The effectiveness of veno-arterial extracorporeal life support (V-A ECLS) in treating neonatal and pediatric patients with complex congenital heart disease (CHD) and requiring cardio-circulatory assistance is well-known. Nevertheless, the influence of left ventricle (LV) distension and its countermeasure, namely LV unloading, on survival and clinical outcomes in neonates and children treated with V-A ECLS needs still to be addressed. Therefore, the aim of this study was to determine the effects of LV unloading on in-hospital survival and complications in neonates and children treated with V-A ECLS.The clinical outcomes of 90 pediatric patients with CHD under 16 years of age supported with V-A ECLS for post-cardiotomy cardiogenic shock (CS) were retrospectively reviewed in relationship with the presence or absence of an active LV unloading strategy.p = 0.037). On the contrary, extracorporeal cardiopulmonary resuscitation decreased the related survival . The most common complications were infections (28.8%), neurological injury (26%), and bleeding (25.6%). However, these did not differently occur in venting and no-venting groups.The patient cohort included 90 patients , 42 of whom were vented with different techniques  or left atria cannula, two with cannula from LV apex, 1 with intra-aortic balloon pump (IABP), and one with pigtail across the aortic valve). The LV unloading strategy significantly increased the in-hospital survival (odds ratio [OR] = 2.74, 95% CI 1.06–7.08; In pediatric patients with CHD supported with V-A ECLS for post-cardiotomy CS, the LV unloading strategy was associated with increased survival. The effectiveness of veno-arterial extracorporeal life support (V-A ECLS) in supporting neonatal and pediatric patients with post-cardiotomy shock, following correction of complex congenital heart disease (CHD), is well-established . AlthougLeft heart overload in pediatric patients managed on V-A ECLS may be mainly addressed by atrial septostomy (AS) , althougMost of the reported experience of LV decompression in pediatric patients supported with V-A ECLS consists of case series and limited populations , 7. The We aimed to determine the effects of LV unloading on in-hospital survival and complications in neonates and children treated with V-A ECLS in a referral center for pediatric cardiac surgery.Between December 2010 and January 2020, a total of 115 patients received V-A ECLS support in our pediatric intensive care unit (ICU). Patients with complex anatomy were excluded. A complex anatomy was defined as the presence of mixing physiology at the atrial or ventricular level with a documented shunt between right and left circulation or when this shunt could not be excluded. Therefore, this could not allow to judge the effect of LV venting.2 with lactates between 2 and 3 mmol/L), cardiogenic shock , or extracorporeal cardiopulmonary resuscitation (E-CPR) .The analyzed patients were <16 years of age, and the mean age was 17.3 ± 31.54 months. Notably, 64.4% of patients were males. The indication for V-A ECLS was the evidence of low cardiac output syndrome  LV unloading strategy.Decompression procedures were performed in the operative room immediately after V-A ECLS initiation. The LV unloading strategy was set at the discretion of the local Heart Team  each time such a procedure was considered necessary. The main criteria for this decision-making process were the hemodynamic status, the ongoing inotropic support, and the related degree of LV distension/dysfunction, defined with an echocardiographic evaluation . A venting strategy was used in patients whenever there was evidence of poor decompression of the left side of the heart. If left-sided structures were distended, a low-moderate dose of epinephrine infusion (<0.1 μg/kg/min) was started to improve the contractility and LV ejection. LV decompression was achieved in different locations in our center: (1) left atrium: either with a direct insertion of a venting cannula through the superior pulmonary vein or through AS, (2) LV: either with a cannula draining blood from the LV apex or pigtail catheter across the aortic valve, and (3) aorta: intra-aortic balloon pump (IABP). The decision among the available unloading techniques was based on three main criteria, namely, clinical scenario, patient anatomical features, and surgical expertise.The unloading effect was carefully monitored during the following ICU stay through serial clinical, echocardiographic, and instrumental (X-ray) evaluations.An atrial septal fenestration (2.5–3.5 mm according to the patient's weight) was surgically performed in the overwhelming majority of the patients, leading to left-right communication. Differently and less frequently, according to the clinical scenario and the applicable cannula size, we also placed a curved venous cannula  in the left atrium as a drainage cannula through the superior pulmonary vein.These techniques can draw directly from the LV. The LV venting cannula needed to be carefully implemented from the LV apex in the operation room. In contrast, a guide wire was first used to cross the aortic valve, allowing the 6 F pigtail catheter to be advanced over it into the LV in a small size neonate, weighing <3 kg. Patients were carefully observed with electrocardiographic and hemodynamic monitoring.The IABP implementation in a pediatric patient should be carefully evaluated and performed. The choice of the insertion site and balloon length, according to the related guidelines , was cruIn-hospital patient survival was the primary endpoint investigated to assess the effect of LV unloading. Furthermore, the secondary endpoints included the mortality on ECLS and after weaning, as well as all the occurred complications, including liver and kidney end-organ damage (defined as creatinine and bilirubin peaks). Data on adverse events included cerebral injury , acute kidney injury requiring continuous renal replacement therapy, hemolysis (defined as increased free hemoglobin level above 50 mg/dl) , periphet-test for independent continuous samples or two-tailed significance chi-square test for categorical variables. The association between the main outcomes and dependent predictors was tested through a binary logistic regression model. Furthermore, based on the binary logistic regression model and depending on the emerged significant variables, the patients were assigned to different groups. Survival assessment included Kaplan–Meier analysis with the log rank test for differences between groups, producing a hazard ratio with a 95% confidence interval. All the statistical tests were performed using computerized packages .Unless otherwise specified, data are presented as mean (minimum–maximum) or frequency (%). Paired vented/no-vented VA-ECLS data were compared using two-tailed significance Among 115 pediatric patients supported with V-A ECLS in our pediatric intensive care unit, 25 patients were excluded according to their complex anatomy. A total of 90 patients were analyzed. All supports were placed in a post-cardiotomy setting. Among them, 26.7% accounted for Dextro-Transposition of the great arteries (d-TGA), 14.4% accounted for pulmonary artery disorders, and 12.2% were represented by other valve diseases. The distribution of CHD is presented in detail in p = 0.021; pulmonary hypertension: no-venting 16.3% vs. venting 23.8%, p = 0.013). E-CPR occurrence did not differ between the two groups . All demographic and clinical features are shown in The two groups didn't present any significant differences in terms of age, weight, risk adjustment for congenital heart surgery method 1, and main baseline features such as kidney or liver function. Patients who received a venting strategy had a higher occurrence of either systemic or pulmonary hypertension , either with a venting cannula (N = 8), or through AS (N = 30). Three patients were directly vented in the LV , two children through a draining cannula from the LV apex (N = 2) and one neonate with a pigtail catheter across the aortic valve (N = 1). Finally, according to the body size, one IABP  was placed as a venting strategy.Different venting techniques were used as LV unloading strategies in our patients. The majority received venting from the left atrium (p = 0.047). Regarding the peripheral setting, the favorite arterial cannulation sites in the peripheral mode were carotid artery and femoral artery, respectively, whereas femoral and jugular veins were the most common sites for the venous cannula. Finally, all central V-A ECLS was placed using the aorta and the right atrium as implantation sites. Bivalirudin was the chosen anticoagulation strategy in 54.2% of no-vented ECLS and 47.6% of vented V-A ECLS (p = 0.535). Technically, V-A ECLS duration was not different between vented and not vented supports. Peripheral cannulation was used more frequently in the no-venting group , although deaths on V-A ECLS did not differ between the two groups, with a higher post-weaning death rate in no-venting V-A ECLS patients .The primary and secondary outcomes are shown in p = 0.037). On the contrary, E-CPR was associated with decreased survival . These results were adjusted for risk adjustment for congenital heart surgery method 1 class, peripheral cannulation, age, and the presence of pulmonary hypertension, as presented in The main predictors of the in-hospital survival were the use of venting strategy and the absence of E-CPR. The venting strategy significantly increased the survival at the discharge by almost three times . The survival function (p = 0.012) between patients with E-CPR and no-venting and patients without E-CPR and receiving venting .Based on the regression model result, the patients were divided into four groups  with adequate statistical power. Furthermore, specific etiology of CS was not available for the study analysis. All these factors might temper the found relationship between left ventricular unloading during V-A ECLS and survival.In pediatric patients supported with V-A ECLS for CS or cardiac arrest, the implementation of a concomitant LV unloading strategy was associated with predicted higher in-hospital survival. LV unloading should be strongly considered for selected pediatric patients with CHD in a post-cardiotomy setting. Further investigations are urgently needed to better clarify this apparently significant advantage.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent from the participants' legal guardian/next of kin was not required to participate in this study in accordance with the national legislation and the institutional requirements.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.Author RL was consultant for Medtronic, Getinge, and LivaNova and member of the Advisory Board for Eurosets and Xenios. Author MR received spekaer's honoraria, consultancy fees, and research grants from: Haemonetics Werfen-IL Haemosonics Roche Diagnostics CSL Behring Livanova Medtronic.The remaining 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.


