Objective: To screen all newborns admitted to a tertiary care hospital to rule out congenital heart disease before discharge and to find out the utility of pulse oximetry to detect congenital heart disease.Methodology: This prospective study was done at Aga Khan University Hospital from January 2014 to December 2014 in 1,650 newborns over a period of 12 months. Pulse oximetry and clinical examination were done. Persistent oxygen saturation less than 95% was considered as positive pulse oximetry. Newborns who had positive pulse oximetry or abnormal clinical examinations findings were subjected to echocardiography.Results: Pulse oximetry was performed on 1,650 newborns, out of which 25 (1.5%) had congenital heart disease. Positive pulse oximetry cases were 16 (0.97%), out of which 10 had only positive pulse oximetry . Positive clinical examination cases were 45 (2.7%), out of which 39 cases had only positive clinical examinations (negative pulse oximetry). Six newborns had both positive pulse oximetry and positive clinical examination. Out of the 25 diagnosed cases of congenital heart disease, ventricular septal defect (VSD) was the most common congenital heart disease, followed by patent ductus arteriosus (PDA). The sensitivity, specificity, positive predictive value, and negative predictive value of pulse oximetry were 32%, 99.5%, 50%, and 98.9% respectively.Conclusion: In the community setting of a developing country, a combination of pulse oximetry screening and clinical examination are better at detecting congenital heart defects than either test alone. Congenital heart disease (CHD) is the commonest group of congenital malformations, affecting 7 to 8 out of every 1,000 newborns . One of This hospital-based prospective study was conducted at the Aga Khan University Hospital, Karachi from January 2014 to December 2014. All newborns admitted to the Well Baby Unit and NICU during the study period were enrolled after taking informed consent from the parent. All those newborns who had gestational age < 34 weeks, birth weight < 1.5 kg, discharge before 48 hours of life, and those babies who were very sick, on a mechanical ventilator, and in whom stable pulse oximeter signals could not be obtained were excluded from the study. The study protocol was approved by the Ethics Review Committee of Aga Khan University.2) measurements of all neonates were recorded by registered nurses using the Ohmeda 3700 pulse oximeter. For each newborn, oxygen saturation at birth, 24 hours, and 48 hours of life were obtained. The pulse oximeter probe was applied on either foot. The recordings were noted after obtaining stable pulse oximeter signals. A SpO2 of ≥ 95% was defined as negative pulse oximetry screening (POS). POS was positive when a SpO2 of ≤ 94% was documented and it was rechecked after one hour. If still positive, it was followed by echocardiography. If the POS was negative, no further workup was done. Clinical examination screening was performed for all newborns with special reference to signs and symptoms related to the cardiovascular system to detect congenital heart disease. Presence of central cyanosis, heart murmurs, abnormal peripheral pulses, abnormal precordium, and tachypnea were taken as positive clinical examination findings suggestive of congenital heart disease [Oxygen saturation  were females and 726 (44%) were males. The mean age was 38.9 weeks. Out of the 1,650 screened cases for pulse oximetry, 16 (0.97%) had positive pulse oximetry. On the other hand, on clinical examination, 45 (2.7%) newborns had positive findings suggestive of congenital heart disease. Six newborns were found to be positive for both pulse oximetry and clinical examinations. In this study, 10 newborns only had positive pulse oximetry and 39 only had a positive clinical examination. On echocardiography of all 55 positive cases, we found 25 newborns had congenital heart disease . Both cases were considered as normal because they were expected to improve with age and required no follow-up. The total congenital heart disease cases detected in our study was 25 (1.5%) out of 1,650 newborns. The sensitivity, specificity, positive predictive value, and negative predictive value of pulse oximetry were 32%, 99.5%, 50%, and 98.9%, respectively , atrial septal defect (ASD), and pulmonary atresia (PA) with an intact ventricular septum (IVS) in this study.Diagnosis and treatment of congenital heart disease have changed dramatically over the last few decades. The relative importance of preoperative morbidity and mortality has been increasing as a result of the great improvements in perioperative and long-term survival. In our study, 25 (1.5%) newborns were detected to have congenital heart disease out of total 1,650 screened cases. Among the congenital heart disease diagnosed, VSD was the most common congenital heart disease, followed by PDA, ASD, and PA with an IVS. Kalita et al. found 34 (1.98%) cases with congenital heart disease in their study of 1,720 newborns . HoweverThis study highlights some restrictions of only POS in developing countries. No prior study applying such methodology has been carried out in Pakistan. The present study reviews the sensitivity, specificity, positive predictive value, and negative predictive value of pulse oximetry screening and clinical examination. In our study, we found the sensitivity, specificity, positive predictive value, and negative predictive value of POS to detect CHD were 32%, 99.5%, 50%, and 98.9%, respectively. Vaidyanathan et al.  from KerThe findings of our study suggested that the benefits of POS shown in high-income countries could be translated to low-income developing countries (like Pakistan) with great success, but clinical examination should be included as part of the screening to detect congenital heart disease.The combination of POS and clinical examination is better at detecting congenital heart defects than either pulse oximetry or clinical examination alone. By detecting congenital heart defects early, infants can often be treated in a timely fashion and lead longer healthier lives.


TTN). This is the first case to propose an overlap syndrome of PPCM and arrhythmogenic RV cardiomyopathy.A middle-aged female patient presented with increasing dyspnoea following delivery of her second child. Echocardiography showed left ventricular (LV) dilatation and severe global impairment of systolic function (ejection fraction < 10%) but normal right ventricular (RV) dimensions. Plasma B-type natriuretic peptide level was elevated. Post-partum cardiomyopathy (PPCM) was considered and after initiating appropriate heart failure pharmacotherapy, her symptoms improved significantly. Cardiovascular MR showed RV free wall dyskinesia and aneurysms at the LV apex, RV free wall and RV outflow tract. Genetic analysis showed a C11842T substitution in the titin gene ( Echocardiography showed a dilated left ventricle with severe global impairment of systolic function and an ejection fraction (EF) < 10%, with, however, normal right ventricular (RV) dimensions. Post-partum cardiomyopathy (PPCM) was diagnosed and appropriate heart failure pharmacotherapy was initiated. Subsequently, cardiovascular magnetic resonance (CMR) imaging showed increased left ventricular (LV) end-diastolic and end-systolic volumes and mild global impairment of LV systolic function, confirming an improvement in the systolic function when compared with the initial echocardiogram. RV volumes and function were normal. However, new RV free wall dyskinesia was noted and, additionally, aneurysms at the LV apex (Supplementary Videos A and B), RV free wall [Supplementary Video C] and outflow tract and thinning of the basal septum were observed. Diagnostic coronary angiography revealed unobstructed major epicardial coronary arteries.A middle-aged female patient from a consanguineous family presented with increasing dyspnoea and in New York Heart Association functional class II, 2 weeks after delivery of her second child. Plasma B-type natriuretic peptide level was elevated at 807 pg ml-–1 . However, in this case, they are without concomitant RV dilatation or impairment required to make a CMR diagnosis by the Revised Taskforce Criteriathe apex  in the c(MYBPC3), which has previously been shown to be causative for dilated cardiomyopathy (DCM)3. In addition, a novel, non-synonymous single nucleotide polymorphism was shown in the titin gene (TTN): there was a C11842T substitution, resulting in a single amino acid change from arginine to cysteine at the 3948 position. Titin plays a key role in cardiac sarcomere assembly, force transmission and maintenance of resting tension4. TTN mutations have previously been implicated in several conditions, including DCM5 and ARVC overlap syndromes6. No desmosomal gene abnormalities were identified. In our study, we describe a case of RV aneurysms and dyskinesia together with PPCM findings, which is likely to reflect an overlap syndrome.In this patient, genetic analysis demonstrated a potential pathogenic mutation of the cardiac myosin-binding protein-C gene A spectrum of cardiomyopathic processes exists as reflected in overlap syndromes.Cardiovascular MRI is useful for the diagnosis of cardiomyopathy and subsequent disease characterization and future monitoring.TTN is a crucial gene that regulates myocardial function.TTN have been associated with DCM and ARVC. Mutations in


In-vivo cardiovascular magnetic resonance (CMR) diffusion tensor imaging (DTI) allows imaging of alterations of cardiac fiber architecture in diseased hearts. Cardiac amyloidosis (CA) causes myocardial infiltration of misfolded proteins with unknown consequences for myocardial microstructure. This study applied CMR DTI in CA to assess microstructural alterations and their consequences for myocardial function compared to healthy controls.Ten patients with CA  and ten healthy controls were studied using a diffusion-weighed second-order motion-compensated spin-echo sequence at 1.5 T. Additionally, left ventricular morphology, ejection fraction, strain and native T1 values were obtained in all subjects. In CA patients, T1 mapping was repeated after the administration of gadolinium for extracellular volume fraction (ECV) calculation. CMR DTI analysis was performed to yield the scalar diffusion metrics mean diffusivity (MD) and fractional anisotropy (FA) as well as the characteristics of myofiber orientation including helix, transverse and E2A sheet angle .− 3 vs 1.41 ± 0.07 10− 3 mm2/s, p <  0.001; FA 0.25 ± 0.04 vs 0.35 ± 0.03, p <  0.001). MD demonstrated an excellent correlation with native T1  while FA showed a significant correlation with ECV in the CA population . HA exhibited a more circumferential orientation of myofibers in CA patients, in conjunction with a higher TA standard deviation and a higher absolute E2A sheet angle. The transmural HA slope was found to be strongly correlated with the global longitudinal strain .MD and FA were found to be significantly different between CA patients and healthy controls  contains supplementary material, which is available to authorized users. Amyloidosis is a multi-system disease that is caused by the synthesis and accumulation of unstable and misfolded proteins leading to a loss of normal tissue architecture and function . While aFor the assessment of cardiac amyloidosis (CA), cardiac imaging plays a fundamental role . BesidesRecently, CMR diffusion tensor imaging (DTI) emerged as a promising method for the determination of myocardial fiber orientation –13 and tThe objective of this study was to determine the consequences of amyloid infiltration on myocardial microstructure in-vivo using CMR DTI and to investigate their effect on myocardial function. Scalar diffusion and relaxation metrics  were correlated in CA patients and controls. In addition, directional diffusion information was assessed to reveal changes in myofiber orientations and compared to parameters of left ventricular (LV) function.2 and the standard exclusion criteria for CMR , p < 0.001, Fig. r = − 0.715, 95% CI ; p < 0.001; Fig. r = 0.744, 95% CI ; p = 0.014; Fig. r = − 0.851, 95% CI ; p < 0.002; Fig. Direct comparison between native T1 values versus MD over the whole study population demonstrates an excellent correlation between the two parameters  of 0.96  for MD and 0.97  for FA which were not significantly different from the diagnostic performance of native T1 . Additional file tmd; p < 0.001). In case of the patients, this leads to a reduced longitudinal orientation of fibers in the epicardial and endocardial layers compared to the controls as shown in the bullseye plots in Fig. Figure p = 0.07). The standard deviation per segment, however, is significantly larger in the CA patients  indicating a higher level of deviation from the circumferential alignment of the myocardial fibers found in healthy subject myocardium. Representative TA maps are shown in Fig. The TA is close to zero degrees in both groups with no significant difference between CA patients and healthy controls .The most prominent difference in the myocardial microstructure between CA patients and healthy controls becomes evident in the comparison of the absolute E2A sheet angle. Patients exhibited higher mean absolute E2A sheet angles in every segment with values approximately 20° greater than those of healthy subjects Additional file 2:Figure S2. (PDF 61 kb)


