histology allow for summarizing some important features ,211,229:Although light microcopy provided some interesting findings, data obtained by electron microscopy might provide additional insight information. An electron microscopy study in Jamaican children with PA-HSOS showed hepatocyte alterations, inluding dilatation of the bile canaliculi, abundant glycogen, nuclear invagination, and naked hepatocytes with a reduction of microvilli . In a moRUCAM is worldwide used to assess causality in 95,885 cases of both DILI and HILI , with adAs a reminder, many details are available in instructions regarding how best to apply the updated RUCAM and how to handle specific questions and conditions that may emerge during causality assessments using RUCAM . Well-acApart from the cessation of PA exposure, symptomatic management of the ascites is the primary therapeutic goal, achieved by restriction of fluid and salt (sodium) intake, a diet rich in proteins, and drug treatment with spironolactone . For refEpidemiological evidence is lacking for increased risks of humans consuming regularly low doses of PAs contaminating foodstufff, teas and herbal infusions . HoweverThreatening is the occurence of human toxicity by higher amounts of PAs, resulting in embryo or fetal PA-HSOS, described in a preterm newborn with hepatomegaly and fetal ascites, diagnosed upon sonography examination, while the mother underwent a Cesarean section because of risky fetal asphyxia with newborn death shortly after birth . AutopsyA major clinical challenge was a recently published case of a 22 year old female Chinese patient, who was diagnosed with HSOS of unknown etiology, but in retrospect, was likely due to PAs, as she was not on drugs that could have caused HSCT-HSOS . She recThe very early literature on PA-HSOS in adults commonly presents case reports of limited value, often lacking a robust causality assessment, and current biomarker such as PPAs were not available at that time. Considering the experimental studies and PA-HSOS cases published recently ,249,250,Senecio brasiliensis as prescribed by a local healer for menopausal symptoms. Causality assessment using the updated RUCAM provided a score of six, in line with a probable causality grading. Imaging and liver histology data were suggestive of PA-HSOS. Although the use of Senecio brasiliensis was immediately stopped, the clinical course was uneventful due to complications such worsening of the mental status in form of hepatic encephalopathy, acute respiratory distress syndrome requiring endotracheal intubation for mechanical respiration, oliguria demanding hemodialysis, spontaneous bacterial peritonitis, sepsis, mesenteric ischemia, confirmed by explanatory laparotomy and requiring resection of the necrotic small bowel segment. Death occured on day 25 after admission. This case clearly shows the problems of using a PA-containing plant for menopausal symptoms as a minor ailment, for which not only data on RCTs are missing, but also an imbalance exists regarding the benefit–risk constellation.A 54-year-old female patient with asthenia, malaise, jaundice, ascites and bilateral effusion . Prior tGynura segetum provided a few details on the indications for which ailments or diseases this herbal medicine was used [A case series of five patients with PA-HSOS due to was used . IndicatGynura segetum for unknown indication but it was mentioned that this TCM plant is commonly used for treating traumatic injury [The 68-year-old female patient used c injury . PA-HSOSGynura segetum for traumatic injuries [Gynura sgetum, but the Nanjing criteria or RUCAM were not used to firmly estabilish the diagnosis. It was argued that liver biopsy would have been needed to make a definite diagnosis of HSOS, a proposal not necessarily shared by others. Alcoholic liver disease was not considered as alternative diagnosis [The 46-year-old man had consumed 200 mL spirits on a daily basis for the last 10 years and had recently used large amounts of injuries . He was iagnosis , althougiagnosis . The cliiagnosis .The 43-year-old male patient had consumed 450 mL of 30% alcohol, daily, for 20 years and consumed 150 g of medicinal liquor containing Gynura segetum for ten days before developing symptoms . The diaGynura segetum [The 83-year-old male patient had a long history of using TCMs, such as  segetum . The diaGynura japonicum, blood PDAs were found, raising the question whether similar results can be achieved in humans. Second, in a subsequent study comprizing 18 patients with RUCAM based PA-HSOS caused by the consumption of Gynura japonica in form of decoction, herbal wine, or ground powder, PDAs were evaluated to diagnose PA genotoxicity and define the early tumorigenic risk in patients [Substantial progress is evident from recent clinical studies on implementing RUCAM in additional PA-HSOS cases and and evaluations of blood pyrrole-DNA adducts (PDAs) . First, patients . PDAs weOther clinical data, including those related more specifically to studies on the updated RUCAM, are highly appreciated and of special interest. For instance, in 11/18 patients (61%) RUCAM scores were 6-8 in line with a probable causality grading, whereas scores of 9–10 were even higher in 7/18 patients (39%), suggesting a highly probable causality grading . The uneGynura japonica and established diagnosis using the updated RUCAM [Gynura japonica was used for 10–20 days by most of the patients (44%), followed by 28% who used it for 1–2 months. All patients received