Intraventricular conduction disturbances (IVCD) are currently generally accepted as ECG diagnostic categories. They are characterized by defined QRS complex patterns that reflect the abnormalities in the intraventricular sequence of activation that can be caused by pathology in the His-Purkinje conduction system (HP) or ventricular myocardium. However, the current understanding of the IVCD's underlying mechanism is mostly attributed to HP structural or functional alterations. The involvement of the working ventricular myocardium is only marginally mentioned or not considered. This opinion paper is focused on the alterations of the ventricular working myocardium leading to the most frequent IVCD pattern—the left bundle branch block pattern (LBBB). Recognizing the underlying mechanisms of the LBBB patterns and the involvement of the ventricular working myocardium is of utmost clinical importance, considering a patient's prognosis and indication for cardiac resynchronization therapy. The ECG diagnostic classification of intraventricular conduction disturbances (IVCD) is currently generally well-defined and accepted and represents a standard diagnostic ECG classification. They refer to abnormalities in the ventricular activation sequence, and, as stated in the scientific statement from the AHA/ACCF/HRS recommendations, “they may be caused by structural abnormalities in the His-Purkinje conduction system or ventricular myocardium that result from necrosis, fibrosis, calcification, infiltrative lesions, or impaired vascular supply” .The His-Purkinje conduction system in the ventricles represents well defined and visible structures, and its role in ventricular impulse propagation was early recognized. After some confusion , the chaAlthough the participation of the ventricular working myocardium in the intraventricular conduction disturbances is explicitly mentioned in the AHA/ACCF/HRS recommendations , the parIn this opinion paper, we stress the role of the pathologically changed ventricular myocardium itself in affecting the sequence of electrical impulse propagation and consequently resulting in the typical QRS patterns. It is demonstrated by using the left bundle branch block (LBBB) as an example.It has been repeatedly documented that the majority of LBBB patients have an underlying heart disease, leading to structural changes of the left ventricular myocardium, the most common being LV hypertrophy/dilation, fibrosis, ischemic heart disease, and cardiomyopathies, as well as advanced age –7. AdditIn clinical practice, the LVH definition is reduced to the increase in LV size/mass—in this respect, the imaging methods are superior for the LVH diagnosis. It needs to be stressed, however, that the increase in the left ventricular size/left ventricular mass (LVM) is associated with a complex interrelated structural and functional rebuilding of the ventricular myocardium, considerably affecting active and passive electrical properties, and consequently the sequence of ventricular activation.Hypertrophied cardiomyocytes differ from normal cardiomyocytes in diameter and length, as well as in branching and the number of connected cardiomyocytes –11. At tHypertrophic rebuilding also includes changes in the interstitium, including fibrosis, inflammation, degenerative changes, and apoptosis . The fibAll of these changes can demonstrate considerable heterogeneity, including the size of hypertrophic cardiomyocytes , 27, theThe altered conduction in the ischemic myocardium is studied extensively as a factor creating conditions for developing arrhythmias . IschemiAcute ischemia affects the morphology of the action potential , 35 and Recent findings of animal and human studies using advanced technologies are consistent with those previous findings , 42, 43.Cardiomyopathy is a rather general term for a whole spectrum of myocardium diseases of ischemic and nonischemic origins affecting cardiomyocytes as well as interstitium. It has been shown that the probability of cardiomyopathy in LBBB patients is high , and theIn cardiomyopathy both the myocytes, as well as the interstitium are considerably affected. In general, histological examination shows hypertrophied cardiomyocytes/prolonged cardiomyocytes with bizarre shapes and pleiotropic nuclei; the regular myocardial architecture is disarrayed –50, whicA common characteristic of cardiomyopathies is the increased proportion of interstitial fibrosis –48, whicThe incidence of LBBB is progressively increasing with age . It is dAging myocardium undergoes substantial changes affecting the ventricular impulse propagation. There are changes in the conduction system, but the working myocardium is also considerably affected. These changes include progressive cardiomyocyte hypertrophy, inflammation, and the gradual development of cardiac fibrosis , 58.These examples of cardiac pathology demonstrate the substantial changes having impact on the conduction velocity in the ventricular myocardium and consequently on the QRS morphology.It is complicated to estimate the effect of the slowed conduction and/or the block separately in the conduction system or in the working myocardium on the resultant QRS patterns in the clinical setting. However, it can be addressed by using computer simulations.T wave orientation  the electrical impulse block/slowing in the left bundle branch; (2) primarily slowed activation in the left ventricular myocardium; and (3) a combination of both. The sole affection of LBB (Lenegre disease)  is reporThe LBBB is presented here as an example. Analogically, the involvement of impaired ventricular myocardium also needs to be also considered in other intraventricular conduction disturbances where the terminology and pathophysiological interpretation imply impairment in the H-P conduction system, such as right bundle branch block, and fascicular blocks. In cases of fascicular block the same questions need to be answered—is it the isolated impairment of the anterior, posterior, and middle fascicles, analogically to the Lenegre  or Lev dIt also needs to be mentioned, however, that patients with severe LV structural alterations and clinical heart failure symptoms can develop a pattern of the right bundle branch block (RBBB). In these patients, the sequence of ventricular activation differs as compared to patients with the LBBB pattern , 73, 74:In cases of fascicular block, the same questions need to be answered—is it the isolated impairment of the anterior, posterior, and middle fascicles, analogically to the Lenegre  or Lev dMoreover, it has been shown in a canine model of acute ischemia as well as in patients with acute myocardial infarction that the working ventricular myocardium is less resistant to ischemia compared to the conduction system , 79. TheThe block/slowing of the impulse propagation in the left bundle branch and the consequent delay of LV activation;The primarily slowed ventricular activation in the working left ventricular myocardium due to its structural and/or functional alteration;The combination of the two above, i.e., the combination of the left bundle branch block and primarily slowed left ventricular activation.Considering the electrophysiological background, the LBBB pattern can result from :The blocThese categories are in accordance with the recent approach in resynchronization therapy using the His bundle pacing or the left bundle pacing in patients with “true” LBBB. Several studies show improved clinical outcomes compared to biventricular pacing , 81. HowThere is time to reconsider the traditional ECG classification and interpretation and to link them to the current knowledge of structural and electrophysiological characteristics of the heart in the cardiac pathology. The suggested interpretation of LBBB corresponds better with the pathophysiological understanding of the intraventricular conduction disturbances and understanding of the underlying etiological factors. The LBBB, as well as other ventricular conduction blocks, should be identified as markers of ventricular electrical/structural remodeling of the myocardium, with diagnostic and prognostic implications, such as risk of arrhythmia, treatment of heart failure, indication for resynchronization therapy, and pacing.


During the 21-month follow-up, the patient did not experience syncope or pre-syncope symptoms while on β-blocker (bisoprolol) therapy. Among the multimodality imaging techniques of the ACM, late gadolinium enhancement on cardiac magnetic resonance (CMR) is accepted as a more objective indicator of myocardial fibrosis. Left ventricular systolic dysfunction, fibrosis on CMR, and frequent PVC are the primary and most sensitive clinical signs of desmoplakin cardiomyopathy. However, echocardiography continues to be the most commonly used imaging modality for assessing focal ventricular movement and structural abnormalities. The pathological characteristics of arrhythmogenic cardiomyopathy of the right ventricular anterior free wall and apical regions near the transducer can be better shown using high-frequency linear ultrasound with a higher resolution.Arrhythmogenic cardiomyopathy (ACM) is a genetic disease characterized by fibro-fatty myocardial replacement and is clinically associated with malignant ventricular arrhythmias and sudden cardiac death. It presents a major diagnostic and therapeutic challenge due to its complex clinical presentation and multiparametric diagnostic scoring system that includes structural, histological, and electrocardiographic data. A 57-year-old man with a history of palpitation and premature ventricular contractions (PVC) experienced syncope and sustained ventricular tachycardia at a rate of 213 bpm, which was successfully rescued by synchronized cardioversion. Multiple ventricular aneurysms were found in the right ventricular free wall and the left ventricular apical regions, as well as mild biventricular systolic dysfunction, according to echocardiography and high-frequency ultrasound. The genetic analysis revealed the following desmoplakin genes, chr6-7585274-7585275, NM_004415, exon24, and c.7780delT (p.S2594Pfs An international task force proposed diagnostic criteria for arrhythmogenic right ventricular cardiomyopathy (ARVC) in 1994, based on identifying structural abnormalities, fatty or fibro-fatty replacement of the right ventricular myocardium, electrocardiographic changes, arrhythmias of right ventricular origin, and familial disease . A definIn 2013, a 57-year-old man had palpitation with normal physical examination findings. He was diagnosed with frequent premature ventricular contractions (PVCs) in 2019 despite not taking the antiarrhythmic medication regularly. He had palpitations, dyspnea, and sweating, followed by syncope during emotional disturbance, and regained consciousness ~10 minutes later, in November 2020. He experienced another loss of consciousness and hemodynamic instability in the emergency department of an outside hospital, with a blood pressure of 84/50 mmHg. The 213 bpm electrocardiographically sustained ventricular tachycardia was quickly terminated by synchronized cardioversion . BecauseThe patient was referred to our institute 20 days later. The 12-lead standard electrocardiogram revealed a single PVC with right bundle branch block (RBBB) morphology and a superior axis, indicating that the PVC originated in the left ventricle . In NoveHolter monitoring revealed 1,226 (1.5%) frequent PVCs in December 2020, including 30 couplets, and 4,065 (4.4%) frequent PVCs in February 2021, including 131 couplets and 1 triplet, with no non-sustained ventricular tachycardia over three consecutive PVCs.*9), a heterozygous and likely pathogenic mutation, were the sites of their mutation.Following the collection of clinical characteristics, electrocardiograms, echocardiograms, and laboratory examinations, a genetic analysis was performed. The peripheral venous blood samples of the patient and his 24-year-old daughter were sent to the medical laboratory of Beijing Mygenostics Co., Ltd. for relevant gene capture, gene enrichment, and Sanger sequencing. The desmoplakin genes, chr6-7585274-7585275, NM_004415, exon24, c.7780delT , echocardiography revealed similar results with multiple ventricular aneurysms in the right ventricular free wall and left ventricular apical regions. The high-frequency ultrasound images were obtained using a commercial Philips EPIQ 7C ultrasound machine  equipped with a 3–12 MHz high-frequency linear transducer probe with a vascular carotid preset. The aneurysm measured by two-dimensional echocardiography was 13 (width) × 10 (depth) mm in the right ventricular apical free wall, 7 × 9 and 11 × 16 mm in the right ventricular anterior free wall, and 15 × 19 mm in the left ventricular apical region. High-frequency linear ultrasound with a higher resolution could better show and measure ventricular aneurysms near transducer regions . The patArrhythmogenic cardiomyopathy is believed to be a heredo-familial cardiac disease characterized by fibro-fatty myocardial replacement and an increased risk of sudden cardiac death. It is a heritable, progressive cardiac disease with a wide range of phenotypes. Although ARVC is the most common phenotype, several other ACM phenotypes have been recognized and described –3. DesmoAlthough echocardiography is the most commonly used imaging technique, cardiac magnetic resonance (CMR) is the preferred initial test for patients with suspected ARVC due to its accuracy, availability, safety, and low cost . Among tWhen evaluating ventricular wall motion, echocardiography has a better temporal resolution than CMR. The high-frequency linear ultrasound with superior spatial and temporal resolution revealed a focal ventricular aneurysm and abnormal ventricular motion in the right ventricular anterior free wall and apical regions near the transducer. However, high-frequency ultrasound with higher attenuation has a limited penetration depth; the optimal exploration distance is <3–4 cm from the transducer to the region of interest.To the best of our knowledge, this is the first case report that uses high-frequency ultrasound to assess a focal ventricular aneurysm associated with arrhythmogenic cardiomyopathy. It can better demonstrate the pathological characteristics of arrhythmogenic cardiomyopathy near the probe.The original contributions presented in the study are included in the article/Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual for the publication of any potentially identifiable images or data included in this article.The patient data were managed, analyzed, and interpreted by JLin and XH. JLin and XH made significant contributions to the composition of the manuscript. The manuscript was written by ZL and ML. The treatment and follow-up of the patient were handled by YW and JLi. The final written manuscript was reviewed and approved by all authors.