Introduction: Relaxin-1 (RLN1) has emerged as a possible therapeutic target in myocardial fibrosis due to its anti-fibrotic effects. Previous randomized clinical trials investigated therapeutic role of exogenous relaxin in patients with acute-on-chronic heart failure (HF) and failed to meet clinical endpoints. Here, we aimed to assess endogenous, circulating RLN1 levels in patients with heart failure with reduced ejection fraction (HFrEF) of ischemic origin. Furthermore, we analyzed relation of RLN1 and left ventricular diastolic function, left and right ventricular fibrosis, and invasive hemodynamic measurements. Unique feature of our study is the availability of ex vivo human myocardial tissue.Methods: Human myocardial samples were available from the Transplantation Biobank of the Heart and Vascular Center at Semmelweis University after local ethical approval and informed consent of all participants (n = 47). Tissue was collected immediately after heart explantations; peripheral blood was collected before induction of anesthesia. Myocardial sections were stained for Masson’s trichrome and Picrosirius red staining to quantify fibrosis. Medical records were analyzed .Results: Average RLN1 levels in HFrEF population were significantly higher than measured in age and gender matched healthy control human subjects (702 ± 283 pg/ml in HFrEF vs. 44 ± 27 pg/ml in control n = 47). We found a moderate inverse correlation between RLN1 levels and degree of myocardial fibrosis in both ventricles . Parallel, a moderate positive correlation was found in left ventricular diastolic function  and RLN1 levels ; a negative correlation with RLN1 levels and left ventricular end-systolic diameter , and diastolic pulmonary artery pressure . RLN1 levels showed moderate correlation with RLN2 levels .Conclusion: Increased RLN1 levels were accompanied by lower myocardial fibrosis rate, which is a novel finding in our patient population with coronary artery disease and HFrEF. RLN1 can have a biomarker role in ventricular fibrosis; furthermore, it may influence hemodynamic and vasomotor activity via neurohormonal mechanisms of action. Given these valuable findings, RLN1 may be targeted in anti-fibrotic therapeutics and in perioperative care of heart transplantation. Relaxin (RLN) is a polypeptide hormone that was first examined for its potential role in reproduction and pregnancy. RLN1 and 2 were reported to increase the collagen solubility in the cervix of the uterine, as well as to soften the pubic symphysis in the pregnant women . The RLNIschemic heart disease is one of the most important causes of heart failure (HF). A key mechanism of HF is cardiac remodeling caused by myocardial fibrosis and cardiomyocyte injury . There aUnique feature of our study is the availability of human myocardial tissue samples (explanted failing hearts) for molecular biology and histology investigations, parallel with a high volume clinical database and clinical datasets in the perioperative period of heart transplantation surgeries. We aimed to evaluate perioperative blood tests, echocardiography, and invasive hemodynamic measurements in comparison with circulating RLN1 levels. We hypothesized that circulating RLN1 levels affect the degree of left and right ventricular myocardial fibrosis and act via the Notch signaling pathway in the failing human myocardium. To underpin our hypothesis, we quantified left and right ventricular myocardial fibrosis and its correlation with circulating RLN1 and investigated gene expression levels of RLN1 and Notch-1 signaling. Furthermore, we aimed to compare relaxin levels with echocardiography results and hemodynamic parameters in the context of postoperative vasoplegia syndrome as well.The study population comprised of 47 patients with HF with reduced ejection fraction (HFrEF), ischemic etiology and clinical criteria for heart transplantation. All of our patients were active on heart transplantation waiting list upon recruitment. The Heart and Vascular Center at Semmelweis University runs a detailed database for the Transplantation Biobank, in which full medical history, anthropometry, clinical data, medications, blood tests, echocardiography results, pharmacologic, and device therapy such as pacemaker (PM), implantable cardioverter defibrillator (ICD), cardiac resynchronization therapy (CRT), and mechanical circulatory support (MCS) data are available upon retrospective collection. For this study, end-stage HF patients with ischemic etiology were recruited. For control subjects, healthy volunteers of a cross-sectional voluntary cardiovascular screening program   were ageBlood sampling for all HFrEF patients was performed immediately before induction of the anesthesia for heart transplantation surgery. Blood sampling among healthy controls was performed at random time points on their visit of our epidemiology study. Echocardiography was performed by various number of investigators from the Heart and Vascular Center and other cardiology centers. Echocardiography data were obtained from the database of the Transplantation Biobank. Given the wide range of referring institutes for a heart transplantation, incomplete echocardiography reports existed, which limits interpretation of advanced imaging (such as TDI or speckle tracking). Echocardiography was performed at the time of candidacy and referral for the heart transplantation list. Invasive hemodynamic measurements were carried out via pulmonary artery catheterization (PAC) to assess eligibility for heart transplantation within 1 month of referral, and at multiple time points in the perioperative period. All patients had PAC and invasive hemodynamic measurements at 24 h follow-up, post-operatively.In the Transplantation Biobank of the Heart and Vascular Center at Semmelweis University, we gather various samples of the patients with end-stage heart disease who undergo heart transplantation at the Heart and Vascular Center at Semmelweis University. These samples include the explanted heart for histology and molecular biology probes, and blood samples.The main steps of the biobanking procedure are the following: first, whole blood is drawn from recipients. After clotting and centrifugation, serum is aliquoted and stored immediately at −80°C for further evaluation. Immediately after excision of the recipients’ heart, sections of left, and right ventricles are freshly frozen in liquid nitrogen in the operation theaters; other samples from the same myocardial areas are preserved in formaldehyde. Later, freshly frozen samples are stored in −80°C and sections in formaldehyde are processed for embedding and tissue histology. The biobanking procedure is strictly organized in 24/7 and follows standard operation protocols.Circulating RLN1 levels were measured from collected serum with solid phase sandwich ELISA . Experimental steps strictly followed product catalog guide. Relaxin-2 (RLN2) levels were also measured from serum . To further assess levels of standard and novel cardiac biomarkers, NT-pro-BNP, CA125 and cholinesterase were measured in our blood laboratory, on site.Sigma Aldrich, 365548) staining. Both methods are gold standard in the examination of tissue fibrosis, however, they are not specific for interstitial myocardial fibrosis.We evaluated the extent of myocardial fibrosis on paraffin-embedded sections of the anterior wall segments of both left and right ventricles  with Masson’s trichrome  and Picrosirius red  and for 5 min in Masson’s trichrome solution, followed by differentiation with 5% phosphortungstic acid for 10 min and Aniline blue for 5 min . For the washing, 0.2% acetic acid  was used. The stained sections were scanned and analyzed at 20× magnification . The digital pictures were taken by Zeiss Axio microscope. In order to assess average myocardial fibrosis, two sections were processed from each sample and pictures of five different areas were scanned from each section (strictly capturing the right and left upper and lower extremities and the center of each section), thus altogether 20 independent images per sample were taken. The quantitative analyzes of the images were carried out with software ImageJ (bundled with 64-bit Java 1.8.0_112). For all images to be analyzed, the software applies a color transformation from the RGB to the CIE LAB color space. Then for each component  specific thresholds were applied, which identified the compartments of interest the best. After the assessment of all the components in pixel, the software presents the results in a table, including the percentage of the fibrotic area: fibrotic area/(fibrotic area + area occupied by cardiomyocytes and cardiac vasculature).® Evolution homogenizer equipped with a Cryolys® dry ice cooling system . Experimental procedure strictly followed product catalog guides. RNA concentrations were measured by spectrophotometry in NanoDrop . cDNA was reverse transcribed from extracted RNA using the High Capacity cDNA Reverse Transcription Kit . TaqMan Gene Expression Assays were used to quantify the mRNA expression levels of genes of interests: Relaxin-1 (Hs04194320_s1), Notch-1 (Hs01062014_m1), and ACTA-2 (Hs00426835_g1). Human glyceraldehyde 3-phosphate dehydrogenase GAPDH (Hs02758991_g1) was used as endogenous housekeeping gene. The PCR was performed with real-time PCR instrument  and the relative expressions were determined by ΔΔCt method.For quantitative real time PCR, fresh frozen interventricular septum samples of patients with end stage HF were analyzed. Total RNA was isolated with the RNeasy Mini kit  following homogenization of all tissue samples in a PrecellysThis study was carried out in accordance with the recommendation of the Hungarian Medical Research Council [ETT TUKEB 7891/2012/EKU (119/PI/12.) and TUKEB 73/2005] and their ethical approval of standard operation protocols of the Transplantation Biobank of the Heart and Vascular Center at Semmelweis University. The healthy subjects were assessed via the Budakalasz Health Examination Survey (ETT TUKEB 8424-0/2011-EKU). All subjects gave written informed consent in keeping with the Declaration of Helsinki.t-test and Pearson’s correlation test were used. Data are presented as mean ± SD; p-values < 0.05 were considered to be statistically significant for all analyzes. Statistics and diagrams were established in GraphPad Prism 7.0.Samples from 47 independent patients and 36 age and sex matched healthy volunteers were used. All ELISA and PCR experiments were performed with at least three technical replicates. For statistical analyzes Student’s non-parametric The mean age of the enrolled patients was 58 ± 6 years. Only 10.6% of the patients were female referring to greater prevalence of ischemic cardiomyopathy in men. All patients were on maximal tolerable doses of evidence based medications of chronic HF. Demographics, medical history are reported in Detailed laboratory