a treament by anticoagulant medications, 67% of the patients were treated by TIPS. Finally, laboratory tests were given as median values and ranges for ALT , AST , total bilirubin  and ALP . The listing of the reference range for each parameter is also perfect. As a result, RUCAM helped provide a solid base for various characteristic features of this disease.Additional demographic details were presented in these patients with PA-HSOS caused by ed RUCAM . Among tPetasites hybridus from the Asteraceae familiy, used as an effective prophylaxis of migraine attacks [Petasites hybridus is listed as a PA-containing herbal medicine  area and a non-affected adjacent area (control) using a structured questionnaire , showing thrived . In addiSenecio seeds containing PAs [In Iraq, a small HSOS outbreak comprizing 14 patients was reported, who consumed wheat accidently contaminated with ning PAs . Clinicaning PAs .®) was found in 19 patients with and without human immunodeficiency virus (HIV) infections, who used a variety of PA-containing plants preferentially from the Asteraceae, Fabaceae, and Lamiaceae families [In Uganda, liver fibrosis as assessed with transient elastography , Boraginaceae , Compositae , and Leguminosae . Further studies on its relevance under field conditions are required, for the fascinating Selmar concept of horizontal PA transfer from PA-producing PAs reaching the soil and being taken up by non-PA-containing plants via their roots.PA-HSOS is primarily a vessel disease of the liver. The diameters of the veins within or approaching the liver are decreased, reducing the blood flow into the liver and causing a backlog by extravasation of fluids into the abdominal cavity, clinically known as ascites, the leading diagnostic feature. LTs like ALT or AST are variable, either within the normal range or moderately increased, conditions that impede early diagnosis of incipient PA-HSOS. It does not seem that the users of small amounts of unsaturated PAs found in foodstuffs in Western countries are at risk of PA-HSOS. On the contrary, following the consumption of larger amounts of PAs cases of PA-HSOS were published as single case reports, small series, or case clusters. Clusters of PA-HSOS were due to foodstuff and drinking water contaminated with unsaturated amounts of PAs, published from countries like Afghanistan, India, Tadjistan, Ethiopia, and Iraq. Single case reports came from several countries, case series preferentially from China, where intoxications by the PA-containing Apart from cessation of PA exposure, symptomatic management of the ascites is the primary therapeutic goal. For refractory ascites, therapeutic options may include anticoagulant therapy, transjugular intrahepatic portosystemic shunt, and liver transplantation, but robust data derived from RCTs are limited. Independent prognostic factors for patients with PA-HSOS are serum albumin, serum urea, and severity grading, facilitating early intervention in patients at risks. Two thirds of the patients with PA-HSOS will recover and one quarter will experience a chronic course of the disease. The lethality rate, ranges from 10% to 40% and is due to liver failure. For the future, prevention of PA-HSOS should be the main goal to reduce the number of PA-HSOS patients, and correct diagnosis using the updated RUCAM for causality assessment is essential.In essence, plants produce, via the homospermidine synthase, various unsaturated PAs, representing multicyclic chemicals with a double bond between C1 and C2, which is broken up in the human liver via the dehydrogenation pathway into toxic radical DHPAs, culprits for the initiation and perpetuation of the severe liver injury called HSOS.


A cardiomiopatia hipertrófica (CMH) e a hipertrofia ventricular esquerda (HVE) secundária à hipertensão arterial sistêmica (HAS) podem estar associadas a anormalidades funcionais do átrio esquerdo (AE). Caracterizar a mecânica do AE na CMH e na HAS e avaliar qualquer correlação com a extensão da fibrose ventricular esquerda medida por ressonância magnética cardíaca (RMC) em pacientes com CMH.speckle tracking foi adquirida a partir de cortes apicais de 60 pacientes com CMH e 34 indivíduos controles, pareados por idade. Pacientes com CMH também foram submetidos à RMC, com medida da extensão do realce tardio por gadolínio. A associação com parâmetros de strain do AE foi analisada. Valores p < 0,05 foram definidos como estatisticamente significativos. A função longitudinal do AE derivada do ecocardiograma bidimensional com strain rate do AE nas fases de reservatório (SRrAE) e na fase contrátil (SRctAE) foram os melhores parâmetros de discriminação de CMH com uma área sob a curva (AUC) de 0,8, seguido do strain do AE na fase de reservatório (SrAE) . O SRrAE e o SRctAE apresentaram elevada especificidade , e o SrAE apresentou sensibilidade de 80%. Um decréscimo de 2,79% no strain rate do AE na fase de condução (SRcdAE) foi preditor de um aumento de 1 cm na extensão do RT pelo gadolínio . A média da fração de ejeção do ventrículo esquerdo não foi diferente entre os grupos. A razão E/e’ estava comprometida no grupo CMH e preservada no grupo controle. A mecânica do AE estava significativamente reduzida na CMH em comparação aos pacientes com HAS. O  O SRrAE e o SRctAE foram os melhores fatores de discriminação de HVE secundária à CMH. O SRcdAE foi preditor do grau de fibrose ventricular esquerda avaliada por RMC. Esses achados sugerem que a mecânica do AE pode ser um potencial preditor de