Peak atrial contractile strain (PACS) significantly increased after ECC-50 (+28.4%) compared to ECC-20 (+17.0%) and control (between sessions p = 0.034). The ratio of transmitral and annular velocities (E/E’) increased significantly after ECC-20 (+10.4%) and ECC-50 (+19.0%) compared to control (between groups p = 0.003). EF, left ventricular longitudinal strain, and stroke volume did not change after ECC-RE sessions compared to control. Cardiac output increased significantly after ECC-20 and ECC-50 compared to control, (between groups p = 0.025). In conclusion, both ECC-RE sessions were well tolerated, and LA functional reserve was properly mobilized in response to ECC-RE in patients with HFmrEF. Cardiac output increased at the cost of an increased LV filling pressure, but no detrimental changes of LV function occurred.In this study, we aimed to assess acute changes occurring on atrial function following single bouts of eccentric resistance exercise (ECC-RE) performed at two different loads. Twenty-five patients with chronic heart failure with middle range ejection fraction (HFmrEF) participated in three experimental sessions in a randomized order and on separate days: two sessions of ECC RE at 20% (ECC-20) of one-repetition maximum (1-RM) and 50% (ECC-50) 1-RM, and one session of control, without exercise. Each session lasted three minutes. Before and immediately after the sessions, patients underwent echocardiography and blood pressure and heart rate measurement. Peak atrial longitudinal strain (PALS) and peak atrial contractile strain (PACS) significantly increased after both ECC-20 (+16.3%) and ECC-50 (+18.1%) compared to control (between sessions  Exercise intolerance is a cardinal symptom of heart failure (HF), and it represents an independent predictor of poor prognosis in patients suffering from this disease . PhysicaThe study included 25 patients referred to a cardiac rehabilitation program at the cardiac rehabilitation center in San Raffaele IRCCS, Rome, between June 2020 and March 2021. Participants of this study were sent to our cardiac rehabilitation facility by their own family doctor or private cardiologist. Inclusion criteria were as follows: diagnosis of HFmrEF (EF between 41% and 49%) with underlying coronary artery disease, stable clinical conditions and stable pharmacological therapy (not being modified in the last three months), sedentary lifestyle (patients not being enrolled in exercise training programs in the previous six months) and sinus rhythm. Exclusion criteria were: BP levels exceeding 160/100 mmHg, heart valve diseases, hypertrophic cardiomyopathy, signs and/or symptoms of myocardial ischemia during a preliminary ergometric test, uncontrolled arrhythmia, neurological and/or orthopedic conditions contraindicating or limiting exercises, significant chronic obstructive pulmonary disease , and symptomatic peripheral arterial disease. For the purpose of the study, the diagnostic criteria for coronary artery disease were: previous myocardial infarction, a history of percutaneous coronary interventions and/or coronary artery bypass graft.The study flowchart is reported in −1 and 90°, respectively. Patients performed, in a random order, a session of ECC-RE at 20% of their ECC 1-RM (ECC-20), a session of ECC-RE at 50% of their ECC 1-RM (ECC-50), or a control session. Every session lasted three minutes, and by keeping a constant rate during the exercises, patients were required to perform 45 repetitions in each session. After the first twenty-five repetitions, patients rested for 30 s and then completed the remaining 20 repetitions. During the control session, patients rested for three minutes in a seated position on the chair of the dynamometer. In order to obtain a pure eccentric exercise, no loads were applied during the concentric component of the movement. The exercise intensities and duration were based on previous studies that used eccentric exercise [The experimental sessions were performed in the morning, between 9:30 and 11:00, on different days. Before testing, patients were instructed to abstain from exercise in the previous 24 h. Moreover they were asked to not smoke, and not drink coffee and alcohol. Patients were allowed to have a light breakfast at least 2 h before the start of the sessions and to regularly take their morning drugs. Before starting the ECC-RE, all participants performed a 5 min warm-up on a stationary bike. Then, they were required to perform leg extension/flexion movements from the sitting position upon the isokinetic; the hip and thigh were carefully fastened to the seat, with both legs attached to the dynamometer lever arm about 2 cm above the medial malleolus, with both arms along the trunk, and with hands holding the bars on the side of the chair. Axis speed and range of movement were fixed at 10° sexercise  and enroexercise . EchocarEchocardiography: All echocardiographic examinations were made using Acuson SC 2000 Prime ultrasound system (Siemens) with a 4.0 MHz transducer by one experienced sonographer who was blinded to the type of experimental sessions performed by individual patients. Echocardiography was performed before starting the exercise (T0) and immediately after the end of the exercise (T1). In the case of control sessions, echocardiography was performed before and after three minutes of rest. Left ventricular end-diastolic volume (LVEDV) and end-systolic volume (LVESV) were calculated from the apical two and four chamber windows using modified Simpson’s method, which was used to calculate stroke volume (SV) as EDV−ESV, cardiac output (CO) as HR × SV, and ejection fraction (EF) as EF = (EDV−ESV)/EDV). LA volume was measured from standard apical 4-chamber views at end systole directly before mitral valve opening. The biplane method of disks was used to calculate LA volume. LAVi was calculated by dividing LA volume by body surface area of the subjects. The reported E/A ratio represents the ratio of peak left ventricle filling velocity in early diastole (E wave) to that in late diastole during atrial contraction (A wave). LV E/E1 ratio was calculated as the ratio between E wave velocity and mean lateral and septal LV E1 wave velocities. Color tissue Doppler tracings were obtained with the range gate placed at the lateral mitral annular segments in the 4-chamber view. Peak systolic LV longitudinal strain and strain rates were assessed using standard 2D apical four chambers and two chambers view using speckle-tracking analysis. Global longitudinal strain (GLS) was determined by averaging all values of the segments of the two views. LA strain was measured from the 4-chamber and 2-chamber views. The software program generated the longitudinal strain curves for each segment and a mean curve of all segments. The 3-chamber apical view was not included for the GLS calculation because of the poor quality of images obtained in the seated position. Peak atrial longitudinal strain (PALS) was measured at the end of the reservoir phase (positive peak during LV systole), and peak atrial contraction strain (PACS) was measured directly before the start of the active contractile phase (positive peak during early diastole). LV stiffness was calculated as E/E1/LVEDV [1/PALS [E1/LVEDV . LA stif [1/PALS . Rate ofp < 0.05. Data were analyzed using SPSS software .Since we did not find in the literature previous direct comparisons between two different eccentric loads on LA function, we were not able to calculate the study sample size, and therefore, this research was conceived as a pilot study. Data are expressed as mean ± SD. The assumption of normality was checked using Shapiro–Wilks hypothesis test. Pre- and post-exercise data of normally distributed variables were assessed using repeated measures two-way ANOVA, with Bonferroni corrections for post hoc testing. Not normally distributed variables were assessed using Kruskal–Wallis test and Bonferroni corrections for post hoc testing. The level of significance was set at Anthropometric and clinical features of patients are summarized in p = 0.013 for systolic BP and p = 0.039 for MAP). There were not significant differences in changes of systolic BP between ECC-20 and ECC-50. Diastolic BP did not change after exercise sessions compared to control. HR increased after both exercise sessions and was unchanged in control session (between sessions p = 0.047). PALS increased in a similar manner after ECC-20 and ECC-50 and was unchanged after control session (between sessions p = 0.022). PACS increased significantly after both exercise sessions compared to control (between sessions p = 0.034). The increase in PACS after ECC-50 was also significantly higher than after ECC-20 (p = 0.038). LAVI and LA stiffness were unchanged after both exercise sessions and control (p = 0.025) and remained unchanged after control. E/E’ increased after both ECC-20 (+0.9 ± 0.2) and ECC-50 (+1.5 ± 0.3) and remained unchanged after control session (between groups p = 0.003).Changes in hemodynamic and echocardiographic parameters are summarized in r ECC-20 . A’ wave control . SV did Overall, both exercise sessions were well tolerated, and all patients completed their tasks. None of them reported any discomfort during RE, and no adverse events occurred during the study.In this study, we investigated LA functional response to a single bout of two different intensities of ECC-RE in patients with HFmrEF. We found that PALS and PACS significantly increased after both ECC-20 and ECC-50, with PACS having the greatest increase with the highest volume. To the best of our knowledge, this is the first study to assess acute LA functional response to different eccentric volumes in HFmrEF patients. LA function has relevant importance in the pathophysiology of HF and plays a key role in modulating LV filling in these patients, particularly during exercise . To dateIn this study, we observed a statistically significant increase in CO after both ECC-20 and ECC-50 versus control. This result suggests that patients with HFmrEF were able to increase CO in response to mild-to-moderate external ECC-RE loads at the price of a mild increase in LV filling pressure. Since SV did not change significantly after both ECC-20 and ECC-50 compared to control, the increase in CO observed in our study was mainly due to the increase in HR. The hemodynamic profile that we found during ECC-RE differed from the findings of Stohr et al.  performeWe observed that HR and SBP increased after ECC-20 and ECC-50 compared to control. The extent of the increase in SBP was similar between the two RE volumes. In our study, patients performed two sessions of RE at different loads, while time of exercise (3 min) was constant and thus was the number of repetitions/sessions. Therefore, our results suggest that SBP response was not related to the magnitude of the external load. Our data are in agreement with previous research performed in healthy subjects and in patients with ischemic heart disease in which the main determinant of the SBP response was the number of repetitions ,41.Limitations. The most important limitation of this study is the small sample size; further larger studies are needed in order to clarify atrial changes in response to different RE loads. We evaluated LA response to eccentric loads in HFmrEF patients; considering the study design and the lack of data in this particular population, our study does not clarify whether the observed response is exclusive of ECC-RE or if it can also be obtained with other exercise modalities such as concentric resistance exercise. Another limitation is the lack of a control group without cardiovascular diseases, and thus, a “normal” response to our protocol cannot be determined. Our results do not establish whether the type of LA response observed is specific to eccentric RE or if it can be extended to concentric RE; new studies comparing LA response to concentric and eccentric RE are needed. All hemodynamic parameters were measured or calculated by echocardiography, and therefore, the study lacks comparison with invasive hemodynamic assessment through cardiac catheterization. This study enrolled only patients with HFmrEF and underlying ischemic heart disease; therefore, our results cannot be extended to patients with different etiology and/or disease severity. In patients with HFmrEF, the hemodynamic response to single ECC-RE session was characterized by a proper increase in LA function and CO without detrimental changes in LV function, albeit at the cost of a modest rise in LV filling pressure. New studies evaluating LA response to different exercise intensities and modalities are needed in order identify the most suitable exercise for the rehabilitation programs of patients with HFmrEF.