test results can be seen in The results of transthoracic echocardiography can be seen in r = 0.64, p = 0.03).HF affects around 26 million people worldwide . HF is aN-[ acetyl]-L-alanyl-2-phenyl-glycine-1,1-dimethylethyl ester), that is an endogenous inhibitor of the Notch-1 pathway, RLN could not exert its effect, resulting in increased cardiac fibrosis. They have also found evidence that RLN (and Notch-1 pathway) influences fibrosis by interacting with the TGF-β-mediated signaling  acting via RXFP1 and glucocorticoid receptors . RelaxinHepatic failure is often caused by congestion accompanied by right heart dysfunction in HF patients. It is well-known that there is a negative correlation between serum cholinesterase level and liver function, decreased level means more severe hepatic condition. In keeping with this phenomenon, our data proved decreased cholinesterase levels in the patients with HFrEF when compared to healthy volunteers, suggesting poor liver condition and comprised right ventricular function in the HFrEF population. Another important hemodynamic observation is that post-operative vasoplegia is often seen and complicates the peri-transplantation period . In mostOur findings are suggestive that circulating RLN1 levels significantly interfere with low cardiac output syndrome and post-operative hemodynamic changes in HFrEF, emphasizing a regulatory role in vasomotor functions. Given that RLN showed correlation with vascular hemodynamic measurements, liver and acute phase proteins (such as CRP and cholinesterase) we suggest that RLN may have and important regulatory role in hemodynamics mainly via acute phase proteins and other paracrine agents. We aim to validate these in a future clinical study in heart transplantation and/or MCS surgeries complicated by post-operative vasoplegia syndrome.The role of RLN1 in the prognosis and therapy of HFrEF is widely investigated, but still a limited amount of data exists and the majority of these studies concentrate on the effects of exogenous RLN, while little is given to the investigation of endogenous RLN. Here, we investigated unique features of relaxin from human serum and explanted heart samples of patients with end-stage ischemic HF and this study permits direct and more accurate examination of myocardial fibrosis and effects of circulating RLN. Although current evidence-based use of renin-angiotensin system inhibitors, beta receptor blockers, statins, and aldosterone antagonists can delay cardiac remodeling, their effect is still unsatisfactory in terms of significant reversal of adverse remodeling . TherefoThe raw data supporting the conclusions of this manuscript will be made available by the authors, without undue reservation, to any qualified researcher.This study was carried out in accordance with the recommendation of the Hungarian Medical Research Council [ETT TUKEB 7891/2012/EKU (119/PI/12.) and TUKEB 73/2005] and their ethical approval of standard operation protocols of the Transplantation Biobank of the Heart and Vascular Center at Semmelweis University. The healthy subjects were assessed via the Budakalasz Health Examination Survey (ETT TUKEB 8424-0/2011-EKU). All subjects gave written informed consent in keeping with the Declaration of Helsinki.JS and EG performed the data collection, molecular biology probes, wrote and edited the manuscript, and prepared the figures. EN performed the clinical data collection, edited the manuscript, and contributed to the biobanking. TR managed the biobanking, consulted the results, and edited the manuscript. GF and BM consulted the results and edited the manuscript. AN, MH-T, and JS contributed to the molecular biology probes. LK and ZB performed the data collection and managed the epidemiology study. All authors contributed to manuscript revision, read, and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Increasing evidence has been presented which suggests that left ventricular (LV) diastolic dysfunction may play an important role in the development of atrial fibrillation (AF). However, the potential for LV diastolic dysfunction to serve as a predictor of AF recurrence after radiofrequency catheter ablation remains unresolved.Dual Doppler and M-PW mode echocardiography were performed in 67 patients with AF before ablation and 47 patients with sinus rhythm. The parameters measured within identical cardiac cycles included, the time interval between the onset of early transmitral flow peak velocity (E) and that of early diastolic mitral annular velocity (e’) (TE-e’), the ratio of E to color M-mode Doppler flow propagation velocity (Vp)(E/Vp), the Tei index, the ratio of E and mitral annular septal (S) peak velocity in early diastolic E/e’(S) and the ratio of E and mitral annular lateral (L) peak velocity E/e’(L). A follow-up examination was performed 1 year after ablation and patients were divided into two groups based on the presence or absence of AF recurrence. Risk estimations for AF recurrence were performed using univariate and multivariate logistic regression.p <  0.05). At the one-year follow-up examination, a recurrence of AF was observed in 21/67 (31.34%) patients. TE-e’ and the Tei index within the recurrence group were significantly increased as compared to the group without recurrence (p <  0.001). Results from multivariate analysis revealed that TE-e’ can provide an independent predictor for AF recurrence (p = 0.001).TE-e’, E/Vp, the Tei index, E/e’(S) and E/e’(L) were all increased in AF patients as compared with the control group (Dual Doppler echocardiography can provide an effective and accurate technique for evaluating LV diastolic function within AF patients. The TE-e’ obtained within identical cardiac cycles can serve as an independent predictor for the recurrence of AF as determined at 1 year after ablation. Atrial fibrillation (AF) is one of the common cardiovascular diseases. Even in patients with good anticoagulation, AF can cause severe stroke, increased mortality, heart failure, and left ventricular (LV) diastolic dysfunction . RecentlFrom the description above, it is clear that an important relationship exists between LV diastolic dysfunction and AF and that dual Doppler echocardiography can serve as an effective technique for assessing LV diastolic function. Therefore, the goals of this study were to use dual Doppler echocardiography as a means to: 1) determine the extent of LV diastolic dysfunction in patients with AF and 2) assess the predictive value of LV diastolic function for the recurrence of AF as determined at 1 year after RFCA.From October 2016 to October 2017, a total of 67 AF patients who were about to undergo RFCA in the Second Affiliated Hospital of Harbin Medical University participated in our study, they were all with preserved left ventricular systolic function . Exclusion criteria included intra-cardiac thrombi, structural heart disease, hyperthyroidism or other autoimmune diseases, rheumatic heart disease and LVEF < 50%. In addition, a total of 47 patients with sinus rhythm and LVEF > 50% were selected as control group, who came to hospital just because of primary hypertension, chronic coronary heart disease, or physical examination. The study complied with the Declaration of Helsinki and was approved by the Ethics Committee of Harbin Medical University. All patients signed a written informed consent form prior to participating in the study._5-MHz Doppler transducer. All patients underwent precordial 2-dimensional, M-mode and Doppler echocardiography while in the left lateral position and all images were stored on a hard disk for subsequent playback and analysis. Left atrial diameter (LAD), LV end-diastolic and end-systolic dimensions were measured from the M-mode echocardiogram. LVEF was calculated by the Simpson method using 2-dimensional images. LA maximum volume was obtained by manually tracing the LA endocardium on the apical four-chamber and the apical two-chamber views by Simpson method before MV opening. LA maximum volume divided by body surface area, we obtained LA maximum volume index. We also recorded the early transmitral flow peak velocity (E: cm/s) and the tissue Doppler-derived mitral annular peak velocity in early diastolic (e’:cm/s), both at the lateral annulus(L) and the interventricular septal annulus(S). Transmitral velocity was tracked and peak acceleration (PkAcc) of the E velocity was measured on the machine  for at least 3 weeks. A transesophageal echocardiography was performed on all patients to verify that no thrombus was present and a pulmonary vein CT to ensure that no significant variation was present among the patients. All 67 AF patients were subjected to RFCA by applying the ablation power at 35 watts with a temperature of 43 °C at the tip of the catheter. The left and right pulmonary vein ostia were ablated under the guidance of 3D electro-anatomical mapping systems (CARTO). The end point of RFCA was the elimination or isolation of pulmonary vein potential throughout the ostial circumference. If AF continued, a 120 J synchronized cardioversion was performed after a transvenous administration of 150 mg cordarone, to achieve sinus rhythm. Morphine was used to alleviate pain during the procedure. All the cases we selected were treated with the same drugs after RFCA.Transthoracic echocardiography was performed immediately after RFCA to exclude the existence of pericardial effusion. Follow-up of patients included detailed inquiries regarding arrhythmia-related symptoms  and echocardiography examinations. A 24-h Holter was performed at 3, 6 and 12 months after the ablation to confirm the presence or absence of AF recurrence. Based on these follow-up results, preoperative echocardiography parameters of the patients were retrospectively analyzed.P <  0.05 to be considered as statistically significant. The SPSS 19.0 statistical software package was used to analyze these data.Continuous data were expressed as Mean ± SD and compared with use of Student t-tests. Categorical data were expressed as percents and compared with use of the Pearson’s chi-squared test, continuity correction chi-squared test or Fisher’s exact test, as appropriate. Risk estimations were evaluated using univariate and multivariate logistic regression models with the presence of AF recurrence as the dependent variable. The Bland-Altman method was used to compare the reproducibility of the two physicians to measure independent risk factors. All data were required to achieve a p <  0.001). TE-e’、 E/e’(S)、 E/e’(L)、the Tei index and E/Vp were all increased in AF patients as compared with that of the control group (p <  0.05). PV-DT and IVRT were shorter in AF patients than the control group (p < 0.05). Of the 67 patients enrolled, 57 who had E/e’(S) ratios and 49 who had E/e’(L) ratios during 8 to 15 were analyzed, in which period E/e’ is indeterminate for the evaluation of left ventricular diastolic pressures. No significant differences between the two groups were obtained for LVEF, LV end-diastolic and end-systolic diameter.Basic characteristics of the study sample were summarized in Table All 67 patients with AF underwent successful pulmonary vein isolation or elimination by RFCA. In our study, 2 patients with AF recurrence underwent secondary radiofrequency ablation at their own discretion.p <  0.001). PV-DT of the recurrence was shorter than the group without recurrence(p = 0.046). The LA maximum volume index of the recurrence was higher than the group without recurrence(p = 0.027). No significant differences were present for LV ejection fraction, LV end-diastolic diameter, LV end-systolic diameter, LAD, PkAcc of the E velocity, E, e’ (S), e’ (L), E/Vp, IVRT and NT-pro BNP between the two groups. Nor were the dual Doppler echocardiography parameters, E/e’(S) and E/e’(L) statistically significant between the groups with or without recurrence.At the one-year follow-up examination after ablation, 21/67 31.34%) AF patients relapsed. In the patients without AF recurrence, 7 of them had arrhythmia-related symptoms but no Holter confirmation of AF recurrence 1 year after ablation and their symptoms gradually improved. Characteristics