gravidade de doença na CMH. Além disso, o remodelamento do AE é uma característica comum tanto da CMH como da HAS.10 A função do VE correlaciona-se com sintomas da insuficiência cardíaca na CMH e é forte preditora do desenvolvimento de fibrilação atrial (FA).12Uma vez que o AE está relacionado com o desempenho do VE dadas as suas funções de reservatório durante a sístole ventricular, condução durante a diástole ventricular precoce, e bombeamento durante a diástole ventricular tardia, a miopatia do AE poderia estar associada a desfechos independentemente da função do VE.speckle tracking (2D-STE) tem se mostrado um marcador viável e reprodutível para a função do AE.14A avaliação da mecânica do AE por meio do ecocardiograma bidimensional com 2 o grau de disfunção do AE em diferentes estados de HVE  não é totalmente entendido. Tanto a hipertrofia como a fibrose ventricular esquerda representam substratos da disfunção diastólica, e podem estar associadas à disfunção do VE na CMH. Assim, o presente estudo teve como objetivo (1) caracterizar os mecanismos do AE em pacientes com CMH e HAS com HVE significativa e (2) correlacionar a função do AE com fibrose do VE avaliada por RMC em pacientes com CMH.Apesar de a HVE parecer ser o principal fator de disfunção na mecânica do VE,Este estudo observacional retrospectivo incluiu 60 pacientes diagnosticados com CMH (diagnóstico confirmado por RMC) e 60 pacientes hipertensos recrutados no ambulatório de nosso departamento. Excluímos pacientes com CMH obstrutiva, com janela acústica inadequada, FA identificada no eletrocardiograma basal, doença valvular grave ou moderada, doença cardíaca isquêmica, ou hipertensão pulmonar definida como pressão sistólica da artéria pulmonar (PSAP) > 45 mmHg. Os pacientes foram diagnosticados com HAS cerca de 4,2 ± 2,3 anos antes. Como controle, incluímos 34 pacientes sadios sem HAS, FA ou doença valvular, pareados por idade com pacientes com CMH e HAS.Nós analisamos dados clínicos e ecocardiográficos de participantes divididos nos grupos CMH, HAS e controle. Dados de RMC dos pacientes com CMH no momento do diagnóstico também foram avaliados. Imagens ecocardiográficas foram coletadas 43±18 dias após o diagnóstico de CHM por RMC. O estudo foi aprovado pelo comitê científico e pelo comitê de bioética do Centro Hospitalar e Universitário de Coimbra , e foi conduzido de acordo com a Declaração de Helsinki.strain longitudinal global (SLG). Utilizamos um aparelho de ultrassom cardiovascular Vivid 7  com um transdutor de imagem harmônica tecidual. Cortes ecocardiográficos padrões foram obtidos com otimização da taxa de quadros (60-80 fps em imagens 2D). Realizamos uma análise offline dos dados ecocardiográficos utilizando um programa específico .Foi realizado um estudo bidimensional completo em todos os participantes, incluindo 2D-STE do VE e do AE com análise do 15 O SLG do VE, derivado do EST, foi obtido usando um modelo de segmentação (em 16 segmentos) do VE.16 Foi também avaliada a função diastólica, incluindo velocidade E mitral, velocidade A mitral, e razão E/’ média.A avaliação do tamanho e da função sistólica do VE, incluindo a medida da fração de ejeção do VE (FEVE), diâmetro diastólico final do VE (DDFVE), e diâmetro sistólico final do VE (DSFVE), seguiu as recomendações atuais.18 com análise offline das curvas do strain longitudinal de cada segmento atrial usando um programa específico18 , no início da diástole (ScdAE e SRcdAE), e no final da diástole (SctAE e SRctAE) foram medidos como indicadores das funções de reservatório, condução, e contração do AE, respectivamente.18A análise da mecânica do AE por 2D-STE foi realizada conforme recomendado previamente,ífico18   . Para ostrain e strain rate por 2D-STE, obtidas de 37 pacientes com CMH selecionados aleatoriamente, foram realizadas por um segundo investigador (JAF) e comparadas com aquelas do primeiro observador (PMA).Para análise da reprodutibilidade entre observadores, as medidas de O primeiro observador repetiu as medidas nos mesmos 37 participantes, e a reprodutibilidade intraobservador foi então avaliada. Os observadores avaliaram diferentes regiões de interesse do AE e desconheciam (eram cegos a) as medidas anteriores.4 As imagens de RT com gadolínio foram adquiridas 10-20 minutos após administração endovenosa do contraste, como recomendado.2 A quantificação do RT foi realizada por ajuste manual do limiar de escala de cinza, para definir áreas de RT identificadas visualmente nos planos do eixo-curto e medidas em centímetros de extensão.Todos os 60 pacientes com CMH foram submetidos à RMC, realizada com aparelhos de 1.5 T , utilizando-se protocolos padrões, como sugerido previamente.one-way . Após rejeitar-se a hipótese nula, o teste de comparação múltipla de Bonferroni foi realizado. Para cada variável com distribuição não normal, a homogeneidade da variância foi avaliada utilizando o teste de Levene. Para as variáveis categóricas, utilizou-se o teste do qui-quadrado ou o teste exato de Fisher, conforme apropriado. Regressão linear foi usada para correlacionar vários parâmetros contínuos. Pressupostos para a regressão linear foram verificadas antecipadamente – relação linear entre os dados foi visualmente avaliada por gráficos de dispersão; não foram detectados outliers ; a autocorrelação foi excluída pelo teste de Durbin-Watson; a homogeneidade da variância dos resíduos (homoscedasticidade) também foi verificada visualmente em gráficos de resíduos versus valores ajustados. Análise de curvas da Característica