Atrial fibrillation was found in 6 (27.2%) female patients and 5 (18.5%) males. In addition, two (7.4%) male patients and one female patient (4.5%) had atrial flutter, and premature ventricular contractions (PVCs) were noted in 10 (37%) and 11 (50%) patients. Left ventricular mass index (LVMI) was 103 gm/m2 in female patients and 119.2 gm/m2 in males. Palpitation was present in 22 (44.9%) female patients and 27 (55.1%) males. The study revealed that hypertensives with LVH have an arrhythmia frequency of 16.3%. The most common arrhythmias were atrial fibrillation and premature ventricular complex.Left ventricular hypertrophy (LVH) caused by high blood pressure is linked to increased mortality and arrhythmia risk. This study aimed to evaluate arrhythmia in hypertensive patients due to left ventricular hypertrophy (LVH). A cross-sectional study was performed, assessing participants' blood pressure, echocardiography and electrocardiography, and Holter monitoring in certain cases. There were 300 hypertensive patients >18 years attending the cardiology unit of Baghdad medical city. The study was conducted between January–June 2022. The electrocardiograms at rest for 300 adults with hypertension were investigated. 130 (43.5%) were females, and 170 (56.5%) were males. The mean age of participants was 58 years. Forty-nine (16.3%) patients had arrhythmia. As compared to those without arrhythmia, participants with arrhythmia were older (62.3  Arterial hypertension is a substantial risk factor for unfavorable cardiovascular events globally due to its link to atherosclerosis, peripheral artery disease, coronary artery disease (CAD), chronic renal disease, heart failure, and stroke . AdditioFurther contributing to the advancement of AF is uncontrolled hypertension. The risks of systemic embolism and stroke, tachycardia-induced cardiomyopathy, chronic heart failure (HF), and acute HF exacerbations are all raised in hypertensive patients with AF , 5. AddiThere are still no clear indications for using echocardiography to treat hypertension . TransthThe most popular non-invasive technique for examining cardiac anatomy is echocardiography. Thin cross-sections of cardiac structures, such as the left and right atriums, left and right ventricles, valves, and related valvular structures can be obtained using echocardiography , 7.Left atrial enlargement is brought on by the sluggish growth of hypertension. Large LA creates an ideal environment for a sinus rhythm to loop inside itself, resulting in AF. Atrial contraction is becoming increasingly important for properly filling the left ventricle (LV). This filling is offset by the sudden start of AF, which results in inadequate LV filling and increased LA pressure that travels to the pulmonary capillaries. The fibrotic region can serve as a substrate for developing ectopic rhythms, which causes chronic intractable AF and increases the risk of clot formation and systemic embolism .A smaller LV cavity and a decreased stroke volume are the results of excessive left ventricular hypertrophy (LVH). Additionally, it causes the distinct levels of the LV contraction to become disorganized. Strain imaging can be used to measure this. When LVH is too high, different regions experience maximum contractions at various times. A strain image can be used to evaluate this mechanical dispersion . There iA cross-sectional study was conducted, including adult participants with hypertension aged 18 years and above who attended the Cardiology Unit of the Baghdad medical city between January–June 2022. Blood pressure, electrocardiography, and echocardiography were assessed for all participants. In addition, Holter monitoring was performed in certain cases.Age and sex, blood pressure, medicines, and clinical diagnosis, were all listed on the ECG request and sheet. Prognostic indicators for hypertension are left ventricular mass, left atrial function, systolic function, diastolic activity, and size. Three-dimensional echo, tissue Doppler, and strain imaging are more recent echo techniques used in evaluating hypertension patients in addition to standard echo methods . Blood pHypertension was diagnosed as SBP ≥140 mmHg and/or DBP ≥90 mmHg or treated with antihypertensive drugs. Electrocardiogram standard supine resting 12-lead ECG was recorded using a machine complying with the recommendations of the American Heart Association for technical specifications. The ECG report was contained in the ECG request form for each patient.These records were screened for the following abnormal rhythms: atrial fibrillation, atrial flutter, atrial and ventricular premature complexes, and supraventricular and ventricular tachyarrhythmias. Those with arrhythmias were confirmed and coded by a cardiologist. The criteria for arrhythmias were based on the standard ECG criteria, and Holter monitoring showed significant premature ventricular contractions.The ECG at rest for 300 Iraqi adults with hypertension was studied. There were 170 (56.5%) males and 130 (43.5%) females with a male to female ratio of 1.3:1. The mean age of the patients was 58 years. The mean ages of patients with and without arrhythmia were 62 and 56, respectively (p=0.010) .vs. 15%, p=0.490) though it was not significant.The frequency of arrhythmias increased with age and was more prevalent in patients 60 years and older . Forty-nvs. 3.2%, p=0.840), although not statistically significant. As compared to those without arrhythmia, patients with arrhythmia were older , had a higher SBP  and DBP  and LVH , and more likely to be in hypertension   . The patThe study also revealed that arrhythmia was more common in older patients, as 64% occurred in those 60 years and above.The study showed that PVC and AF were the most common arrhythmias in adult patients with hypertension in our setting, constituting 42.8% and 22.4%, respectively. This is consistent with the findings in some previous studies . PVC is The mechanism of the arrhythmia may be automatic, activity-triggered, or re-entry, and increased sympathetic tone and QTc prolongation may play a role in the progression to ventricular tachyarrhythmia, particularly in the presence of LVH and ventricular dysfunction . The stuThe increased prevalence of arrhythmia and other ECG findings in the elderly is due to the increased prevalence of cardiovascular disease and the impact of physiological aging changes. Electrocardiographic changes may occur due to the substantial changes in cardiovascular structure and function linked with aging . Thus, aIn our study, although the overall prevalence of AF was 3.8%, 4.3%, 43.5%, and 52.2%, the cases occurred in patients <50 years, 50–69 years, and 70 years and older, respectively. Atrial fibrillation prevalence was significantly correlated with age. This is similar to findings reported by Alan et al.  and otheAF is one of the most common arrhythmias in elderly persons and a significant risk factor for ischemic stroke, increasing the chance of having one and contributing to fifteen percent of all strokes in the US. In addition to lowering the quality of life and heart performance, symptomatic AF is linked to higher medical expenses and mortality risk .In our study, although not statistically significant, females were more likely to have an arrhythmia than males, including AF, except for those at and above 70 years. This corresponds to the study by Yamaguchi et al. , which sThis study also showed that hypertensive patients with arrhythmia were significantly more likely to be in heart failure (HF) than those without HF. There is a two-way relationship between arrhythmia and HF . While aIn patients with hypertension, left ventricular hypertrophy raises the chance of ventricular and atrial arrhythmias, systolic and diastolic heart failure, and sudden cardiac arrest. Regression of LVH and reduction in cardiovascular morbidity and death are made possible by controlling arterial blood pressure.


This study compares three-dimensional (3D) high-resolution (HR) late gadolinium enhancement  imaging using a respiratory navigated, electrocardiographically-gated inversion recovery gradient echo sequence with conventional LGE imaging using a single-shot phase-sensitive inversion recovery (PSIR) balanced steady-state free precession  sequence for routine clinical use in the pediatric population.Pediatric patients (0–18 years) who underwent clinical cardiovascular magnetic resonance (CMR) with both 3D HR-LGE and single-shot PSIR-bSSFP LGE between January 2018 and June 2020 were included. Image quality (0–4) and detection of LGE in the left ventricle (LV) (per 17 segments), in the right ventricle (RV) (per 3 segments), as endocardial fibroelastosis (EFE), at the hinge points, and at the papillary muscles was analyzed by two blinded readers for each sequence. Ratios of the mean signal intensity of LGE to normal myocardium (LGE:Myo) and to LV blood pool (LGE:Blood) were recorded. Data is presented as median (1st–3rd quartiles). Wilcoxon signed rank test and chi-square analyses were used as appropriate. Inter-rater agreement was analyzed using weighted κ-statistics.102 patients were included with median age at CMR of 8 (1–13) years-old and 44% of exams performed under general anesthesia. LGE was detected in 55% of cases. 3D HR LGE compared to single-shot PSIR-bSSFP had longer scan time , higher image quality ratings , higher LGE:Myo , detected more segments of LGE in both the LV  and RV , and also detected more cases of LGE with 13/56 (23%) of patients with LGE only detectable by 3D HR LGE (p < 0.001). 3D HR LGE specifically detected a greater proportion of RV LGE , EFE , and papillary muscle LGE . Inter-rater agreement for the recorded variables ranged from 0.42 to 1.00.3D HR LGE achieves greater image quality and detects more LGE than conventional single-shot PSIR-bSSFP LGE imaging, and should be considered an alternative to conventional LGE sequences for routine clinical use in the pediatric population.The online version contains supplementary material available at 10.1186/s12968-023-00917-0. Late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) evaluation of myocardial injury and fibrosis provides essential diagnostic and prognostic information in a variety of congenital and pediatric heart conditions –4. One oAdvantages of 3D HR-LGE include higher spatial resolution, increased signal to noise, better fat saturation, and ability to perform multiplanar reconstructions. Disadvantages include a long scan time and potential for compromised quality due to inconsistent breathing, motion, significant heart rate variation, arrhythmia, or inappropriate inversion time . The perThe purpose of this study was to evaluate the use of a 3D HR-LGE sequence compared to a conventional single-shot PSIR-bSSFP LGE sequence for detection of LGE in routine pediatric clinical CMR.This single institution retrospective study received institutional Research Ethics Board approval with waiver of informed consent. Patients between 0 and 18 years of age that underwent a clinical CMR that included LGE imaging performed between January 2018 and June 2020 were included. CMRs that did not have both 3D HR-LGE and single-shot PSIR-bSSFP LGE were excluded. This was related to variable adoption of 3D HR-LGE early in the inclusion period along with standardization of our clinical practice by using conventional single-shot PSIR-bSSFP LGE exclusively as opposed to occasional alternative use of conventional segmented PSIR-FLASH LGE. Non-diagnostic exams related to technical factors were also excluded, which mostly were related to variable attempts at optimization of technique parameters early in the adoption period. Note that exams with excessive patient motion artifact were not excluded.Studies were performed on a 1.5 T CMR system . Conventional LGE was performed using a two-dimensional single-shot PSIR-bSSFP sequence acquired in axial and short-axis planes 10 min following intravenous injection of 0.2 mmol/kg of gadobutrol . 