of patients with or without AF recurrence after ablation are summarized in Table 1.34% AF p = 0.001)  Table .Table 5Bland Altman analysis of two physicians’ measure for TE-e’ was shown in Fig. With use of dual Doppler echocardiography, we have demonstrated that TE-e’, E/e’(S), E/e’(L) and the Tei index in patients with AF were all significantly increased as compared with that observed in control patients with sinus rhythm. TE-e’ and the Tei index increased in patients with AF recurrence versus those without recurrence after ablation. TE-e’ obtained with use of dual Doppler echocardiography was found to be an independent predictor of AF recurrence at 1 year after RFCA. These findings suggest that TE-e’ could serve as an integrating marker for various risk factors of AF, and as an independent predictor for the recurrence of AF after RFCA. To the best of our knowledge, this study represents the first report in which TE-e’ has been demonstrated to function as a predictor of AF recurrence as determined at 1 year after RFCA.LV diastolic dysfunction plays an important role in the development of AF , 15 and Li et al. have demonstrated that E/e’ and LV filling pressure are highly correlated in patients with AF, particularly in the dual-Doppler mode ; and KusLA maximum volume index is one of the important parameters for LV diastolic function rating . In our Since AF is a heterogeneous disease, the use of simple and objective parameters to identify high-risk groups for AF recurrence may be helpful in tailoring patient-specific therapeutic strategies. Factors such as interatrial conduction time, neutrophil/lymphocyte ratio and left atrial pressure have all been previously reported as predictors of AF recurrence after ablation –25. HoweIn the present study, neither duration of AF, LAD, LV ejection fraction, E, e’, E/e’, IVRT, NT-proBNP, PkAcc of the E velocity or PV-DT predicted recurrence of AF. Our univariate analysis has showed that LA maximum volume index and TE-e’ were associated with AF recurrence 1 year after radiofrequency ablation, consistent with previous studies , 27. HirThe results of Sohn et al. have led to the suggestion that prolongation of TE-e’ might be involved with an elevated filling pressure in the setting of prolonged tau . MoreoveThree notable limitations of our study should be acknowledged. The first being that this study involved a single-center, retrospective evaluation for AF recurrence. Second, the limited sample size of our study precluded our ability to achieve the necessary cutoff value of TE-e’ for prediction of recurrence. Third, the one-year follow-up of patients after ablation in this study may underestimate the recurrence rate of AF, because only intermittent 24-h Holter records and follow-up may lead to the omission of asymptomatic recurrence patients during clinical follow-up.Dual Doppler echocardiography can provide an effective and accurate technique for evaluating LV diastolic function within AF patients. The TE-e’ obtained within identical cardiac cycles can serve as an independent predictor for the recurrence of AF as determined at 1 year after ablation.


Background and Objectives: The influence of cardiac magnetic resonance (CMR) derived left ventricular (LV) parameters on the prognosis of patients with aortic stenosis (AS) was analyzed in several studies. However, the data on the relations between the LV parameters and the development of pulmonary hypertension (PH) in severe AS is lacking. Our objectives were to evaluate the CMR-derived changes of the LV size, morphology, and function in patients with isolated severe AS and PH, and to investigate the prognostic impact of these parameters on elevated systolic pulmonary artery pressure (sPAP). Materials and Methods: Thirty patients with isolated severe AS  underwent a 2D-echocardiography (2D echo) and CMR before aortic valve replacement. Indices of the LV mass and volumes and ejection fraction were analyzed by CMR. The LV global longitudinal (LV LGS) and circumferential strain (LV CS) were calculated using CMR feature tracking (CMR-FT) software . The LV fibrosis expansion was assessed using a late gadolinium enhancement sequence. PH was defined as having an estimated sPAP of ≥45 mm Hg. The statistical analysis as performed using SPSS version 23.0  Results: 30 patients with severe AS were included in the study, 23% with severe isolated AS had PH (mean sPAP 55 ± 6.6 mm Hg). More severe LV anatomical and functional abnormalities were observed in patients with PH when compared with patients without PH—a higher LV end-diastolic volume index (EDVi) , larger LV fibrosis area , as well as lower LV global longitudinal strain ] vs. −21.1% [−23.4–(−17.8)], p = 0.004). By receiver–operating characteristic (ROC) curve analysis, LV EDVi > 107.7 mL/m² (Area Under the Curve (AUC) 95.7%), LV GLS < −15.5% (AUC 86.3%), and LV fibrosis area >5% (AUC 89.3) were found to be robust predictors of PH in severe AS patients. Conclusions: In patients with severe aortic stenosis, a larger end-diastolic LV volume, impaired LV global longitudinal strain, and larger LV fibrosis extent can predict the development of pulmonary hypertension. Pulmonary hypertension (PH) is related to poor outcomes regardless of surgical or interventional treatment in aortic stenosis (AS) patients ,2,3. TheThe study included 30 patients with symptomatic severe AS, defined as an aortic valve area less than or equal to 1 cm², who underwent an 2D-echocardiography (2D echo) and CMR evaluation before aortic valve replacement surgery. The patients were divided into two groups according to the presence or absence of PH, with an sPAP cut-off value of 45 mm Hg derived by 2D echo. The patients with documented coronary heart disease, chronic pulmonary disease, atrial fibrillation, and moderate or severe mitral regurgitation were excluded from the study.The study was approved by the Kaunas Regional Biomedical Research Ethics Committee, no. BE-2-8, issued on 29 October 2014. All of the patients gave their informed written consent.The 2D echo was performed using a GE Vivid 7 system , by an independent, experienced echocardiographer. Digital loops were stored and analyzed offline . A conventional 2D echo was performed from the left parasternal and apical windows. Echocardiographic LV and aortic valve area measurements were performed according to the American Society of Echocardiography recommendations . PH was CMR was performed using a 1.5T whole-body system . The CMR protocol consisted of an ECG gated cine sequence obtained during a short breath-hold. The cine views were obtained in three LV long  and short axis views. The end-diastole and end-systole of the LV were defined as the maximum and minimum volumes on balanced steady-state free precession (bSSFP) sequences. The end-diastolic volume (EDV), end-systolic volume (ESV), myocardial mass (MM), and ejection fraction (EF) of LV were calculated in standard cine images using an MR analysis software system  and myocardial mass index (MMi) were calculated based on the body surface area. The LV fibrosis expansion was assessed using a late gadolinium enhancement (LGE) sequence. The LGE images were obtained 10 minutes after the infusion of gadolinium (0.2 mmol/kg). The LV fibrosis extent was assessed using a CMR analysis software system . To assess the midwall LGE quantitatively, short-axis slices were inspected visually, the area of LGE was traced manually, and the fibrosis area results were expressed as a percentage of the myocardial mass.The CMR images were analyzed by two experienced radiologists using a commercial FT software package . The endocardial contours of LV end-diastole and end-systole were marked semi-automatically throughout the cardiac cycle on standard CMR balanced steady-state free precession (bSSFP) sequences. The contours were manually corrected, if necessary. The LV global longitudinal strain (GLS) was calculated by averaging the strain curves of two-, three-, and four-chamber long-axis views. The LV global circumferential strain (GCS) was calculated by averaging the strain curves of the basal, mid, and apical segments obtained from the short-axis views. p-value was <0.05.The continuous variables were expressed as the median (interquartile range), and the categorical variables were described as a percentage (number). The continuous variables distribution was verified using the Shapiro–Wilk test. The Mann–Whitney test was used to compare the quantitative sizes of two independent samples. The correlations were computed using Spearman’s method. Chi-square (Fisher’s Exact Test) tests were used to compare the frequencies of the qualitative variables. The results were considered statistically significant when the two-tailed The incremental value of the CMR variable in predicting the development of sPAP ≥ 45 mm Hg was assessed in terms of the construction of the receiver–operating characteristic (ROC) curves. All of the statistical analyses were performed with SPSS 23.0 software .Thirty symptomatic patients (mean age 70 (64–75) years) with severe AS  were prospectively enrolled in the study. Among all of the patients, seven (23%) had PH (mean sPAP 55 ± 6.6 mm Hg). The clinical, echocardiographic, and demographic characteristics of the overall cohort, and those with and without PH are shown in The patients in both groups were similar in terms of age, sex, and body mass index. The groups did not differ in terms of the New York Heart Association (NYHA) functional class and with the prevalence of comorbidities such as arterial hypertension, diabetes mellitus, and renal insufficiency. The aortic valve area did not differ between the groups. p > 0.05; p > 0.05). For LV EDV and EDVi, ESV, and ESVi, the LV fibrosis area was significantly larger in the PH group when compared to the AS patients without PH (p < 0.05) (p = 0.004)  . The LV = 0.004) .r = 0.6, p < 0.000), LV GLS , and LV fibrosis , however it did not correlate with LV EF  and LV GCS .Increased sPAP (≥45 mm Hg) correlated with LV EDVi  may predict the development of pulmonary hypertension in severe AS patients .Our study evaluated the changes of LV size, morphology, function, and mechanics in patients with severe AS, and found that a larger LV end-diastolic volume, impaired LV global longitudinal strain, as well as more significant larger LV fibrosis extent derived by CMR are predictors of the development of PH in severe AS patients. p = 0.52), probably because a higher LV mass reflects a normal adaptation to an increase in pressure overload, or maybe our PH study group was too small to reflect changes. Increased afterload in severe AS is the leading cause of LV hypertrophy . All of p < 0.001). Lancellotti et al. confirmed that the LV EDV measured by 2D echocardiography could be a predictor of exercise PH in asymptomatic severe AS [In the end-stage of the hypertrophic process, LV dilatation can be observed in AS patients . In our evere AS . HoweverIn our study, patients had a normal or slightly reduced LV EF, while a significant correlation between LV EF and elevated sPAP was not found. This data coincides with other studies demonstrating that the LV systolic function was not also associated with PH in AS ,17. HoweThe longitudinal LV global strain is influenced by LV overload, hypertrophic remodeling, and chamber dimensions, and first begins to decline when the LV EF is maintained . Our FT-r = 0.6, p = 0.01) and LV volume  is a well-established imaging method to detect myocardial fibrosis in AS . SeveralLarger scale studies using CMR and CMR-FT are needed in severe AS with PH patients, in order to assess the changes of the ventricles size, morphology, function, and their association with elevated sPAP. Evaluation of these risk factors for the development of PH in this group of patients is critical to improve the risk stratification. These findings could help to select the patients who would benefit from earlier surgery before the PH development.In patients with severe aortic stenosis, a larger end-diastolic LV volume, impaired LV global longitudinal strain, and larger LV fibrosis extent can predict the development of pulmonary hypertension.