de Operação do Receptor (curvas ROC) foi realizada para se estimar o poder discriminatório dos parâmetros da mecânica do AE na CMH versus HA. As curvas foram comparadas pelo método Delong. Para a avaliação da variabilidade entre observadores e intraobservador das medidas de strain e strain rate foram utilizados método Bland-Altman, coeficiente de correlação intraclasse, e coeficiente de variação. Valores p < 0,05  foram considerados como estatisticamente significativos. As análises estatísticas foram realizadas utilizando o programa Stata IC para Windows . Em relação ao tamanho amostral, planejamos um estudo de uma variável de resposta contínua em pacientes e controles independentes, na proporção de 0,5 indivíduos controle por paciente. Na análise da mecânica do AE ( strain do na fase de reservatório e na fase de contração), a resposta desejável em cada grupo é normalmente distribuída com um desvio padrão de cinco.10 Se a diferença entre pacientes e controle fosse quatro, necessitaríamos de 51 pacientes e 26 controles para conseguirmos rejeitar a hipótese nula de que as médias populacionais dos grupos experimental e controle fossem iguais com uma probabilidade (poder) de 0,9. A probabilidade de se cometer um erro do tipo I associado com esse teste com essa hipótese nula é de 0,05. Poderíamos ainda incluir 60 pacientes com CMH e 60 pacientes com HAS para melhorar o poder estatístico do estudo.A normalidade da distribuição das variáveis contínuas foi avaliada por análise do histograma e o teste de Kolmogorov-Smirnov. As variáveis contínuas foram expressas em média ± desvio padrão, e as variáveis categóricas expressas em frequência (porcentagem). Diferenças entre grupos foram avaliadas pela análise de variância (ANOVA) As características clínicas da população do estudo estão resumidas na No grupo com CHM, observou-se um uso maior de betabloqueadores, enquanto no grupo com HAS, observou-se uma maior prescrição de inibidores da enzima conversora de angiotensina (IECA) e bloqueadores de receptores da angiotensina (BRA).As características ecocardiográficas dos participantes estão resumidas na Em relação à função diastólica do VE, a velocidade mitral E não variou entre os grupos, e a velocidade A foi maior no grupo HAS. Valores anormais da razão E/e’ foram encontrados no grupo com CMH e, no grupo controle, essa razão estava preservada.strain (mas não o strain rate ) na fase de contração estava alterado nos pacientes com HAS  significativamente maiores   . Os parcom HAS   .Todas as fases de deformação do AE estavam significativamente reduzidas no grupo CMH que no grupo HAS   . De tod2, a espessura média do septo interventricular (SIV) foi 18,7±3,5 mm. Aproximadamente 34% dos pacientes apresentaram movimento sistólico anterior da valva mitral, e 12% dos pacientes apresentaram CMH apical. RT com gadolínio foi observado em 52 (87%) dos pacientes com CHM, e a média da área de extensão foi de 2,8 cm.Todos os pacientes com CMH foram submetidos à RMC (método padrão-ouro para o diagnóstico). O volume diastólico final indexado (VDFi) médio foi 96±32 mL/mA strain a strain rate do AE.Os parâmetros de deformação do AE mostraram valores de coeficiente de correlação intraclasse de 0,64 a 0,94, indicando uma boa a excelente reprodutibilidade dessas medidas (Tabela suplementar). Os gráficos de Bland-Altman revelaram uma discrepância muito baixa entre observadores    e intra19 Conseguimos demonstrar que a mecânica do AE está diminuída tanto na HAS como na CMH. A função do AE está prejudicada na CMH ao se comparar com a HAS  e um pior desfecho nos pacientes com CMH, com uma correlação linear entre SrAE e níveis de peptídeo natriurético tipo-B.21O comprometimento na função de reservatório do AE é acompanhado por uma deterioração da função do VE, e é maior nos pacientes com CHM que nos pacientes com HA. A redução na função de reservatório do AE na CHM está relacionada à disfunção longitudinal do VE, devido à diminuição da sístole na base do VE, o que leva a um comprometimento no relaxamento e consequente rigidez do AE.20 Em nosso estudo, o SRcdAE foi o parâmetro que melhor se correlacionou com a extensão da fibrose do VE. Tal fato deve-se provavelmente à redução da complacência do VE devido à fibrose do miocárdio, com redução da função de condução atrial na CMH.Apesar de a função de condução do AE estar associada à função sistólica do VE (dissincronia ventricular), ela está relacionada à extensão de hipertrofia.2 Isso pode estar relacionado ao fato de que 87% dos nossos pacientes com CMH já apresentavam RT com gadolínio na RMC e, assim, possível comprometimento da função contrátil do AE.A fase contrátil do AE também esteve comprometida na CMH, o que é de certa forma inconsistente com estudos prévios que mostraram uma tendência de aumento (embora não estatisticamente significativo) da função contrátil e de bombeamento na CMH com ausência de fibrose do VE.strain do VE anormal.22 Tal fato pode sugerir que a fibrose do AE seja secundária ao remodelamento do VE e aumento da pressão de enchimento. Apesar de a mecânica do AE não ter sido investigada por 2D-STE no presente estudo, podemos relacionar esses achados com nossos resultados sobre a mecânica do AE: comprometimento das funções de reservatório e contrátil, e uma correlação entre função de condução e extensão da fibrose do VE.Quanto à presença de fibrose, um estudo mostrou uma correlação significativa entre o RT por gadolínio do AE e do VE na RMC, bem como um strain do AE. Contudo, o IPM não foi preditivo