3D HR-LGE was performed using a 3D ECG-gated, respiratory-navigated inversion recovery-prepared (IR) fast low angle shot (FLASH) pulse sequence with fat saturation acquired in coronal plane, and obtained 15–20 min following intravenous administration of gadolinium-based contrast agent. Respiratory navigation was performed using pencil-beam navigation. As exact nulling of myocardium is not necessary for this sequence, an empiric inversion time of 220 ms was used with quiescent interval chosen in systole. However, when the Look-Locker acquired before conventional LGE gave a myocardial nulling inversion time ≥ 300 ms, an empiric inversion time of 280 ms was used for the 3D HR-LGE sequence with quiescent interval in diastole. Other specific sequence parameters are shown in Table Each sequence was analyzed by two independent, blinded readers (A.S and J.A.). Presence or absence of LGE per myocardial segment was recorded for each sequence. The left ventricle (LV) was divided into 17 myocardial segments according to standardized American Heart Association LV segmentation . The rigImage quality of each sequence was rated on a four-point ordinal scale: 1) poor with no clear distinction of myocardial margins; (2) fair with blurred myocardial edges; (3) good with clear myocardial margins; (4) very good with sharp myocardial margins  and LGE to LV blood pool (LGE:Blood) signal intensity ratios were calculated and compared.Continuous variables are summarized as median (1st–3rd quartiles) and categorical variables are summarized as frequency (percentage). κ-statistics were used for inter-rater agreement of LGE detection and image quality ratings between the two sequences. Wilcoxon signed rank test and chi-square analyses were used to compare conventional LGE and 3D HR LGE sequences. All statistical tests were two-sided and considered statistically significant if p < 0.05. Analyses were performed using SPSS for Windows .One-hundred and sixty-six patients underwent clinical CMR that included LGE imaging during the study period. Thirty-eight patients were excluded due to the lack of concomitantly performed 3D HR-LGE and conventional single-shot PSIR-bSSFP LGE sequences. One patient was excluded due to extra-cardiac artifact obscuring the heart. Twenty-six 20%) of the remaining patients were excluded due to non-diagnostic images related to inappropriate sequence timing or inversion time, the majority as part of sequence testing and optimization early in the adoption period. This left a final study population of 102 patients  years) with 45/102 (44%) of cases performed under general anesthesia. Demographic data are summarized in Table 0% of theMedian 3D HR-LGE scan time was 4:30 (3:35–5:34) minutes and was shorter when performed under general anesthesia . Ninety-eight (96%) of 3D HR-LGE sequences were performed in systole. Median combined short-axis and axial single-shot PSIR-bSSFP total scan time was 1:11 (0:47–1:32) minutes and also was shorter when performed under general anesthesia . Image quality ratings were higher for 3D HR-LGE compared with single-shot PSIR-bSSFP at 3 (3–4) vs 2 (2–3) respectively (p < 0.001). Image quality ratings were not different between sedated or awake 3D HR-LGE and PSIR-bSSFP cases . LGE:Myo signal intensity was higher for 3D HR-LGE compared with single-shot PSIR-bSSFP at 23.7 (16.9–31.2) vs 5.0 (2.9–9.0) (p < 0.001), while there were no difference in LGE:Blood signal intensity at 1.2 (0.9–1.8) vs 1.2 (0.6–1.5) (p = 0.284). Boxplots of these data are depicted in Fig. 6 vs 5:18Fifty-six 55%) of exams demonstrated myocardial LGE. Specifically, 24 (24%) had LV LGE, 27 26%) had RV LGE, 8 (8%) had LV EFE, 3 (3%) had RV EFE, 34 (33%) had subendocardial LGE, 41 (40%) had mid-myocardial LGE, 26 (25%) had subepicardial LGE, 16 (16%) had hinge point LGE, and 15 (15%) had papillary muscle LGE. The 3D HR-LGE sequence detected a greater extent of LGE than single-shot PSIR-bSSFP, with median number of positive LV segments of 4 (2–8) vs 3 (1–7) (p = 0.045), and median positive RV segments of 1 (1–1) vs 1 (0–1) (p < 0.001), respectively , 3 related to excessive patient motion (poor patient cooperation or inconsistent breathing pattern) and 1 related to technical artifact. Moreover, our results may be confounded by heterogeneity in exams including comparisons of 3D HR-LGE acquisitions in systole versus single-shot PSIR-bSSFP in diastole. Nonetheless, we feel our results remain valid, showing that 3D HR-LGE as we performed in clinical routine is superior to the conventional method of acquiring single-shot PSIR-bSSFP. Finally, this study was limited by the lack of pathologic correlation or gold-standard for presence of LGE.3D HR-LGE is feasible for routine use in pediatric clinical CMR, and compared to single-shot PSIR-bSSFP LGE, achieves greater image quality and detects more LGE. Given wide-spread availability and superior performance, 3D HR-LGE can be used as the primary standard LGE sequence in the pediatric population, with conventional LGE sequences reserved only for situations when proper ECG gating and/or respiration navigation are not possible.Additional file 1:Table S1. Inter-rater agreement for presence or absence of LGE by myocardial location for conventional single-shot PSIR-SSFP LGE and 3D HR LGE sequences.


This study indicates that NT-proBNP and hs-cTnT are associated with structural and functional alterations in HCM. NT-proBNP is a stronger predictor for DD, while hs-cTnT is associated with the extent of focal myocardial fibrosis. Both biomarkers might be useful in the diagnostic procedure in addition to imaging parameters.Serum biomarkers such as N-terminal prohormone of the brain natriuretic peptide (NT-proBNP) and cardiac troponins are elevated in patients with hypertrophic cardiomyopathy (HCM). At present, it is not clear if these markers are associated with distinct clinical alterations in HCM, such as left ventricular hypertrophy, outflow tract obstruction, myocardial fibrosis and/or diastolic dysfunction (DD), which are associated with adverse cardiovascular outcome. Here we evaluate the association of NT-proBNP and high sensitivity cardiac troponin T (hs-cTnT) to a variety of cardiac imaging parameters in HCM patients in a multivariable regression analysis. This retrospective cross-sectional study included 366 HCM patients who underwent transthoracic echocardiography (TTE), 218 of whom also obtained cardiovascular magnetic resonance (CMR) to assess focal myocardial fibrosis by LGE. Multivariable regression analyses revealed the strongest association of the DD parameters E/E′ mean and E/E′ septal with NT-proBNP (b = 0.06, 95%-CI [0.05–0.07],  Hypertrophic cardiomyopathy (HCM) is characterized by an inappropriate hypertrophy of the left ventricle with hypertrophic and disarrayed myocytes as a result of mutations in genes encoding for sarcomere proteins . PreviouTTE and CMR are generally accepted and established techniques but also entail limitations due to, for instance, contraindications or availability in the case of CMR, or operator-dependency in the case of TTE. Circulating biomarkers on the other hand are easy to determine as objective parameters in the diagnostic procedure.Here, we aim to evaluate the association of N-terminal prohormone of the brain natriuretic peptide (NT-proBNP) and hs-cTnT with characteristic disease markers of HCM, by applying an overall comprehensive assessment that allows for the analysis of both biomarkers and multiple imaging parameters.2. A medical history of coronary artery disease (CAD), diabetes mellitus, and arterial hypertension was confirmed by self-report or the use of corresponding medication. The diagnosis of atrial fibrillation (AF) was established by a positive history and electrocardiogram (ECG) documentation within the last five years prior to examination. Cardiac symptoms were classified according to the New York Heart Association (NYHA) classification. All participants received a 12-lead surface ECG, a TTE, and had routine blood work done, including measurement of hs-cTnT and NT-proBNP. Serum levels of NT-proBNP were assessed by the Atellica® IM NT-proBNP assay . For the measurement of serum hs-cTnT levels, the Elecsys Troponin T hs STAT assay  was performed. In addition, 218 patients underwent CMR. The study was conducted in compliance with the principles outlined in the Declaration of Helsinki and was approved by the local ethics committee . All study participants gave their written informed consent.A total of 366 HCM patients were included in this retrospective cross-sectional study. Participants were enrolled during routine visits at the outpatient clinic of the University Heart & Vascular Center Hamburg between January 2011 and December 2019. HCM was defined by a maximum wall thickness (MWT) of ≥15 mm in one or more left ventricular (LV) myocardial segments in the absence of abnormal loading conditions according to current guidelines  % of LV mass. CMR was not conducted in patients due to claustrophobia, metal implants, or non-MR compatible cardiac pacemaker or implantable cardioverter defibrillator (n = 43). A total of 11 patients received an ICD early after MRI. Externally performed MRI studies were not included.Detailed clinical characteristics of the study population are presented in p = 0.092) and provoked LVOT flow gradient (p = 0.101). Judged by the R2, the strongest association was found for E/E′ mean  and E/E′ septal . An increase in NT-proBNP by 50 ng/L was associated with an increase in E/E′ mean by 0.06 or in E/E′ septal by 0.08. As shown in p = 0.161) and the logarithmized resting and provoked LVOT gradient . Overall, LGE size showed the strongest association with hs-cTnT . The results of the multivariable regression analysis to evaluate the association between hs-cTnT and the respective imaging markers are presented in We evaluated the association of NT-proBNP and hs-cTnT with different disease features of HCM. Both biomarkers were associated with a variety of characteristic markers such as LVH, DD, and focal fibrosis. However, our data indicate the strongest association of elevated NT-proBNP levels with echocardiographic parameters of DD and hs-cTnT levels with LGE size measured by CMR.The neurohormone NT-proBNP is released in response to LV wall stress due to ventricular volume or pressure overload ,39. It iThe majority of HCM patients exhibit some level of DD, and most of them suffer from HFpEF in the course of disease progression ,42,43,44In line with our findings demonstrating elevated NT-proBNP levels > 125 pg/mL in 86% of HCM patients, several studies have reported abnormal proBNP or NT-proBNP levels in HCM ,5,9,10. BNP levels have been found to be associated with multiple HCM disease markers such as NYHA functional class, LVEF, LVOT obstruction, LVH ,18,48,49Although we detected only a marginally stronger association of NT-proBNP with septal E/E′ than with lateral E/E′ in our cohort, this was supported by the findings of Nakamura et al. showing a slightly stronger correlation of BNP values with septal E/E′ than with lateral E/E′ . These fHowever, Binder et al. could only show a weak correlation of BNP with calculated wall stress as a marker for DD . OverallMoreover, we found an association of NT-proBNP with SW thickness, the predominant location of LVH , which hHCM patients with LVOT obstruction have been reported to have particularly high levels of BNP , and stuWe detected focal myocardial fibrosis on LGE imaging in 150 HCM patients (77%), which is consistent with previously published studies that have reported LGE in 42 to 72% of cases ,27,32,57CMR is a reliable alternative to endomyocardial biopsy in identifying myocardial fibrosis , but nevHs-cTnT is already an established biomarker for the detection of myocardial injury with high sensitivity and specificity ,60. An aIn HCM, several studies have described elevated troponin levels with a prevalence of 40 to 55% ,8,11,13.The cause of myocardial cell death and troponin release in HCM still remains unclear. Possible underlying mechanisms include myocardial ischemia due to increased oxygen demand, and reduced capillary density of the hypertrophic myocardium as well as overdistension of sarcomeres due to reduced compliance and myocyte disarray ,63,64,65A higher frequency of myocardial cell death is accompanied by myocardial replacement fibrosis, which supports a potential relation of cTn levels and fibrosis. Previous studies have reported an association of hs-cTnT levels with LGE as a marker for fibrosis in HCM, similar to our results. In addition, several studies have demonstrated elevated serum levels of cTnI in LGE-positive HCM patients compared to LGE-negative patients ,8,11,17.The fact that LGE is often found in hypertrophic segments ,68 and aFinally, in line with our observations, previous studies have also reported a relation between cTn and markers of DD ,13,16, aOverall, our results show associations of the blood biomarkers NT-proBNP and hs-cTnT with structural and functional alterations in HCM. Hence, these biomarkers might be useful in a comprehensive assessment of patients next to diagnostic imaging. Further investigations are needed to evaluate the reliability of these blood biomarkers for early assessment of fibrosis and DD in HCM patients.We found associations of NT-proBNP and hs-cTnT with structural and functional alterations in HCM patients. As NT-proBNP is more closely associated with DD, while hs-cTnT is associated with the size of focal myocardial fibrosis, it might be useful to incorporate both biomarkers in the diagnostic procedure next to diagnostic imaging. After further analyses, the biomarkers might also be helpful parameters for the identification of a more precise phenotype and for potential guidance of specific therapeutic strategies in these patients.We acknowledge the following limitations: First, there are limitations due to the cross-sectional study design. Our results should therefore be confirmed in a longitudinal study including serial measurements. Secondly, blood biomarkers are prone to several influencing factors, which might impact their predictive value. However, this study demonstrates significant associations of circulating and imaging biomarkers and provides supportive evidence for future analyses. Thirdly, LGE imaging was not available for all patients, and we did not assess T1 mapping. We could therefore not evaluate diffuse fibrosis next to LGE as a marker for focal fibrosis.