We aimed to characterize gender specific left ventricular hypertrophy using a novel, accurate and less time demanding cardiac magnetic resonance (CMR) quantification method to differentiate physiological hypertrophy and hypertrophic cardiomyopathy based on a large population of highly trained athletes and hypertrophic cardiomyopathy patients.Elite athletes , HCM patients (n = 194) and athletes with hypertrophic cardiomyopathy (n = 10) were examined by CMR. CMR based sport indices such as maximal end-diastolic wall thickness to left ventricular end-diastolic volume index ratio (EDWT/LVEDVi) and left ventricular mass to left ventricular end-diastolic volume ratio (LVM/LVEDV) were calculated, established using both conventional and threshold-based quantification method.CQ:0.998, AUCTQ:0.999). Cut-off value for LVM/LVEDVCQ<0.82 mm×m2/ml and for EDWT/LVEDViTQ<1.27 discriminated between physiological and pathological left ventricular hypertrophy with a sensitivity of 77.8% and 89.2%, a specificity of 86.7% and 91.3%, respectively. LVM/LVEDV evaluated using threshold-based quantification performed significantly better than conventional quantification even in the male subgroup with EDWT between 13-16mm (p<0.001).Whereas 47.5% of male athletes, only 4.1% of female athletes were in the grey zone of hypertrophy (EDWT 13-16mm). EDWT/LVEDVi discriminated between physiological and pathological left ventricular hypertrophy with excellent diagnostic accuracy (AUCAlmost 50% of male highly trained athletes can reach EDWT of 13 mm. CMR based sport indices provide an important tool to distinguish hypertrophic cardiomyopathy from athlete’s heart, especially in highly trained athletes in the grey zone of hypertrophy. Regular and intensive physical training triggers structural and functional changes of the heart, including increased left ventricular wall thickness and cardiac mass, contributing to a clinical challenge of differentiating between athlete’s heart and hypertrophic cardiomyopathy (HCM) –3. RelevBased on large cohort studies, the physiological upper limit for maximal end-diastolic wall thickness (EDWT) is 16 mm, athletes with a maximal EDWT >16 mm may be considered to have pathological left ventricular hypertrophy , 6. AccoOur goal was to characterize gender specific left ventricular (LV) hypertrophy including sport indices for highly trained professional athletes and HCM patients with conventional and threshold-based quantification method. We aimed to determine accurate CMR cut-off values based on a large population which can help to distinguish physiological left ventricular hypertrophy from HCM in both gender. We tested whether threshold-based quantification (TQ) method is useful in the diagnostic workup in the differentiation of physiological and pathological left ventricular hypertrophy especially in athletes in the grey zone of hypertrophy.2), healthy athletes  and athletes with HCM  were examined by CMR. Ethical approval was obtained from the Central Ethics Committee of Hungary, informed consent was obtained from all individual participants included in the study. HCM patients with ejection fraction>50% were consecutively enrolled. HCM was defined according to the current ESC guideline [Our prospective observational study was conducted in the Heart and Vascular Center of Semmelweis University between 2011 and 2015. The total study population of nonathlete HCM patients  = 2±0.17 mCMR examinations were conducted on a 1.5 T MR scanner  with a 5-channel cardiac coil. Retrospectively-gated, balanced steady-state free precession (bSSFP) segmented cine images were acquired in 2-chamber, 4-chamber and LV outflow tract views. Additionally, short-axis images with full coverage of the left ventricle were obtained. Slice thickness was 8 mm with no interslice gap, field of view 350 mm on average adapted to body size. Late gadolinium enhancement (LGE) imaging was performed in 253 cases after the patients gave their informed consent (71% of athletes and 98% of HCM patients). During an inspiratory breath-hold, a bolus of gadobutrol (0.15 mmol/kg) was injected at a rate of 2–3 ml/s through antecubital intravenous line. Peripheral bolus injection was performed with a MR-conditional power injector followed by saline flush. Contrast-enhanced images were acquired using a segmented inversion recovery sequence with additional phase sensitive reconstructions in the same views used for cine images 10–20 min after contrast administration. Using TQ the trabeculae and papillary muscles (TPM) were also quantified, the semi-automatic threshold-based algorithm allows to estimate the spatially varying signal intensities of blood and muscle within an observer-provided epicardial contour. Voxels with signal intensities above the specified threshold are considered to be blood, voxels with signal intensities below the threshold are considered to be muscle. For the analysis, the SI threshold was set to 50% invariably. Left ventricular volumes and masses were standardized to body surface area (BSA)–LVESVi, LVEDVi, LVSVi, LVMi, TPMi. Maximal end-diastolic wall thickness (EDWT) measurements were taken in a short axis slice perpendicularly to the myocardial center line excluding right ventricular trabeculation. Minimal EDWT was measured in the same slice as the maximal EDWT. To characterize the left ventricular hypertrophy, sport indices were derived using both conventional and threshold-based quantification method, such as left ventricular maximal diastolic wall thickness to end-diastolic volume index ratio (EDWT(mm)/LVEDVi(ml/m2)) and left ventricular mass to end-diastolic volume ratio (LVM(g)/LVEDV(ml)). Using threshold-based quantification TPM% (TPM% (TPM(g)/LVM(g)*100) was also established.All images were evaluated with Medis QMass 7.6 quantification software . Endocardial and epicardial contour detection was performed by a blinded expert observer  manually on short axis cine images. Quantification of the left ventricular ejection fraction (LVEF), end-systolic volume (LVESV), end-diastolic volume (LVEDV), stroke volume (LVSV) and myocardial mass (LVM) were performed using two different quantification methods: conventional quantification method (CQ) (Medis QMass 7.6) and threshold-based quantification method (TQ) . All continuous variables are expressed as mean ± standard deviation, categorical variables are expressed as percentages. Between-groups comparisons of CMR parameters and sport indices were based on least-squares linear regression if normality assumptions were satisfied, and median regression otherwise. Models were stratified by HCM when comparing males versus females, and stratified for sex when comparing HCM patients versus athletes . Adjustment for age and heart frequency was applied by including these terms in the models as explanatory variables. Diagnostic accuracy of CMR parameters was evaluated using receiver operating characteristic (ROC) curve analysis. Cut-off values of sport indices for HCM patient versus athlete classification were set to maximize the proportion of subjects correctly classified. P-values <0.05 were considered to indicate statistical significance.None of our healthy athletes had positive family history of sudden cardiac death or HCM, all of them were asymptomatic. Seventy percent of athletes showed J-point elevation, 27% Sokolow or Cornell index positivity. Three athletes had T-wave inversion in more than one contiguous leads, all of them in V1-V3 leads without signs of left ventricular hypertrophy. None of the athletes showed pathological Q wave or ST-depression, and none of them showed any LGE (n = 108).Twenty-eight percent and 30% of our HCM patients had positive family history for sudden cardiac death or HCM, respectively. Twenty-seven percent of HCM patients reported syncope and 32% palpitation. Only 55% of HCM patients showed positive Sokolow or Cornell index, 82% showed T-wave inversion. Seventy-five percent (n = 143) of HCM patients demonstrated LGE, mainly in the hypertrophic segments (80%) localized to the septum and anterior wall, in the right ventricular insertion points (55%), or only mild enhancement in the hypertrophic segments (19%). In our study population LGE showed excellent positive predictive value , 8 patients had positive Sokolow or Cornell index and 9 patients showed T wave inversion on 12-lead ECG. Only two patients showed diastolic dysfunction on echocardiography.  Apical HCM morphology was confirmed in four patients. Only four patients showed LGE in the hypertrophic regions and/or in the right ventricular insertion points. Ten additional athletes , basketball (n = 2), snowboard (n = 1), pentathlon (n = 1), kayak (n = 1), water-polo (n = 1), wrestling (n = 1)) were examined with CMR during training or competition period because of the suspicion of HCM, where the comprehensive investigation including resting ECG, ambulatory ECG monitoring, echocardiography, CMR, patient and family history confirmed the diagnosis. No secondary cause for left ventricular hypertrophy was observed, and after training cessation for 3 months only blunted, or no deconditioning effect was observed, left ventricular mass and wall-thickness remained in the pathological range. EDWT measured by CMR was 17.7 ± 2.7 mm, five of them showed EDWT between 13–16 mm. Left ventricular CMR parameters of athletes with HCM are present in CQ and LVMCQ/LVEDVCQ were significantly lower in athletes compared to HCM patients. Using threshold-based quantification method, LVMiTQ was lower in male athletes compared to HCM patients, TPM and TPM% were also lower in athletes than in HCM patients. Sport indices EDWT/LVEDViTQ and LVMTQ/LVEDVTQ were also lower in athletes compared to HCM patients. Both male and female HCM patients had higher EDWT compared to athletes , 14.8% of male HCM patients, 47.5% of male athletes, 19.8% of female HCM patients and 4.1% of female athletes were in the grey zone of borderline hypertrophy (EDWT 13–16 mm). Thirty-five percent of our male rowers, 52% of canoe and kayak paddlers and 54% of water-polo players showed EDWT between 13–16 mm. Using conventional quantification sport indices EDWT/LVEDViCompared to female athletes, male athletes showed significantly higher maximal EDWT, left ventricular volumes, mass and LVM/LVEDV using both conventional and threshold-based quantification method. TPMi was also higher and TPM% was lower in male athletes, LVEF showed no significant difference between male and female athletes.  Both sport indices established using TQ performed significantly better than max/min EDWT (p<0.05). Cut-off value for max/min EDWT>2.4 (AUC 0.900) discriminated with a sensitivity of 81.4 and a specificity of 86.7%. Sport indices showed also high diagnostic accuracy in the male subgroup with EDWT between 13-16mm, LVM/LVEDV evaluated using TQ performed significantly better than CQ.  Cut-off value for ratio of EDWT/LVEDViCQ less than 0.14 mm×m2/ml and cut-off value for EDWT/LVEDViTQ less than 0.17 discriminated between physiological and pathological LV hypertrophy with a sensitivity of 99.5% and 99.0%, a specificity of 98% and 99.3%, respectively. Cut-off value for ratio of LVM/LVEDVCQ less than 0.82 mm×m2/ml and cut-off value for LVM/LVEDVTQ less than 1.27 discriminated between physiological and pathological LV hypertrophy with a sensitivity of 77.8% and 89.2%, a specificity of 86.7% and 91.3%, respectively.  