The imbalanced network of adipokines may contribute to the development of systemic low-grade inflammation, metabolic diseases and coronary artery disease (CAD). In the last decade, three classic adipokines—adiponectin, leptin and resistin—have been of particular interest in studies of patients with CAD due to their numerous properties in relation to the cardiovascular system. This has directed our attention to the association of adipokines with cardiac structure and function and the development of heart failure (HF), a common end effect of CAD. Thus, the purpose of this study was to analyse the associations of plasma concentrations of adiponectin, leptin and resistin with parameters assessed in the echocardiographic examinations of CAD patients. The presented study enrolled 167 Caucasian patients  with CAD. Anthropometric, echocardiographic and basic biochemical measurements, together with plasma concentrations of adiponectin, leptin and resistin assays, were performed in each patient. Adiponectin concentrations were negatively associated with left ventricular ejection fraction (LVEF) and shortening fraction (LVSF), and positively associated with mitral valve E/A ratio (E/A), left ventricular end-diastolic volume (LVEDV), left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter LVESD, and left atrium diameter (LAD). Resistin concentrations were negatively associated with E/A. Leptin concentrations, although correlated with HF severity assessed by the New York Heart Association (NYHA) Functional Classification, were not independently associated with the echocardiographic parameters of cardiac structure or function. In conclusion, adiponectin and resistin, but not leptin, are associated with the echocardiographic parameters of cardiac remodelling and dysfunction. These associations suggest that adiponectin and resistin might be involved in mechanisms of cardiac remodelling or compensative response. We also suggest the possible benefits of adiponectin and resistin level measurements in the monitoring of patients with CAD. Coronary artery disease (CAD) is the leading global problem of public health because it is related to high morbidity and mortality and is a large burden for financial and health systems . Both caThe consequence of chronic positive caloric balance is adiposopathy, which is a pathologic state of adipose tissue characterised by anatomic and functional disturbances with adverse endocrine and immune responses . ChangesAdiponectin is a multifunctional adipokine released almost exclusively by adipocytes with a broad range of target tissues, including adipose tissue, skeletal muscles, liver and cardiovascular system. This adipokine is considered to be a protective mediator in CAD due to its numerous beneficial properties, among them anti-insulin resistance, anti-inflammatory, anti-oxidant, anti-apoptotic, vasodilatant and cardioprotective effects ,16,17. ALeptin, like adiponectin, is mainly secreted by adipocytes. The main function of leptin is suppression of the appetite and food intake signal in the hypothalamus, in addition to regulating energy expenditure . It is aHuman resistin is mainly secreted by peripheral blood mononuclear cells and resident macrophages. Among the wide range of effects of resistin, the following should be mentioned: the stimulation of inflammation, disruption of insulin-signalling in myocytes and hepatocytes, induction of vascular endothelium dysfunction, stimulation of very low-density lipoprotein (VLDL) production and suppression of low-density lipoprotein (LDL) receptors ,9. StudiDue to the growing need to fully understand the impact of cytokines secreted by adipose tissue on cardiac structure and function, the aim of this study was to analyse the associations between adiponectin, leptin and resistin plasma concentrations, and the parameters assessed in the echocardiographic examinations of CAD patients.This study enrolled 167 patients  with CAD aged 59.2 ± 8.4 years. This Caucasian, Polish population was treated at the Clinical Department of Cardiology of the Pomeranian Medical University in Szczecin. This same study group was described in our previous research ,39. The HF was confirmed in 70 (42%) patients based on clinical symptoms, echocardiography and BNP plasma concentration. The extent of HF was evaluated with the New York Heart Association (NYHA) Functional Classification and the severity of CAD symptoms was evaluated by the Canadian Cardiovascular Society (CCS) Angina Grading Scale. Basic anthropometric parameters, systolic and diastolic blood pressures (SBP and DBP) and heart rate (HR) were measured for each patient. The body mass index (BMI) and waist-to-hip ratio (WHR) were also calculated.Study protocol conformed to the Declaration of Helsinki principles and was approved by the Pomeranian Medical University in Szczecin Ethics Committee (No. BN-001/124/03). Informed consent was obtained from each patient. The clinical characteristics, and laboratory and echocardiographic parameters of the study group are shown in Fasting blood samples were collected into tubes with EDTA for plasma and clotting activator for serum separation. The concentrations of blood haemoglobin, fasting plasma glucose, serum lipid profile  and LDL cholesterol levels and triacylglycerols), creatinine and uric acid were measured routinely in a hospital laboratory. Plasma BNP concentrations were measured with the AxSym assay . Estimated glomerular filtration rate (eGFR) was calculated using the simplified Modification of Diet in Renal Disease Study (MDRD) equation. Plasma samples for the measurements of adipokines and BNP were stored at −80 °C until analysed.Concentrations of adiponectin, leptin and resistin in plasma were assessed with commercially available ELISA kits  according to the manufacturer’s protocol. Absorbance was read at 450 nm (with correction at λ = 540 nm) using automated Microplate Reader EnVision 2104 .Echocardiographic assessment of the cardiac anatomy and function was performed in each patient by one experienced cardiologist (A.W.) using Vivid 7 Pro  equipment. The cardiac parameters were acquired and interpreted according to the recommendations of the American Society of Echocardiography . The folp-value < 0.05 was considered statistically significant.Statistical analysis was performed using Statistica 13.0 . The Spearman rank correlation coefficient (Rs) was used for univariate analysis of the associations between the quantitative variables. Multiple linear regression was used for multivariate analysis after logarithmic transformation of the adipokine concentration values. The standardised β regression coefficients were calculated to compare the relative effect of each independent variable on the prognosis of the values of dependent variables. Comparisons of plasma adipokine concentrations of the CAD patients without and with HF were performed using the Mann–Whitney U test. A The plasma concentrations of adiponectin, leptin and resistin were 