do desfecho, diferentemente do strain do AE.23Apesar de a disfunção do VE, avaliada pelo SLG do VE, estar muito presente no grupo com CMH, não se observou uma relação com fibrose do VE. Outro parâmetro da disfunção do VE, o índice de performance miocárdica (IPM), também está comprometido na CMH e está relacionado com o 24 Ainda, o strain e o strain rate foram melhores preditores de cardiomiopatias.24 Tal fato sugere que a mecânica do AE seja um marcador mais precoce tanto de disfunções atrial como miocárdica. Além disso, em pacientes com HAS e HVE significativa, nos quais a exclusão de CMH pode ser um desafio, a avaliação da mecânica do AE pode ser útil, uma vez que as três fases  não estão afetadas nesse grupo. Em nosso estudo, apesar de estatisticamente mais baixos em comparação a pacientes com CMH, os valores da espessura do SIV na nossa coorte de pacientes hipertensos ainda estavam elevados .Ao avaliar a disfunção diastólica na CMH versus HAS, observamos que o VAEi e as velocidades E e A mitral não foram diferentes entre os grupos. Tal fato demonstra a importância da mecânica do AE como um fator discriminante de miopatia do AE, a qual está comprometida mesmo antes de uma dilatação atrial esquerda. Ainda, esse dado estabelece valores basais de deformação do AE, que não sejam influenciados por outros fatores tais como FA (excluída) ou dilatação atrial esquerda importante. Com a progressão da doença, podemos esperar que a deformação do AE piora com a dilatação do AE, apesar de não termos provado isso em nosso estudo. Apesar dos diferentes valores da relação E/E’, o parâmetro não foi um bom parâmetro de discriminação entre os grupos e não se correlacionou com a extensão da fibrose miocárdica do VE na CMH. A mecânica do AE parece mais um fator discriminatório entre os grupos com HVE e está relacionada ao grau de fibrose miocárdica do VE na CMH. Esses achados também foram relatados em outras cardiomiopatias, em que não se observaram diferenças nos valores de E/E’ ou VAEi entres os três grupos de cardiomiopatia .strain e o strain rate do AE são fatores discriminatórios potenciais entre CMH e HAS, não somente na resposta fisiológica à HVE como determinantes da disfunção. As implicações clínicas para o uso do strain rate do AE para o diagnóstico de CMH em pacientes com HVE ainda são incertas, uma vez que a RMC é o método de imagem mais preciso. Contudo, pudemos demonstrar que a mecânica do AE foi um fator discriminatório mais forte de HVE secundária à CMH quando comparada a outros parâmetros clássicos, como o VAEi, razão E/E’, e mesmo espessura do SIV (Tabelas 2 e 3). Ainda, observou-se uma correlação moderada entre a mecânica do AE e a extensão de fibrose do AE na CMH, o que poderia se tonar um marcador de gravidade e prognóstico em estágios iniciais ou casos duvidosos.Em nosso estudo, demonstramos que o strain foi dedicado à análise do strain do VE, e não do AE, o que poderia distorcer de alguma forma nossos resultados.Nosso estudo tem várias limitações. Primeiro, o programa usado para a análise de Segundo, a heterogeneidade da população do nosso estudo, com diferentes comorbidades, pode afetar os resultados obtidos. O fato de que uma maior proporção de pacientes hipertensos apresentou diabetes e obesidade poderia afetar a análise da mecânica do AE, devido à piora na função diastólica do VE. No entanto, essa é uma associação intrínseca que não pôde ser excluída, uma vez que há poucos pacientes que apresentassem HAS como o único fator de risco cardiovascular. A maioria dos pacientes eram adequadamente tratados com IECA e BRA, o que poderia ter afetado a remodelação do VE e compensado a disfunção sistólica nesses pacientes. Em contraste, os betabloqueadores na CMH não afetam diretamente a remodelação do VE, não influenciando, assim, a função diastólica do VE ou a mecânica do AE. No entanto, nós não pudemos avaliar se, e em que extensão tal fato tenha ocorrido. Contudo, a partir de uma comparação direta de dois grupos heterogêneos de pacientes do mundo real com HA ou CMH, podemos avaliar as detectar diferenças na mecânica do AE entre esses dois grupos, conforme observado na prática diária.25 demonstrou que pacientes com CMH com FA paroxística podem apresentar um maior grau de miopatia do AE que pacientes sem FA. Em nosso estudo, apesar de termos excluído pacientes com FA no eletrocardiograma basal, é possível a existência de pacientes com FA paroxística que não tenham sido identificados, com um fenótipo cardíaco mais grave, que não foram totalmente caracterizados em nossa análise.Terceiro, um estudostrain do AE como um fator de discriminação preciso.Quarto, nós não temos a validação externa dos pontos de corte propostos, de modo que não podemos sugerir propriamente o uso do Quinto, não incluímos pacientes com HAS na análise de variabilidade, o que seria importante para avaliar realmente a reprodutibilidade de todos os parâmetros.strain rate do AE nessa população. No entanto, este estudo tentou esclarecer a mecânica da deformação do AE na HVE secundária à CMH e à HAS. Mais estudos com um tamanho amostral maior são necessários para esclarecer o valor prognóstico do strain rate do AE na HVE.Finalmente, uma vez que este foi um estudo baseado em desfechos, não podemos tirar conclusões acerca do valor prognóstico do A mecânica do AE está globalmente comprometida na HVE secundária à HAS e à CMH. Em comparação à HAS, os melhores fatores de discriminação de CMH foram SRrAE e SRctAE. No entanto, o SRcdAE correlacionou-se melhor com o grau de