Despite the apparent gender-specific differences in cardiovascular sport adaptation our cut-off values regarding sport indices are applicable in both males and females.We compared the efficiency of CMR based sport indices in differentiation athlete’s heart from HCM evaluated using conventional and threshold-based methods. Although efficiency of EDWT/LVEDVi evaluated using TQ and CQ showed no significant difference, LVM/LVEDV evaluated using TQ performed significantly better than CQ in both males and females. CQ, EDWT/LVEDViTQ, LVMCQ/LVEDViCQ and LVMTQ/LVEDViTQ were in the pathological range in 9, 9, 8 and 10 athletes with HCM, respectively. According to our cut-off values EDWT/LVEDViThirteen percent of our HCM patients or athletes and 30% of our athletes with HCM were reclassified based on EDWT/LVEDVi or LVM/LVEDV evaluated using TQ.Although numerous studies have investigated the morphologic cardiac adaptation of elite athletes, we have only limited published data providing CMR based cut-off values to differentiate athlete’s heart and HCM , 21. To TQ/LVEDViTQ TQ provides significantly better diagnostic accuracy than the conventional method even in subjects in the grey zone of hypertrophy.Increased left ventricular trabeculation observed in 18% of highly trained athletes suggests the importance of quantification of trabeculae in athletes therefore quantification of trabeculae may have an important effect on LV parameters especially in athletes . A previIn contrast with prior–mainly two-dimensional echocardiographic–data referring 2–15% of male athletes in the grey zone of left ventricular hypertrophy , 23, 47.In young army recruits, 23% fall into the grey zone of hypertrophy (EDWT>13mm) measured by CMR , and theAlthough we observed that highly trained male athletes may reach the grey zone of hypertrophy in almost 50%, this pronounced cardiovascular response is absent in female athletes. Our findings indicate that gender-specific differences in cardiovascular sport adaptation are not negligible. In our study the AUC value of 1 evaluated in EDWT/LVEDVi using both conventional and threshold-based methods among female patients characterized a perfect classification result in female individuals, suggesting that differentiation between HCM and athlete’s heart in female individuals presents no remarkable difficulty.TQ and LVM/LVEDVTQ) provide higher negative predictive values . In the group of athletes with HCM patients without LGE the sport indices established using TQ method (EDWT/LVEDViTQ and LVM/LVEDVTQ) were in the pathological range in 83.3% and 100%, respectively. These findings suggest that in athletes with grey zone hypertrophy and without LGE threshold-based quantification could help in the differential diagnosis.Detection of LGE in the hypertrophic segments or in the insertion points may help the diagnosis of HCM in athletes, but lack of myocardial fibrosis does not rule out the possibility of the disease. In our study population none of the healthy athletes showed delayed enhancement, 75% of non-athlete HCM patients and only 40% of athletes with HCM showed delayed enhancement. Based on our findings LGE has an excellent positive predictive value, but low negative predictive value, in athletes with HCM even lower than in sedentary HCM patients. Compared to LGE our sport indices established using threshold-based quantification  showed high diagnostic accuracy both in the whole patient population and in the male subgroup with EDWT 13–16 mm. In all of our athletes with HCM, the only parameter falling into the pathological range was the LVMTQ/LVEDVTQ ratio.This study highlights that elite healthy male athletes with very intensive and regular training may reach the grey zone of hypertrophy in almost 50%, which may cause diagnostic challenge in the clinical routine. However, only 4.1% of highly trained female athletes reach EDWT of 13 mm. CMR based sport indices provide an important tool to diagnose HCM and distinguish it from athlete’s heart. Not only EDWT/LVEDVi


The ability of this large animal CTEPH model to replicate the hemodynamic consequences of the human disease suggests that it could be utilized for future studies to gain insight into the pathophysiology of CTEPH development, following further optimization.Chronic thromboembolic pulmonary hypertension (CTEPH) is a debilitating disease that progresses to right ventricular (RV) failure and death if left untreated. Little is known regarding the progression of RV failure in this disease, greatly limiting effective prognoses, and therapeutic interventions. Large animal models enable the use of clinical techniques and technologies to assess progression and diagnose failure, but the existing large animal models of CTEPH have not been shown to replicate the functional consequences of the RV, i.e., RV failure. Here, we created a canine embolization model of CTEPH utilizing only microsphere injections, and we used a combination of right heart catheterization (RHC), echocardiography (echo), and magnetic resonance imaging (MRI) to quantify RV function. Over the course of several months, CTEPH led to a 6-fold increase in pulmonary vascular resistance (PVR) in four adult, male beagles. As evidenced by decreased cardiac index (0.12 ± 0.01 v. 0.07 ± 0.01 [L/(min Chronic thromboembolic pulmonary hypertension (CTEPH) is a debilitating, fast progressing vascular disease associated with poor prognosis and significant morbidity and mortality –3. It isThe mechanical obstruction of the pulmonary vascular bed in CTEPH increases pulmonary vascular resistance (PVR) and right ventricular (RV) afterload. The RV can adapt to the increased afterload for some time to maintain cardiac output (CO), but without treatment, CO and ejection fraction (EF) typically drop and death ensues , 10, 11.A common approach to address pathophysiological knowledge gaps is preclinical or animal models of disease. Due to their cost-effectiveness, efficiency, and potential for genetic manipulation, rodents are frequently used. Common techniques for studying venous thrombus generation/resolution or CTEPH include pulmonary artery (PA) ligations , balloonIn contrast, large animal models, which incur increased costs and complexities in housing and care, more closely mimic human physiology and pathophysiology . InvestiHere, we sought to create a canine model of CTEPH that could be developed using less invasive surgical procedures, as well as utilize only microsphere injections. We utilized a similar approach as Hori et al., but followed animals until RV failure occurred as evidenced by clinically used invasive and non-invasive metrics such as CO, EF, and end-diastolic volume (EDV) . By defiCTEPH was induced in five, adult male beagles (12 ± 1 kg body weight) following a modified version of an established canine model , 27. The2 levels (30–50 mmHg). Sterile saline was infused via IV access at a rate of 10 mL/(kg*h). Cephalexin (30 mg/kg) was given IV. Once stable under anesthesia, the animals were transferred to a magnetic resonance imaging (MRI) suite before returning to the procedure room.Following pre-medication with hydromorphone  and midazolam , general anesthesia was induced by an intravenous (IV) injection of propofol (10 mg/kg). The animals were then intubated, and anesthesia was maintained with isoflurane (1–3%) in 100% oxygen; ventilation was adjusted as needed to maintain appropriate end-tidal COMRI studies were performed on a clinical 3T scanner , using previously reported parameters . BrieflyCTEPH was induced by repeated injections of microspheres into the PA via an indwelling catheter. The indwelling catheter was inserted into the femoral vein and advanced into the PA under fluoroscopic guidance with contrast. The distal end was tunneled under the skin and exteriorized at the dorsum between the shoulder blades, where it was sutured in place to prevent movement. A Luer stub was placed on the end of the tubing and a Luer access split septum port was attached.The femoral artery was catheterized to monitor systemic arterial pressure and arterial blood gases, and the femoral and external jugular veins were catheterized for right heart catheterization (RHC), angiography contrast delivery, and blood sampling. Baseline PA, RV, and right atrial (RA) pressures  were obtained. CO was measured using thermodilution, in triplicate. Lastly, the indwelling catheter was filled with heparinized saline (1000 USP Units/mL) and the end was taped shut using self-adherent wrap.n = 4; body weight = 11 ± 1 kg).Transthoracic echocardiography was performed by a board-certified veterinary cardiologist (HBK). Animals were gently restrained in lateral recumbency on a purpose-built table, with small cut-out areas under the thorax. Two-dimensional echocardiography was used to evaluate RV size and function, while color flow and spectral Doppler imaging were performed to assess valve regurgitation. Echocardiographic measurements were also obtained from weight- and sex-matched healthy controls  were vigorously mixed with 20 mL of sterile saline and divided into 2 mL aliquots. Every 3–4 days, 2 mL of this suspension was slowly injected through the access port of the indwelling catheter followed by 2 mL of sterile saline. The access port was replaced with a new or disinfected port as needed. A pressure transducer connected to the port recorded PA pressures. Then, a heparinized solution was added to refill the catheter. Animals were monitored for signs of distress  before, during, and following the procedure. To protect catheter integrity, dogs were fitted with surgical jackets and Elizabethan collars, and were housed individually. They were fed a commercial dry food diet and had free access to water. The access port was disinfected with 70% isopropyl alcohol and iodine, and aspirated and replaced with new heparinized saline daily. Microsphere injections were continued until there was evidence of hemodynamically significant PH as determined by the veterinary cardiologist, utilizing echo to monitor progression. Echo measurements of tricuspid regurgitation flow velocity, RV septal flattening, RV concentric hypertrophy, RV dilation, notching of the PA flow profile, and pulmonic regurgitation velocities were performed monthly, at a minimum ). Animals were transferred to the MRI suite where RV and PA structural and flow measurements were measured. The echocardiographic measurements were obtained, and then fluoroscopic guidance was used to insert a pressure catheter where end-point PA and RV pressures were recorded. These pressure measurements were obtained followed by CO measurements, again in triplicate. The CO was corrected for body weight to account for growth, resulting in CI. Lastly, digital subtraction angiography images were acquired to assess changes in lung perfusion  and midazolam , and general anesthesia was induced by an IV injection of propofol (10 mg/kg). Atropine (0.02 mg/kg) was used as needed to stabilize the heart rate. Animals were then intubated, and 0.9% saline was started IV  and the heart, pulmonary vasculature, and lungs were harvested and preserved for histological analysis and mechanical testing as previously reported .The axial ECG-gated CINE balanced steady-state free precession images were used to manually contour the RV in each of the 20–30 time frames for each slice location using Segment software . The RV volume was calculated for all phases of the cardiac