The images were visually evaluated by doctors and radiological technologists, and the grade of uptake reduction was scored by Heart Risk View-S software (Nihon Medi-Physics). The scores were deployed in a 17-segment model of the heart. The distribution of the scores were analyzed. (3) Results: Nine patients (9%) could not undergo UCG. No correlation was found between left ventricular ejection fraction (LVEF) and Heart Risk View-S scores of 201Tl myocardial perfusion scintigraphy nor those of BMIPP myocardial metabolism scintigraphy. In a 17-segment model of the heart, the scores of the middle rings were higher than for the basal ring. (4) Conclusions: Evaluation by UCG is not possible for some patients. Myocardial scintigraphy cannot serve as a perfect alternative to UCG. However, it will become the preferable second-choice screening test, as it could point out the early stage of CTRCD.(1) Background: The mortality of breast cancer has decreased due to the advancement of cancer therapies. However, more patients are suffering from cancer-therapeutics-related cardiac dysfunction (CTRCD). Diagnostic and treatment guidelines for CTRCD have not been fully established yet. Ultrasound cardiogram (UCG) is the gold standard for diagnosis of CTRCD, but many breast cancer patients cannot undergo UCG due to the surgery wounds or anatomical reasons. The purpose of the study is to evaluate the usefulness of myocardial scintigraphy using Iodine-123 β-methyl-P-iodophenyl-pentadecanoic acid ( The five-year survival rate of breast cancer exceeds 90% in high-income countries, while breast cancer mortality dropped by 40% between the 1980s and 2020 [Diagnostic and treatment guidelines for CTRCD have not been established until just recently. The European Society of Cardiology (ESC) Position Paper published in 2016 and the American Heart Association (AHA) statement published in 2019 have only been recently regarded as alternatives to guidelines . The worUltrasound cardiogram (UCG) is the current initial choice for diagnosis of CTRCD. However, many breast cancer patients are not able to undergo UCG due to surgery wounds, implants, or other anatomical issues in their chest. It is also known that shortfalls in echocardiography are caused by constraints due to dependency on acoustic windows and variable operator skills . Inter-oIn ESC Position Paper, proposed diagnostic tools for the detection of cardiotoxicity other than UCG are nuclear cardiac imaging , cardiac magnetic resonance, and cardiac biomarkers such as Troponin I and benign natriuretic peptide (BNP) . The adv123I-BMIPP) has been widely used in Japan to detect myocardial damage. 123I-BMIPP is a tracer for metabolism of fatty acid which is known to account for more than 90% of myocardial energy requirements [123I-BMIPP was introduced in Japan in the early 1990s. It is noted that 123I-BMIPP has still not yet been commonly used elsewhere. 123I-BMIPP is typically utilized in dual-isotope myocardial scintigraphy with 201-Thallium (201Tl) called Tl/BMIPP dual-isotope myocardial scintigraphy.Myocardial scintigraphy with Iodine-123 β-methyl-P-iodophenyl-pentadecanoic acid  intravenously. Single Photon Emission Computed Tomography (SPECT) images were acquired starting from 15 min after tracer injection using a digital gamma camera Symbia E .Tl/BMIPP dual-isotope myocardial scintigraphy was performed on an outpatient basis. Patients fasted for at least 6 h prior to the study, then were injected with 111Mbq of 201Tl and 123I-BMIPP database developed for Japanese patents by the Japanese Society of Nuclear Medicine working group [Myocardial SPECT images were then analyzed by the automated software program, Heart Risk View-S software . The software generated polar maps of the heart from myocardial SPECT data that are divided into 17 segments as recommended by the guideline of the American Heart Association : basal ring, mid-cavity ring, apical ring, and apex, as nomenclated by AHA [Since d by AHA . The aveA total of 100 patients were enrolled in this study. The anti-cancer treatments used for the patients are shown in Measuring LVEF was not possible for 9 patients (9%) due to anatomical issues such as surgery wounds, radiation scars, or implants. 4 patients (4%) were diagnosed with CTRCD according to the criteria of LVEF lower than 53%. However, no symptoms of heart failure were shown. One patient (Case A) was diagnosed with CTRCD 30 months prior to the study; however, her LVEF was normal at enrollment of this study. Another patient (Case B) was diagnosed with myocardial infarction during chemotherapy 18 months prior to this study; however, her LVEF was also normal at enrollment. The details of these 6 patients are described in 123I-BMIPP scores are higher in the middle rings of the 17-segment model. She had no other known cardiac diseases or coronary risk factors.Tl/BMIPP dual-isotope myocardial scintigraphy was performed for all patients. SPECT images, polar map with 17-segment model, and Heart Risk View-S scores deployed in 17-segment model were obtained. As an example of CTRCD, 123I-BMIPP uptake, however her LVEF was normal (74.4%). Her chest X-ray, electrocardiogram (ECG), and BNP level were all normal. Her scintigraphy data are shown in 123I-BMIPP uptake was remarkably low. She had no other known cardiac diseases or coronary risk factors. She was not diagnosed with CTRCD according to the current diagnostic criteria.One patient (Case G) revealed remarkably decreased 201Tl and 123I-BMIPP scintigraphy for CTRCD patients are shown in The total Heart Risk View-S scores of LVEF and the scores did not appear to be correlated. We evaluated the correlation in the next 201Tl scores may have been increased by artifacts; therefore, we focused on evaluating 123I-BMIPP. For most of the patients, 123I-BMIPP scores appeared to be higher in the middle rings as shown in 201Tl uptake reduction of all 100 patients are shown in Scatter plot of LVEF and Heart Risk View-S scores for 123I-BMIPP uptake reduction of all 100 patients are shown in Scatter plot of LVEF and Heart Risk View-S scores for 123I-BMIPP were randomly distributed, and the pattern of score distribution was different from that of 201Tl. These revealed that myocardial metabolism decreased diffusely unrelated to myocardial perfusion.All the SPECT images were visually evaluated by cardiologist, breast surgeon, and radiologist. The Heart Risk View-S scores of 123I-BMIPP uptake appeared to decrease more in the middle rings of 17-segment model. In order to evaluate the difference between the rings, the average Heart Risk Vies-S scores of each ring  were compared and mathematically analyzed using the software JMP 16.Upon visual evaluation, Equation (1) is for the vertical scale of the scatter plots in Equation (2) is for the horizontal scale of the scatter plots in p = 0.0012). However, there was not a significant difference between mid-cavity ring and apical ring (p = 0.7324), nor between apical ring and apex (p = 0.0981). The results are shown in We conducted paired two-sided t-test (significance level of 5%) for basal ring vs. mid-cavity ring, mid-cavity ring vs. apical ring, and apical ring vs. apex. According to null hypothesis for this t-test, there is not any difference between the average scores of the 2 paired rings. For multiple tests, we utilized Bonferroni correction. As a result, we found a significant difference between the average scores of basal ring and mid-cavity ring . Myocardial metabolism may have lowered prior to decrease in LVEF.Comparison of LVEF and Heart Risk View-S scores did not reveal any correlation. This is not good news for those who anticipated a new imaging modality replacing with UCG. If the scores of 123I-BMIPP uptake revealed mismatch with 201Tl uptake as expected. Distribution pattern of Heart Risk View-S scores was mathematically analyzed to show how and which part of the heart was damaged by chemotherapy. As a result, middle portions of the heart  were shown to be more damaged. It was a surprising observation that segments 6,12, and 16 revealed lower scores. It may therefore imply that LCX area was spared from damage. Further research is thereby anticipated.The results of this research constitute observational findings from scintigraphy that have not been heretofore used to evaluate CTRCD. UCG should be the first choice for diagnosis as it is less costly and less invasive than scintigraphy. Alternatively, for patients who cannot undergo UCG, myocardial scintigraphy may become a second choice. Isotopes for scintigraphy must be carefully selected, as each isotope has different characteristics. Nuclear cardiologic techniques visualize pathophysiologic processes at the tissue level; therefore, myocardial injury could be detected at an earlier stage . LVEF re123I-BMIPP was introduced as a promising new tracer in some reviews [123I-BMIPP has been used in Japan for over 2 decades, although it has not yet been approved by Food and Drug Administration (FDA) in the U.S. [123I-BMIPP scintigraphy performed for CTRCD [123I-metaiodobenzylguanidine (MIBG) and 123I-BMIPP for 13 patients who received chemotherapy with anthracycline [123I-MIBG and 123I-BMIPP, and reported that 123I-MIBG could detect myocardial damage at early stage because H/M ratio was lower in the chemotherapy group, while H/M ratio of 123I-BMIPP was similar with the control group. However, the H/M ratio is not an established method for evaluating 123I-BMIPP scintigraphy. Saito K et al. performed quantitative assessment of the early kinetics of 123I-BMIPP by dynamic myocardial SPECT for 26 patients receiving chemotherapy with doxorubicin, and reported that 123I-BMIPP uptake was significantly lower after chemotherapy than before hemotherapy [123I-BMIPP myocardial SPECT for 25 lung cancer patients to conclude that 123I-BMIPP is useful for evaluating the cardiotoxicity induced by taxan, because taxan impairs myocardial fatty acid metabolism [ reviews ,6,14. 12or CTRCD ,15,16. Tacycline . They us123I-BMIPP scintigraphy is also interrupted by certain illnesses, such as fatty acid translocase (FAT)/CD36 gene mutation or triglyceride deposit cardiomyovasculopathy (TGCV). FAT/CD36 gene mutation causes a total defect in 123I-BMIPP uptake, and its prevalence is 0.47% (33/6970) [123I-BMIPP for CTRCD screening. TGCV is a recently discovered disease which is known to cause decreased 123I-BMIPP uptake [123I-BMIPP uptake  . Another33/6970) . TherefoP uptake . TGCV isP uptake . This pa123I-BMIPP has shown possible early signs of CTRCD, it may thus be used for one of the screening tests, especially for patients who are unable to undergo UCG.Since the early detection and treatment of CTRCD is key to preventing adverse cardiovascular outcomes, new imaging modalities for screening have been anticipated. Biomarkers, cardiovascular magnetic resonance, positron emission tomography, and nuclear imaging have been discussed as potential candidates for screening ,21. It iThe world’s first guideline on onco-cardiology was published on 26 August 2022 [123I-BMIPP myocardial metabolism scintigraphy revealed possible early signs of CTRCD for breast cancer patients. 123I-BMIPP uptake has shown to decrease in the middle rings of the 17-segment heart model in this study. FAT/CD36 gene mutation and TGCV may be contraindications for 123I-BMIPP scintigraphy screening for CTRCD. For breast cancer patients who are unable to undergo UCG, 123I-BMIPP scintigraphy will become the preferable second-choice screening test for CTRCD.