fibrose do VE avaliada por RMC nos pacientes com CMH. Esses achados sugerem que a mecânica do AE pode ajudar na diferenciação de HVE entre HAS e CMH e ser um preditor potencial de gravidade da doença na CMH.Para informação adicional, por favor, clique aqui. 2 In HTN, LVH occurs as a response to pressure overload, and in HCM, a complex remodeling process is initiated as a response of cardiomyocyte and noncardiomyocyte components to dynamic mechanical and neurohumoral stimuli.3 HCM is an autosomal-dominant disorder, associated with mutations in sarcomeric genes, affecting the atrial and ventricular myocardium.2Left ventricular hypertrophy (LVH) present in hypertrophic cardiomyopathy (HCM) and arterial hypertension (HTN) is often related to myocardial dysfunction and increased risk of sudden death.4 Quantitative LV LGE characterizes HCM stages, LV remodeling and systolic dysfunction and is an important predictor of sudden death.5 Systolic dysfunction commonly occurs in end-stage HCM, and a significant portion of patients have some extent of diastolic dysfunction.6Cardiovascular magnetic resonance (CMR) allows a thorough description of HCM-related LVH and fibrosis, by means of late gadolinium enhancement (LGE).7 Furthermore, LA size and volume have been shown to be determinants of exercise capacity8 and of major adverse cardiac and cerebrovascular events in HCM patients.9Increased LV mass and diastolic dysfunction are associated with progressive left atrial (LA) dilatation and dysfunction. Accordingly, LA remodeling is a common feature in both HCM and HTN.10 LA function is correlated with heart failure symptoms in HCM and is a strong predictor for the development of atrial fibrillation (AF).12Since the LA is related to LV performance by its reservoir function during ventricular systole, conduit function during early ventricular diastole, and booster pump function during late ventricular diastole, LA myopathy could be associated with outcomes independent of LV function.14The assessment of LA mechanics using two-dimensional (2D)-speckle tracking echocardiography (STE) has been shown as a feasible and reproducible marker for LA function.2 the degree of LA dysfunction in different states of LVH  is not fully understood. LVH and fibrosis, both representing substrates of LV diastolic dysfunction, might be associated with LA dysfunction in HCM. Therefore, this study aimed (1) to characterize LA mechanics in HCM and in HTN patients with significant LVH and (2) to correlate LA function with LV fibrosis assessed by CMR in HCM patients.Although LVH seems to be the major factor of dysfunction in LV mechanics,This retrospective observational study included 60 patients diagnosed with HCM (diagnosis confirmed by CMR) and 60 HTN patients recruited from our outpatient department. We excluded patients with obstructive HCM, poor acoustic window, AF identified in the basal electrocardiogram, moderate or severe valvular disease, ischemic heart disease, or pulmonary hypertension defined as pulmonary artery systolic pressure (PASP) >45 mmHg. Patients were diagnosed with HTN about 4.2±2.3 years before. As controls, we included 34 healthy individuals without HTN, AF, or valvular disease, age-matched to HCM and HTN patients.We analyzed clinical and echocardiographic data of participants divided into the HCM group, HTN group, and control group. Data from CMR of HCM patients at the time of diagnosis were also assessed. Echocardiographic images were collected 43±18 days after HCM diagnosis was made by CMR. Echocardiographers were blinded to CMR results. The study was approved by the scientific and bioethics committees of Coimbra Hospital and University Center  and was performed in accordance with the Declaration of Helsinki.A complete two-dimensional echocardiographic investigation was performed in all participants, including LV- and LA-STE with global longitudinal strain (GLS) analysis. We used a Vivid 7  cardiovascular ultrasound device, with a 1.7/3.4-MHz tissue harmonic transducer. Standard echocardiographic views were obtained with frame-rate optimization (60–80 fps in 2D imaging). We performed an offline analysis of echocardiographic data using a specific software .15 STE-derived LV-GLS was obtained using a 16-segment model of the LV.16 Diastolic function including mitral E velocity, mitral A velocity, and mean E/e’ ratio, was also evaluated.Assessment of LV size and systolic function, including measurement of LV ejection fraction (LVEF), LV end-diastolic diameter (LVDD), and LV end-systolic diameter (LVSD), followed the current recommendations.18 with offline analysis of the automatically averaged longitudinal strain curves for each atrial segment by specific software18  and compared with those of the first observer (PMA).The first observer repeated the measurements in the same 37 participants, and the intra-observer reproducibility was then assessed. The observers evaluated different regions of interest of the LA and were blinded to previous measurements.4 LGE images were acquired 10-20 min after intravenous administration of gadolinium as recommended.2All 60 HCM patients underwent CMR, performed with 1.5 T scanners  using standard protocols as suggested previously.Quantification of LGE was performed by manual adjustment of gray scale threshold, to define areas of visually identified LGE in short-axis planes and measured in centimeters (cm) of extension.Normality of the distribution of continuous variables was assessed by histogram analysis and the