cycle, and the EDV and end-systolic volume (ESV) were taken as the maximum and minimum reconstructed volume, respectively. Stroke volume (SV) and EF were then calculated as:and a volume-only method was used to estimate the ventricular-vascular coupling (VVC) ratio :(3)VVC By combining volumes with recorded pressures, the total arterial compliance, right ventricular stroke work (RVSW), and pulmonary vascular resistance were calculated as:max) and end diastole (Amin) were then used to calculate the RAC in each of the PAs RAC=a), a measure of RV afterload Ea=mt-test. Comparisons between baseline and CTEPH MRI and RHC data were analyzed using a paired t-test. A p-value < 0.05 was used to indicate statistical significance. All analyses were conducted on MiniTab® software .All data are reported as the mean ± standard error. The Ryan-Joiner test was used to check for normality. Comparisons between the control and the CTEPH echocardiography data were conducted using a two-sample p = 0.046 and p = 0.036, respectively), while sPAP increased by almost 70% (p = 0.106). The PCWP remain unchanged at 10.3 ± 1.3 mmHg (p = 1.0).CTEPH was successfully induced in four of the five dogs—the data from one dog was excluded from analysis for failing to meet the requirements for PH diagnosis, mainly insufficient increases in PA pressures. Table p = 0.022)    Figure . It also) Figure . The inc) Figure .Proximal artery stiffening was assessed non-invasively using the RAC of the main, left, and right pulmonary arteries  calculated from the MRI images. The RAC of the MPA was decreased by approximately 45% and the RPA by approximately 26% Figure . In addiThe average blood flow was also calculated utilizing the two-dimensional phase contrast images of the PA, which decreased through the MPA after chronic embolization Figure . DespiteRV volumes calculated from the MRI contours revealed significant increases in the RV end-diastolic and end-systolic volumes Table . Figure CTEPH also caused RV failure, as evidenced by a 40% reduction in the CI Figure , a 36% rThe lack of small and large animal models that recapitulate the key features of clinical CTEPH has impeded progress on successful, early diagnostics and greatly limited the available therapeutic and pharmaceutical treatment options. Many investigators have attempted to create large animal models of CTEPH utilizing various approaches with varying success, but few have successfully captured the clinical endpoint—RV failure. In this present study, we replicated this hallmark feature of clinical CTEPH in a canine model utilizing only the recurring injections of microspheres.Contrary to several other studies where microspheres alone did not sufficiently invoke a hemodynamic or histological response , 25, we An extended induction phase does have some advantage as it is notably closer to the rate of disease progression seen in humans , and unlWhile not the focus of this study, this model could offer the opportunity to study the mechanistic progression of CTEPH development. Optimization of the embolic delivery may allow for insight into the vascular response and adaptation occurring between each embolization, as well as how these alterations lead to RV remodeling, the transition from adaptive to maladaptive RV remodeling, as well as mechanistic sex differences. A better understanding of this progression could lead to earlier diagnostic markers and better treatment options.Digital subtraction angiography images showed that there was an uneven distribution of microspheres delivered to the LPA compared to the RPA, which was visually confirmed at necropsy. Since the RPA typically has more flow, we believe this is due to the tip of the catheter being directed more toward the LPA, causing a disproportionate number of beads to be delivered. If the catheter tip was placed more proximally, we speculate that there would have been a significant decrease in flow through the RPA between baseline and CTEPH measurements, and the flow distribution would be more equal across both lungs. Furthermore, two catheters could be utilized and positioned such that the microsphere distribution between the two lungs could be delivered as desired.Limitations of this study include the asynchronous acquisition of pressures, volumes, and cardiac output, the variable induction time for CTEPH development, as well as the lack of histological analysis from the RV. In addition, PH is associated with increased anesthesia risk so several of the animals were given a dose of atropine, an anti-muscarinic agent that directly increases heart rate by decreasing the parasympathetic tone on the sinoatrial node . The halIn conclusion, CTEPH was induced in a canine model using repeated injections of microspheres into the PA via an indwelling catheter, successfully inducing RV failure and RV remodeling, which has not been observed in previous acute embolization models . Since tNC, CF, TH, MB, HK, and OF designed the study. HK, TH, and OF collected the data and managed animal care. AM, HK, and NC contributed to data analysis and interpretation. AM wrote the manuscript. All authors reviewed and approved the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The clinical features, CMR characteristics and outcomes of arrhythmogenic left ventricular cardiomyopathy (ALVC), which is a very rare nonischemic cardiomyopathy, are currently not well studied. The purpose of the study is to investigate the clinical and cardiovascular magnetic resonance (CMR) imaging characteristics of arrhythmogenic left ventricular cardiomyopathy (ALVC). Fifty-three consecutive patients with ALVC were divided into two groups: ALVC patients without right ventricular (RV) involvement  and those with RV involvement . Clinical symptoms, cardiac electrophysiological findings, and CMR parameters  were evaluated in both groups. The two groups showed no significant difference in age, gender, or presenting symptoms (P > 0.05). Right bundle branch block ventricular arrhythmia was less common in patients without RV involvement . There were no significant differences in left ventricular function between the two groups, however right ventricular ejection fraction was significantly lower in group 2 . Inverse correlations of left ventricular ejection fraction with fat volume , late gadolinium enhancement (LGE) volume , ratio of fat/LGE , indexed left ventricular end diastolic volume  and indexed left ventricular end systolic volume  were all significant. ALVC is a rare disease with fibro-fatty replacement predominantly in the left ventricle, impaired left ventricular systolic function, and ventricular arrhythmias originating from the left ventricle. ALVC with right ventricular involvement may have a worse prognosis. It has been described as an inherited cardiomyopathy characterized by progressive fibro-fatty or fatty replacement of the right ventricular (RV) myocardium resulting in abnormalities of RV morphology and function5. Left ventricular function is often preserved at early stages of ARVC and even with end-stage disease, left ventricular morphology and function are much less affected than the right ventricle6. However, cases of isolated left ventricular (LV) fibro-fatty infiltration/replacement also exist and although these cases may have some overlapping features with ARVC, there are also many different features and these cases should not be referred to as ARVC9. Patients with left ventricular myocardial fibro-fatty disease usually complain symptoms of both arrhythmia 11 and LV heart failure12. Imaging modalities usually reveal severe LV dysfunction with preserved to mildly impaired RV function. Often this entity has been misdiagnosed as dilated cardiomyopathy, chronic myocarditis, myocardial infarction, or double ventricular involvement type ARVC13. Although there have been a handful publications detailing this rare disease, the majority of these have been case reports15, and both the clinical cardiac magnetic resonance (CMR) characteristics remain poorly studied and consistent nomenclature for this cardiomyopathy is not present. It has been referred to as both arrhythmogenic left ventricular cardiomyopathy(ALVC)16 and desmosomal cardiomyopathy17. ALVC has also been referred to as arrhythmogenic cardiomyopathy with left ventricular involvement11.Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare cardiomyopathy with a prevalence of 1/1000 to 1/5000The aim of the present study is to report the frequency, clinical manifestations, and CMR characteristics of this rare cardiomyopathy with predominantly left ventricular fatty or fibro-fatty infiltration. We also hope to improve the clinical awareness of this disease, which will be referred to as arrhythmogenic left ventricular cardiomyopathy (ALVC) in this manuscript, and to provide information that will aid in both clinical decision making and further management of this group of patientss.11 including 7 different criteria in 4 categories and  LV aneurysms, 2) Mild LV dilation and/or systolic impairment ;3. Biopsy/CMR: 1)Myocyte loss with fibrofatty replacement on histology, 2).Extensive LGE of LV myocardium ; 4. ECG: Unexplained T-wave inversion in V5, V6 ± V4, I, and aVL. All the patients must meet at least the first three of the four categories of diagnostic criteria, so the minimum requirement of inclusion criteria was 3 criteria in the last 3 categories, up to 7 criteria in 4 categories).We systematically evaluated 35,845 patients who were referred for CMR examinations at Fuwai Hospital  between 2004 and 2017. Patients with arrhythmogenic cardiomyopathy who had predominantly left ventricular fibro-fatty involvement were retrospectively collected according to clinical criteria mainly from Dr. Sen-Chowdhry’s study5; (2) Patients with other nonischemic cardiomyopathies including hypertrophic cardiomyopathy, dilated cardiomyopathy, restrictive cardiomyopathy and myocarditis;(3) coronary artery disease  or myocardial infarction; (4) congenital heart disease, (5) moderate or severe valvular heart disease; (6) sustained, rapid, uncontrolled supraventricular arrhythmia, or (7) a contraindication to CMR scanning.Patients were excluded if they had any of the following: (1) Patients who meet the definite diagnostic criteria for ARVCThis study was approved by the Ethics Committee of Fuwai Hospital and it complies with the ethical principles of the Declaration of Helsinki. Written informed consent was waived by the Ethics Committee of Fuwai Hospital because this study was retrospective.All CMR exams were performed on one of three MR scanners: 1.5 T Magneton Avanto , 3.0 T MR750 , and 3.0 T Ingenia (Philips). All patients were imaged in the supine position. The study consisted of morphological and functional imaging including 2D transverse and sagittal imaging as well as short and long axis ventricular cine imaging, LGE imaging, tissue characterization with T1 and T2 weighted imaging and water-fat-separating imaging.