Observational studies have shown that central obesity is associated with adverse cardiac structure and function. However, causal association between central obesity and left ventricular (LV) structure and function in preserved ejection fraction (EF) population is still uncertain.n = 224,459). Outcome datasets for LV parameters including LV end-diastolic volume (LVEDV), LV end-systolic volume (LVESV), LV ejection fraction (LVEF), LV mass (LVM), and LV mass-to-end-diastolic volume ratio (LVMVR) were obtained from the participants without prevalent myocardial infarction or heart failure (LVEF ≥ 50%) in UK Biobank Cardiovascular Magnetic Resonance sub-study . Two-sample Mendelian randomization (MR) was performed with the inverse-variance weighted (IVW) method as the primary estimate and with the weighted median and MR-Egger as the supplemental estimates. Sensitivity analysis was used to assess the heterogeneity and pleiotropic bias in the MR results.Genome-wide association studies summary data of waist circumference adjusted for body mass index (WCadjBMI) and waist-to-hip ratio adjusted for body mass index (WHRadjBMI) were selected as instrumental variables from the Genetic Investigation of Anthropometric Traits (GIANT) Consortium (P = 6.418 × 10–8) and lower LVEDV  after Bonferroni adjustment. No heterogeneity and horizontal pleiotropy were detected in the analysis. No association of WCadjBMI was found with LVEF, LVEDV, LVESV, LVM, or LVMVR.In the IVW analysis, every 1-standard deviation (SD) higher WHRadjBMI was significantly associated with higher LVMVR (β = 0.4583; 95% confidence interval [CI]: 0.2921 to 0.6244; Our findings provide evidence of significant causal association between WHRadjBMI and adverse changes in LV structure and function in preserved EF population. Heart failure (HF) is a global health epidemic and burden, leading to increased morbidity and mortality . The totObesity is commonly defined by body mass index (BMI) to describe the total adipose accumulation. However, regional fat distribution may play a pivotal role in the development of HF . CentralMendelian randomization (MR) is an epidemiological technique capable of elucidating causal estimate of exposures to outcomes, using genetic variants as instrumental variables (IVs) . As genevia the exposures of interest (As shown in interest .P < 5 × 10–8) were obtained in 224,459 European individuals from the Genetic Investigation of Anthropometric Traits (GIANT) Consortium  among the SNPs based on the 1000 Genomes European reference panel  as instrumental variables associated with WCadjBMI and WHRadjBMI at the genome-wide significance level (nsortium  16). Af. AfP < 5ce panel , we extratabase1 . Additioatabase1 , 2 were atabase1 . F statiariables .The outcomes of the study were selected based on the GWAS conducted by Aung et al. comprising 16,923 European UK Biobank participants without prevalent myocardial infarction or heart failure (LVEF in every participant ≥ 50%) to identify the genetic loci for 6 relevant cardiac magnetic resonance (CMR)-derived LV imaging phenotypes, including LV end-diastolic volume (LVEDV), LV end-systolic volume (LVESV), LV stroke volume (LVSV), LV ejection fraction (LVEF), LV mass (LVM), and LV mass-to-end-diastolic volume ratio (LVMVR) . The GWA2 according to Burgess’s method (The random effects inverse-variance weighed (IVW) was used as the main MR method in our study while MR-Egger, weighted median and MR-PRESSO were also performed for more robust estimates. IVW analysis estimates the effect of each SNP on the outcome by calculating the Wald ratio and performs a meta-analysis for the combined causal effect with the inverse variance of SNPs as weights . MR-Egges method .P-value < 0.005 (0.05/10) was considered a significant association, and a P-value < 0.05 and ≥ 0.005 was regarded as nominally significant after Bonferroni adjustment.All analyses were performed in R software (version 4.2.1) using the packages Two SampleMR (version 0.5.6) and MR-PRESSO (version 1.0). The association with F statistics  without horizontal pleiotropy  and higher LVMVR . Additionally, every 1-SD increase in genetic liability to WHRadjBMI was nominally significantly associated with lower LVESV  and higher LVM . Weighted median and MR-Egger analyses also showed similar associations  we could not further explore the causal association upon gender, age, etc. via subgroup analyses because our study used the summary-level data rather than individual-level data; (2) our study was confined to individuals of European descent, which limits the generalizability of the findings to other populations; (3) central obesity in our study did not include measurement of visceral fat, which is closely associated with cardiac structure and function as well; (4) all exposure data from the individuals with preserved LVEF in UK Biobank led to healthy worker effect.Our two-sample MR analysis had several strengths: (1) The MR method could minimize confounding and reverse causality compared with conventional observational studies; (2) all summary data were based on the population from European descent, which effectively mitigated the bias of population stratification; (3) to reduce pleiotropic effects, we selected the IVs through a rigorous procedure and no significant pleiotropy was observed In summary, this MR study supports the genetic causality between WHRadjBMI and adverse changes in LV structure and function in preserved EF population. Our findings may strengthen our understanding of the critical role of central obesity in cardiac remodeling.https://gwas.mrcieu.ac.uk/. Data on LV parameters were contributed by the UK Biobank investigators and have been downloaded from https://www.ebi.ac.uk/gwas/home.Data on WCadjBMI and WHRadjBMI have been contributed by the GIANT investigators and have been downloaded from the IEU OpenGWAS Project  at: Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.JZo and YG designed the study. YG and JZe performed the data analysis and drafted the manuscript. FZ, XZ, ZQ, YW, and XH revised the manuscript. JZo supervised the study and acquired funding for the work. All authors have read and agreed to the published version of the manuscript.