Kolmogorov–Smirnov test. Continuous variables were expressed as mean ± standard deviation, and categorical variables were expressed as frequency (percentage). Between-group differences were evaluated using one-way ANOVA. After rejecting the null hypothesis, the Bonferroni multiple comparison test was conducted. For each variable with non-normal distribution, the homogeneity of variance was assessed using the Levene test. For categorical variables, the chi-square test or the Fisher’s exact test was used, as appropriate. Linear regression was used to correlate several continuous parameters. Assumptions for linear regression were checked beforehand. Namely, a linear relationship between data was visually assessed using scatter plots; no outliers were detected; autocorrelation was excluded using the Durbin-Watson test; homogeneity of variance of the residuals (homoscedasticity) was also checked visually by plotting residuals versus fitted values. Analysis of receiver operating characteristic (ROC) curves was performed to compute the discriminative power of LA mechanics parameters in HCM versus HTN. The curves were compared using the Delong method. We used the Bland–Altman method, intraclass correlation coefficient, and coefficient of variation to assess the inter- and intra-observer variability of LA 2D-STE strain and SR measurements. Statistical significance was set at p-<0.05. Stata IC for Windows  and MedCalc for Windows  were used for the statistical analyses.10 If the true difference between experimental and control subject means is four, we would need 51 experimental subjects and 26 control subjects to be able to reject the null hypothesis that the population means of the experimental and control groups are equal with a probability (power) of 0.9. The type I error probability associated with this test of this null hypothesis is 0.05. We could further include 60 HCM patients and 60 HTN patients to further improve the statistical power of the study.Regarding sample size, we planned a study of a continuous response variable in independent control and experimental subjects, with 0.5 control(s) per experimental subject. In LA mechanics analysis (LA strain in reservoir and contractile phases), the desirable response within each subject group is normally distributed with a standard deviation of five.mellitus , dyslipidemia, and obesity.The clinical features of the study population are summarized in In the HCM group, there was a higher use of beta-blocker therapy, while in the HTN group, a higher prescription of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) was found.The echocardiographic characteristics of participants are summarized in Regarding LV diastolic function, mitral E velocity did not vary among groups, and mitral A velocity was higher lower in the HTN group than in the control group. E/e’ ratio was significantly impaired in the HCM group and preserved in the control group.Compared to controls, HCM and HTN patients had significantly larger LA volume indexed to the body surface area (LAVi)   . LA defAll LA deformation phases were significantly reduced in the HCM group than in the HTN group   . Of all2 , the mean interventricular septum thickness (IVS) was 18.7±3.5 mm. Approximately 34% of the patients had systolic anterior movement of the mitral valve, and 12% of the patients had apical HCM. LGE was present in 52 (87%) HCM patients, and the mean area of extension was 2.8 cm.All HCM patients underwent CMR (the gold standard method for diagnosis). The mean indexed end-diastolic volume (EDVi) was 96±32 mL/mThe parameters of LA deformation showed intraclass correlation coefficient values of 0.64 to 0.94, indicating good to excellent reproducibility of such measurements . The Bland–Altman plots revealed very small inter-observer    and int19 We could demonstrate that LA mechanics is globally decreased in both HTN and HCM. LA function is significantly impaired in HCM in relation to HTN  and worse outcome in HCM patients, with a linear correlation between LASr and B-type natriuretic peptide levels.21LA reservoir function impairment is accompanied by deterioration of LV function, and is greater in HCM than in HTN. The reduction in LA reservoir function in HCM is related to the LV longitudinal dysfunction, due to a reduction in the systolic descent of LV base, which leads to an impaired LA relaxation and stiffness.20 In our study, LASRcd was the parameter with the best correlation with the extent of LV fibrosis. This is probably explained by reduction of LV compliance due to myocardial fibrosis, with accompanying reduction of the atrial conduit function in HCM.Although LA conduit function is associated with LV systolic function (ventricular desynchrony), it is less related to the extent of hypertrophy.2 This might be related to the fact that 87% of our HCM patients already presented with LGE on CMR, so LA contractile function might already be compromised.LA contractile phase was also impaired in HCM, which is somewhat inconsistent with previous reports that showed a trend toward increased LA contractile booster pump function in HCM with absent LV fibrosis .22 This might suggest that LA fibrosis is secondary to LV remodeling and increased filling pressure. Although LA mechanics by 2D-STE was not performed in this study, we could relate these findings to our results on LA mechanics: impaired reservoir and contractile functions, and correlation between conduit function and the extent of LV fibrosis.Regarding the presence of