®, Bayer and Schering®) was administered and a dose of 0.2 mmol/kg was used. LGE images were collected 10–15 minutes after the contrast administration. Gadolinum contrast was administered with an automated injector .For each imaging sequence, identical slice locations were used. These slices consisted of 8 parallel 6-mm-thick short-axis slices with a 4–6 mm section gap. The slices extended from the base to the apex of the heart. A balanced steady-state free precession (bSSFP) was used for cine imaging. Late gadolinium enhancement (LGE) imaging was performed with a T1-weighted pulse sequence with phase sensitive inversion recovery (PSIR). Intravenous gadodiamide  VARPRO multi-point Dixon reconstruction method® Version 5.0 . For all patients, the CMR scans were anonymised and placed in a random order for interpretation. Interpreting physicians evaluating the CMR exams were blinded to the clinical data. Dimensions of both atria and ventricles were measured as previously described21. End-diastole (ED) and end-systole (ES) were visually determined. Semi-automatic tracing with manual correction of epicardial and endocardial borders of contiguous short-axis left ventricular slices was performed to measure ventricular mass (VM), end-diastolic volume(EDV), and end-systolic volume (ESV). The EDV and ESV were used to derive the ejection fraction (EF), cardiac output (CO) and cardiac index(CI). The LVM was calculated by subtracting endocardial from epicardial volume at end diastole and multiplying by 1.05 g/cm3. All the global functional parameters were indexed to body surface area.All images were analyzed offline using a workstation with commercially available software  and Medis22 by using the fat only (F) and water only (W) images. Before doing the fat fraction map processing, a magnitude discrimination was performed to correct bias from T1 and noise23 and fat pixels were defined as higher than 50% in the fraction map24.Hyper-enhanced pixels were defined as LGE if the signal intensities were 5 standard deviations greater than the mean signal intensity within nulled, remote myocardial region on the same image. The 17-segment AHA model was used to categorize areas of LGE into corresponding LV segments. The amount of LGE was calculated into mass. A fat fraction(FF) map . Comparisons between continuous variables determined in the subgroups of patients included in the study were performed by using the student t test. Linear correlation was used to evaluate the correlation indices  between LVEF and fat, and LVEF and LGE, as well as between LVEF and LV mass index. Interobserver variability was assessed using the Bland -Altman method25.Continuous variables with normal distribution are summarized as the mean ± standard deviation and data not fulfilled with normal distribution were presented as median  and GraphPad Prism statistical software package .Categorical variables are presented as a frequency or a percentage and were compared via the Fischer exact test. A multiple regression model was used to analyze the independent predictive values of fat deposition and LGE volumes on global cardiac functional variables. For survival analysis, Kaplan-Meier survival curves were compared using log-rank statistics. We use a combined end-point including death from non-cardiovascular disease, heart transplantation, heart failure death and sudden cardiac deathA total of 33,849 patients were primary excluded for not presenting with ventricular arrhythmia. Another 575 patients with normal LV function and 769 with negative LGE were further excluded. Finally, a total of 53 patients0.16%) from the whole cohort of 35,845 patients fulfilled the inclusion criteria and were included for the analysis in current study  had a family history of sudden cardiac death. The most common clinical presentations were palpitations (73.6%) and exertional dyspnea (39.6%). Twelve of 53 patients (22.6%) presented with syncope as the onset symptom. Beta-blockers were used in 67.9% of the patients. Twenty-three patients with systolic impairment and nine patients with severe ventricular arrhythmia were on angiotensin-converting enzyme inhibitors and amiodarone, respectively.All patients underwent standard 12-lead ECG and 24-hour Holter examinations. The detailed results were summarized in Table The detailed results of the CMR imaging study were summarized in Table Intramyocardial fatty infiltration of the LV was observed in 53 patients (100%). The most common location of fatty infiltration was the basal inferolateral wall (85.9%) followed by basal anterolateral wall (83.0%), mid inferoseptal wall (50.1%), midinferolateral wall (50.1%) and mid anterolateral wall (50.1%). LGE of the LV was observed in all 53 patients. The area of LGE overlapped with the areas that contained fat. Quantitative analysis of fat and LGE showed that the amount of LGE was always greater than the amount of fat both in left and right ventricles, consistent with the presence of both fat and fibrosis within the observed areas of LGE Fig. . The ROCSince there were no statistical differences in left functional parameters between patients with and without RV involvement, linear correlation was performed in the whole cohort. There was a significant inverse correlation between fat volumes , LGE volume, fat/LGE ratio, LVEDVI  and LVESVI  with LVEF Fig. . HoweverP = 0.102, Fig. The mean follow-up periods were 59 months for the whole cohort (56 months for No RV involvement group and 64 months for RV involvement group). During the follow-up period, a total of 10 patients (18.9%) reached primary end points, including 4 patients in the group with No RV involvement (1 heart failure-related death and 3 heart transplantations) and 6 patients  in the RV involvement group. Figure 25, −0.10 g, Q75,0.10 g) and 0.10 ± 0.18 g , and an inter-observer variability of 0.10 ± 0.19 g  and 0.12 ± 0.39 g , respectively  prevalence of T wave in genetic-positive patients29. 4.Typical CMR characteristics of ALVC include left ventricular fatty or fibro-fatty infiltration with LV systolic dysfunction. Some of the patients  also had right ventricle fibro-fatty infiltration with mild to moderate RV dysfunction. We can determine whether ALVC has right ventricular involvement by RVEF, and the area under the ROC curve is 0.994.There have been a few reports/studies regarding ALVC in the literatureFurthermore, we also found that an increased amount of fibro-fatty infiltration, increased amount of LGE, and increased Fat/LGE correlated with a worse left ventricular ejection fraction. Although our multiple regression analysis showed that fat, LGE, and LVEDVI/LVESVI were independent predictors of LVEF, the cause and effect remain unknown at this stage and should be investigated in multicenter studies with larger cohorts. In addition, the results of survival analysis showed that patients with the RV involvement had a relatively poorer prognosis at a mean follow-up of 59 months, however this did not reach statistical significance likely due to the relatively small number of patients and short time follow-up period.12. ALVC has distinctive CMR findings. In our study, we found that the key findings of ALVC are fibro-fatty infiltration of the left ventricle with associated left ventricular dysfunction and arrhythmias from the left ventricle. We also found that when the right ventricle was involved too, left ventricular involvement tended to still be more severe than the right ventricle dysfunction and the ejection fraction of the left ventricle was significantly lower than that of the right ventricle. These findings are similar to what has been previously reported in the literature28. This is significantly different compared to end-stage arrhythmogenic RV dysplasia. In end-stage ARVC, the left ventricle can also be involved but compared to the right ventricle it is much less severely affected where the right ventricle is much more severely affected30. Using CMR feature-tracking technique, Dr. Vives-Gilabert et al. reported two important mechanisms in arrhythmogenic cardiomyopathy patients with LV involvement including 1) decreased myocardial deformation with global LV affectation and 2) delayed myocardial contraction at localized regions31.ALVC and ARVC can both have biventricular involvement, and CMR exam findings are the key to differentiating these two disease entities34. Some special gene mutations in dilated cardiomyopathy such as DSP, LMNA, SCN5A, and FLNC have an arrhythmia rate of more than 30%35. Dr. Spezzacatene et al.36 reported that they found up to 38.2% (109/285) of DCM met criteria for arrhythmogenic-DCM phenotype, which is consistent with previous publications. However, the inclusion criteria of that study only consisted of left ventricular ejection fraction assessed by echo and ECG. No myocardial tissue characteristics  were included in the inclusion criteria. Therefore, it is not possible to exclude the patients with dilated cardiomyopathy caused by idiopathic ventricular arrhythmias. In addition, dilated cardiomyopathy usually does not affect the right ventricle until at the end-stage. However, according to the results of the ROC curve(AUC: 0.994) in current study, the reduction of the RVEF is one of the essential characteristics of ALVC involving the right ventricle. And further survival curves indicate that it is not only an important parameter for differential diagnosis but also for prognostic prediction. Regarding the differentiating from ischemic cardiomyopathy. Since the basal to middle lateral wall of left ventricle was usually involved in ALVC, we need to distinguish it from ischemic heart disease. When differentiating ALVC from myocardial infarction, the most important issue from our study is that ALVC has predominant subepicardial to endomyocardial involvement whereas myocardial infarction is just opposite (from endocardium to epicardium). Furthermore, the patients with ALVC also have the following additional characteristics: nearly all of the left ventricular inferolateral wall has fatty/fibro-fatty replacement and impaired systolic function, fatty/fibro-fatty replacement may also exist in other portions of the LV , Holter/ECG suggest frequent ventricular arrhythmias origin from the LV, there is usually no angina or coronary artery disease, and finally, the most frequent presenting symptoms are usually palpitations and/or syncope.It should be noted that ALVC with LV segmental dysfunction can be confused with dilated cardiomyopathy or ischemic cardiomyopathy . The prevalence of frequent ventricular arrhythmias reported in the literature was 30–42%38. In this cohort, the majority of the patients have disease within the LV rather than the RV, thus a RV biopsy was not an adequate means for evaluation. As a result, in this study we relied more on clinical/imaging criteria and heart transplantation to make the diagnosis of ALVC. Although MRI is crucial in the diagnosis of this disease, it still has intrinsic limitations in this study41. Finally, Genetic testing yields a pathogenic mutation in only 50% of patients. Classical genotype-phenotype correlation does exist, allowing early identification of the disease. However, there are still many common genetic mutations among various cardiomyopathy. There are still great uncertainties in using genotypes to determine phenotypes.Myocardial biopsy is considered the gold standard for the diagnosis of ARVC. However, due to the limitation of sample location and number, false negatives are a common problemIn conclusion, ALVC is a rare disease with fibro-fatty replacement predominantly in the left ventricle, impaired left ventricular systolic function, and ventricular arrhythmias originating from the left ventricle. In comparison to ALVC patients without RV involvement, ALVC with RV involvement may have a worse prognosis, but this still needs to be further investigated.