The purpose of the present study was to determine retrospectively whether the quantitative indices of Sixty-eight patients with biopsy-proven ATTRwt-CM who underwent PYP SPECT/CT were enrolled. Baseline clinical characteristics, echocardiographic parameters, and qualitative and/or quantitative indices of planar and SPECT/CT imaging in PYP scintigraphy for each patient were included. For quantitative analysis of SPECT/CT, the accumulation ratio of PYP in the septum, posterior, anterior, lateral, and apex walls to the cavity pool was calculated as the septal wall-to-cavity ratio (Se/C), lateral wall-to-cavity ratio (La/C), anterior wall-to-cavity ratio (An/C), inferior wall-to-cavity ratio (In/C), and apical wall-to-cavity ratio (Ap/C), respectively. Endpoints for prognostic accuracy evaluation were cardiac death or hospitalization due to heart failure. Event-free survival rate was evaluated through Cox proportional hazards regression analysis, providing estimated hazard ratios (HRs) with 95% confidence intervals (CIs) and Kaplan–Meier curves.E/e′ ratio in the septal wall were significantly associated with event-free survival (P < 0.05). For a multivariable Cox proportional hazards analysis, hs-cTnT , La/C , and age  were significant independent prognostic factors.High-sensitivity cardiac troponin T (hs-cTnT), La/C, age, interventricular septal thickness in diastole, and This study indicated that the quantitative indices of PYP SPECT/CT can help to predict the prognosis of ATTRwt-CM patients. Wild-type transthyretin-related amyloidosis cardiomyopathy (ATTRwt-CM) is associated with heart failure in a considerable number of elderly patients . An autoCardiac amyloidosis (CA) results from the progressive accumulation of amyloid protein in the myocardial interstitium and is associated with increased wall thickness, and it can cause diastolic and systolic dysfunctions; cardiac involvement greatly influences the prognosis outcome . The gol99mTc-pyrophosphate (PYP) and 99mTc-3,3-diphosphono-1,2-propanodiacarboxylic acid (DPD), show specific features for transthyretin-related amyloidosis (ATTR) deposits. International scientific literature agrees on the usefulness of bone-avid compounds for the accurate identification of transthyretin [Bone-avidity, phosphate-based isotopes, including thyretin , and PYPthyretin , 7.99mTc-methylene diphosphonate (MDP) scintigraphy is said to be more useful for single-photon emission tomography (SPECT) than planar imaging [For qualitative and quantitative evaluation of myocardial accumulation of PYP planar images in ATTR-CM patients, the Perugini grading system and heart-to-contralateral ratio (H/CL) are reported to have prognostic utility . However imaging –13, ther imaging . FurtherBetween November 2013 and November 2020, 568 patients underwent PYP SPECT/CT at our hospital. Of these, 148 patients had cardiac biopsy and 85 proved to be ATTRwt-CM cases. Of the 85 patients with ATTRwt-CM, 17 were excluded due to inadequate follow-up data. Ultimately, 68 patients were enrolled and their baseline demographic characteristics, co‐morbidities, laboratory results, echocardiographic data, imaging data, and pathological findings were recorded. Clinical examination was performed while each patient was in a clinically stable, non‐congestion condition.This study was conducted in accordance with the principles outlined in the Declaration of Helsinki. The institutional review board of our institution approved the study and waived the necessity of obtaining informed consent.Diagnosis of amyloid deposition in the myocardium was based on Congo red staining and apple‐green birefringence with cross‐polarized light microscopy. To confirm the presence of transthyretin (TTR) in the amyloid, immunohistochemical staining was performed using antibodies that react with TTR. Wild-type transthyretin-related amyloidosis (ATTRwt) was diagnosed based on the absence of mutation in the TTR gene, which was ascertained through genetic testing, or the absence of a family history of amyloidosis in the elderly patients if genetic testing was not performed.Each patient’s baseline clinical characteristics were classified as follows: gender, age, body mass index (BMI), body surface area (BSA), history of hypertension, diabetes mellitus (DM), dyslipidemia (DL), chronic kidney disease (CKD), systolic blood pressure (SBP), diastolic blood pressure (DBP), hemoglobin (Hb), hemoglobin A1c (HbA1c), high-density lipoprotein cholesterol (HDL-cho), low-density lipoprotein cholesterol (LDL-cho), creatinine (Cr), estimated glomerular filtration rate (eGFR), C-reactive protein (CRP), brain natriuretic peptide (BNP), high-sensitivity cardiac troponin T (Hs-cTnT), New York Heart Association (NYHA) functional Class, and each indicator of echocardiography.E/eʹ) in the septal and lateral wall , which was determined by pulsed wave tissue Doppler imaging. Trans-mitral peak flow velocities were measured from mitral inflow velocities. LVEF was calculated using a modified Simpson’s method [Echocardiography was performed using commercially available ultrasound equipment. Chamber size and wall thickness were measured in the transthoracic view. Echocardiographic findings included left ventricular ejection fraction (LVEF), left ventricular end diastolic volume (LVEDV), left ventricular end systolic volume (LVESV), interventricular septal thickness in diastole (IVSTd), posterior left ventricular wall thickness in diastole (PLVWd), and the ratio between early mitral inflow velocity and mitral annular early diastolic velocity . To enable CT-based attenuation correction (CTAC), non-contrast enhanced helical CT images  were obtained with breath-holding in resting exhalation position. After registration of the SPECT and CT images, a CT-derived attenuation-coefficient map was created. Projections and reconstructed matrix size were 128 × 128 pixels, with a pixel size of 4.42 × 4.42 mm. The 3-dimensional ordered subset expectation maximization (3D-OSEM) iterative reconstruction  was done both with CTAC and DEW scatter correction. 3D-OSEM images were also filtered after reconstruction with a Butterworth filter . Reconstruction of SPECT images was performed on the Xeleris workstation .PYP scintigraphy was performed using a GE Discovery 670 dual‐headed SPECT/CT camera . All patients were intravenously administered 555–740 MBq of PYP and planar and SPECT/CT imaging were performed 3 h later. Anterior and lateral planar images were acquired for 5 min each with a large field of view (FOV), using a 256 × 256 matrix with a 1.5 zoom factor, and the energy window was set at 140.5 keV (± 10%) with low‐energy, high‐resolution (LEHR) collimators. Following the planar imaging, SPECT imaging was obtained with LEHR collimators using a 10% energy window centered on the 140.5 keV photopeak in the main-energy window and a 5% energy window centered on the 120.0 keV photopeak in the sub-energy window for the dual-energy-window (DEW) scatter correction2 circular ROI was placed at the maximum uptake area of the septal and lateral walls on the axial SPECT/CT image and of the anterior, inferior and apical walls on the coronal SPECT/CT image , lateral wall-to-cavity ratio (La/C), anterior wall-to-cavity ratio (An/C), inferior wall-to-cavity ratio (In/C), and apical wall-to-cavity ratio (Ap/C).For quantitative analysis in both planar and SPECT images, region-of-interest (ROI) measurements were performed in consensus with two experienced nuclear imaging specialists blinded to all patient data. For the analysis of planar images, a circular ROI was drawn over the heart, which was copied and mirrored to the contralateral chest to normalize background uptake. Mean total heart ROI counts were measured and corrected for contralateral chest ROI counts by calculating a heart-to-contralateral (H/CL) ratio . In the age Fig. . A 1 cm2The endpoint for prognostic assessment was cardiac death or hospitalization due to heart failure. For each patient in the event group, an event date was set as the first occurrence of one of the events during the follow-up period. Baseline dates were the same as the date when PYP scintigraphy was performed. Associations between the baseline clinical characteristics and the prognosis were analyzed.t test. Categorical variables were compared using the Chi-square test. Event-free survival was evaluated with Cox proportional hazards regression analysis, providing estimated hazard ratios (HRs) with 95% confidence intervals (CIs) and Kaplan–Meier curves. All variables were first explored with univariate Cox regression analysis. The variables that were statistically significant predictors of prognosis on simple Cox regression analysis were entered into a multivariable Cox proportional hazards analysis to determine which covariates were independent predictors of a prognosis. Patients were stratified according to indicators with significant differences and patient prognosis was compared using the log-rank test. The optimal cutoff value of each parameter was determined as a value to maximize the Youden Index. A two‐tailed value of P < 0.05 was considered statistically significant. All statistical analyses were performed using SPSS software .Parameters of continuous variables were expressed as mean ± standard deviation (SD), whereas categorical values were presented as numbers (percentages). Continuous variables were compared in two groups (event-free group vs. event group) with the student Baseline characteristics of all patients are shown in Table E/eʹ septal were significantly associated with event-free survival (P < 0.05); the HR was 1.137 (95% CI 1.055–1.225) for hs-cTnT, 2.297 (95% CI 1.146–4.601) for La/C, 1.085 (95% CI 1.001–1.175) for age, 1.177 (95% CI 1.009–1.373) for IVSTd, and 1.064 (95% CI 1.002–1.130) for E/eʹ septal. In the multivariable Cox proportional hazards analysis (Table P < 0.01), La/C , and age    were the best predictors for all causes of mortality in ATTRwt-CM patients with advanced heart failure due to amyloid cardiomyopathy [. In our study, BNP and albumin levels, and LVEF were not statistically significant indicators as prognostic factors.In this study, hs-cTnT and also age were significant independent factors for predicting prognosis in ATTRwt-CM patients. Some prognostic indicators for ATTR-CM patients have been previously reported. A staging system with a combination of NT‐proBNP and serum hs‐cTnT levels or estimated glomerular filtration rate was proposed for predicting the survival period of ATTR‐CM patients , 18. In myopathy . Ochi etmyopathy . Yamada myopathy . In our Although several SPECT quantification methods have been presented, this study used the accumulated ratio of the myocardial wall to the left ventricular cavity as the quantitative indices of PYP SPECT/CT. A standardized uptake value (SUV) can be used as a quantitative index of PYP SPECT/CT , 23. HowOur study has some limitations. First, the number of patients was relatively small. Only patients with ATTRwt-CM confirmed by cardiac biopsy were included. Second, cardiac death or hospitalization due to heart failure became the endpoints for the prognostic assessment as the duration of the research was relatively short. A longer period is required to clearly assess the survival rate of ATTRwt-CM patients. Finally, late gadolinium enhancement (LGE) and extracellular volume (ECV) data from the MR imaging were not used in this study. Further study is being planned to compare the degree and distribution of PYP myocardial accumulation with ECV and LGE data from MRI.This study showed that La/C, hs-cTnT, and age were significantly independent prognostic factors in ATTRwt-CM patients. Among the metrics of myocardial uptake on PYP planar and SPECT/CT images, La/C can be a useful biomarker for predicting the prognosis of such patients.


In the last few years, in the context of a growing interest in investigating novel pathways involved in heart failure (HF) pathophysiology, the association between the gastrointestinal (GI) system and HF represents an important model of attention, the so called ‘gut hypothesis’.FigureTo date, most of the research has identified a choline and L‐carnitine metabolic by‐product, trimethylamine N‐oxide (TMAO), derived by the gut microbiota from the precursor trimethylamine (TMA) and subsequent oxidation via the liver enzyme flavin‐containing monooxygenase 3 (FMO3) From a clinical point of view, since the first investigations regarding the association between TMAO and HFrEF as of about 10 years ago,The role of TMAO in risk stratification is not limited to the chronic setting; indeed, TMAO showed its value also in the acute setting, in which elevated levels (except in one investigation)Finally, when all these findings have been analysed in three independent meta‐analyses, consistent results show elevated TMAO levels are associated with poor prognosis  in HF patients, even when adjusted for multiple confounders.ESC Heart Failure journal, Li et al. showed that elevated TMAO levels were associated with poor prognosis  in patients with acute myocardial infarction complicated by HF,In this context, in the present issue of the Another finding of interest of the present investigation, considering the positive dose‐dependent association between TMAO plasma levels and increased cardiovascular risk and mortality,One important limitation for the present study is the lack of dietary information. Indeed, adjusting TMAO data for dietary information is paramount to ascribing the ‘true’ normal ranges, association with HF/MI and intervention in a ‘real‐world’ scenario. To elaborate, TMAO levels in Caucasian patients showed increased association with adverse outcomes, but not in non‐Caucasian patients despite any differences between ethnicity and association with outcome, suggesting that dietary sources could be the contributing factor.Figure Notably, TMAO is just the ‘tip of the iceberg’ of one of the complex pathways involved in the association between the gut and the cardiac metabolism .The importance of the association between GI and HF goes further with the identification of novel biomarkers for risk stratification.In conclusion, data available from literature so far have shown that TMAO levels are increased in HF patients compared with healthy subjects and that elevated levels are associated with a poor prognosis. Although additional studies needed to address the current limitations in the field, TMAO, its precursors, and the gut‐derived biomarkers in general, represent a promising biomarkers of risk stratification with a possible role as a therapeutic target in the future.None.