fibrosis, one study showed a significant correlation between LA and LV LGE on CMR, as well an abnormal LV strain.23Although LV disfunction, assessed by LV-GLS, was very present in the HCM cohort, it was not related to LV fibrosis. Another parameter of LV disfunction, the myocardial performance index (MPI), is also impaired in HCM and is related to LA strain. However, MPI was not predictive of outcome, in contrast to LA strain.24 LA strain and strain rate values had a significant progressive decrease along the groups . Also, LA strain and strain rate were the best discriminators of cardiomyopathies.24 This suggests that LA mechanics might be an earlier marker of both atrial and myocardial dysfunctions. Furthermore, in HTN patients with significant LVH, in whom excluding HCM might be challenging, the evaluation of LA mechanics might be useful, since the three  phases are not very impaired in this group. In our study, despite statistically lower as compared with HCM patients, values of IVS thickness in our HTN cohort were still high (mean of 14.3±3.6 mm).When evaluating diastolic dysfunction in HCM versus HTN, we noted that LAVi and mitral E and A velocities were not different between the groups. This fact demonstrates the importance of LA mechanics as a discriminator of LA myopathy, that is impaired even before significant LA dilation. Also, it establishes LA deformation baseline values, that are not influenced by other factors such as AF (excluded) or significant LA dilatation. With progression of disease, we can expect that LA deformation worsens with LA dilation, however we could not prove this in our study. Despite the differences in the E/E’ ratios values, the parameter was not a good discriminator between groups and was not correlated to the extent of LV myocardial fibrosis in HCM. LA mechanics appears more as discriminator between LVH groups and is related to the degree of LV myocardial fibrosis in HCM. These findings have also been described in other cardiomyopathies, in which no differences were found in E/E’ and LAVi values among three cardiomyopathy groups .In the present study, we demonstrated that LA strain and strain rate were potential discriminators between HCM and HTN, not only in physiologic response to LVH, but also to the determinants of dysfunction. The clinical implications for the use of LA strain rate imaging for diagnosis of HCM in patients with LVH remains uncertain, since CMR is the most accurate imaging method. Nevertheless, we could demonstrate that LA mechanics was a stronger discriminator of LVH secondary to HCM, when compared to other classic parameters, such as LAVi, E/E’ ratio, and even IVS thickness (Tables 2 and 3). In addition, LA mechanics was moderately correlated to LV fibrosis extension in HCM, which could potentially become a marker of severity and prognosis in earlier stages or doubtful cases.Our study has several limitations. First, the software used for strain analysis was dedicated to the analysis of the LV strain, and not to LA strain, which could distort our results to some extension.Second, the heterogeneity of our study population in terms of different comorbidities can affect the obtained results. The fact that a higher proportion of HTN patients had diabetes and obesity could affect the analysis of LA mechanics, due to a worsening in the LV diastolic function. However, this is an intrinsic association that could not be excluded, as there are few patients with HTN as the only cardiovascular risk factor. Most patients were adequately treated with ACEI and ARB, which could counteract the diastolic dysfunction in these patients, by affecting LV remodeling. In contrast, beta-blockers in HCM does not directly affect LV remodeling, without necessary changes in LV diastolic function or LA mechanics. However, we could not evaluate if and to what extent this was true. Nevertheless, by directly comparing two heterogenous groups of real-world patients with HTN or HCM, we could detect differences in LA mechanics between these two groups as seen in everyday practice.25 In our study, although we excluded patients with AF on basal electrocardiogram, there may still exist unidentified patients with paroxysmal FA, with a more severe cardiac phenotype, that were not entirely characterized in our analysis.Third, it has been demonstrated that HCM patients with paroxysmal AF might have a greater degree of LA myopathy than patients without AF.Fourth, we did not have external validation for the proposed cutoffs, so we could not properly suggest LA strain as an accurate discriminator.Fifth, we did not include HTN patients in the variability analysis, which would be important to truly evaluate reproductivity of all parameters.Finally, this was not an outcome-based study, so we could not draw any conclusions about the prognostic value of LA strain rate in this population. Nevertheless, this study attempted to clarify the LA deformation mechanics in LVH secondary to HCM and to HTN. Future studies with larger samples are warranted to clarify the prognostic value of LA strain rate in LVH.LA mechanics is globally impaired in LVH secondary to HTN and to HCM. Compared to HTN, the best discriminators of HCM were LASRr and LASRct. However, LASRcd was better correlated with the degree of LV fibrosis assessed by CMR in HCM patients. These findings suggest that LA mechanics can help differentiating LVH between HTN and HCM and is a potential predictor of disease severity in HCM.For additional information, please click here.