5.25 ± 3.22 µg/mL, 15.3 ± 17.9 ng/mL and 7.81 ± 3.28 ng/mL, respectively . The plaIn the case of adiponectin concentrations, positive correlations were observed with age and severity of HF (as defined by the NYHA), as well as severity of CAD symptoms evaluated using the CCS, but also plasma BNP. Negative correlations with parameters of left ventricular systolic function, LVEF and LVSF, were observed. Positive correlations regarding the echocardiographic parameters were noted with MR, left ventricular end-diastolic diameter/body surface area (LVEDDBSA) and left ventricular end-diastolic volume/body surface area (LVEDVBSA).Leptin concentration correlated positively with HF severity, as evaluated using NYHA, BMI, SBP and DBP; whereas, negative correlations were found with LVEDDBSA, Ao, IVRT and TEI.In the case of resistin concentration, the only significant negative correlation was observed with E/A.The multivariate analysis  revealedAccumulating evidence corroborates that adipokines play an important role in the development and progression of CVD . In our CAD is one of the major risk factors for HF development. The main feature of HF and its extent is myocardial remodelling. Initially, an adaptive and functional mechanism allows the heart to maintain its function in harmful conditions, such as ischaemic injury and pressure or volume overload. However, a persistent response of myocardium cells, myocytes and interstitial cells to noxious haemodynamic, metabolic and inflammatory stimuli leads to alterations of energy metabolism and structure and contractile dysfunction, resulting in the progression of HF . In addiThe associations of adiponectin with cardiac dysfunction and remodelling have been considered in many research studies. In patients without advanced CVD, but with obesity or HT, a decrease in adiponectin level is the cause of harmful changes in the heart ,46,47,48We also found that the positive correlation of plasma adiponectin concentration with severity of HF is followed by independent associations with parameters of systolic and diastolic function and remodelling features. Among them were inverse relationships of plasma adiponectin concentration with LVEF and LVSF, as well as positive associations with E/A, LVEDD, LVESD, LVEDV and LAD. The relationships between adiponectin level and left ventricular systolic and diastolic dysfunction have also been studied by other authors. The inverse association of adiponectin level with LVEF was indicated in elderly men  or with Leptin is another potential mediator of cardiac remodelling and HF. Our study indicated a positive correlation of plasma leptin levels with the severity of HF (as assessed by NYHA), but not with plasma BNP concentration. The lack of correlation between leptin levels and the levels of heart-failure-specific biomarkers, N-terminal pro-brain natriuretic peptide (NT-proBNP), mid-regional pro-atrial natriuretic peptide (MR-proANP) and galectin-3 was also found by Dadarlat et al. , who stuMany researchers believe that leptin is involved in the pathogenesis of heart dysfunction in obese people because of its pro-inflammatory and pro-fibrotic effects, which impair cardiac metabolism and the functions of the myocardium and vasculature ,31,63. TIn contrast, we found negative correlations between leptin concentrations and parameters such as LVEDD from BSA formula, IVRT and TEI, suggesting a beneficial effect of leptin, rather than a harmful one. However, in our multivariate analysis, we have not confirmed any independent associations between leptin concentration and echocardiographic parameters of cardiac remodelling or function. The position of other researchers on this issue is ambiguous. On one hand, the beneficial impact of leptin on the structure and function of the heart  has been suggested in multiethnic participants without CVD ,69 and nResistin has been proposed as a new potential contributing factor in the development and progression of HF. High levels of resistin are associated with an increased risk of new-onset HF ,75,76, aOur study has some limitations. First, as a cross-sectional study, it does not identify cause-effect relationships between adipokine levels and the echocardiographic parameters of cardiac structure and function. Secondly, it should be emphasised that our results were obtained from CAD patients with a high prevalence of positive history of MI and HF, so these results cannot be generalised to patients with less severe forms of CAD. Thirdly, all patients received optimal pharmacological treatment. The use of drugs, such as statins, might have affected plasma adipokine concentrations and metabolic parameters, although the results of the meta-analyses indicated the impact of statin therapy only on the plasma concentration of adiponectin , but notIn conclusion, the plasma concentrations of classical adipokines are associated with multiple echocardiographic parameters of cardiac structure and function in patients with CAD, suggesting that they might be involved in the mechanism of cardiac remodelling or, on the contrary, be part of a protective response to cardiac remodelling. Among these adipokines, adiponectin is of particular interest because its high concentrations were independently associated with features of systolic and diastolic dysfunction, as well as with structural indicators of cardiac remodelling. However, it is unclear whether adiponectin protects or participates in remodelling. Resistin concentrations were only negatively associated with E/A, which suggests a detrimental effect of resistin on left ventricular diastolic function. In addition, leptin concentrations were positively correlated with HF severity (as assessed by NYHA), but we found no evidence of its independent association with features of cardiac dysfunction and remodelling. The exact relationship between adipokines and the mechanism of heart remodelling in CAD patients remains unclear. Further studies on larger groups of patients are required to confirm our suggested potential benefits when it comes to using measurements of plasma concentrations of adiponectin and resistin as biochemical markers of cardiac dysfunction and remodelling in the monitoring of patients with CAD.


Congenital heart defects are the most common types of birth defects in humans. Children with congenital heart defects frequently require heart valve replacement with an implant. Unfortunately, conventional heart valve implants do not grow. Therefore, these children are committed to serial re-operations for successively larger implant exchanges. Partial heart transplantation is a new and innovative approach to deliver growing heart valve implants. However, the transplant biology of partial heart transplant grafts remains unexplored. This is a critical barrier for clinical translation. Therefore, we investigated the cellular viability of partial heart transplants in cold storage. Histology and immunohistochemistry revealed no morphological differences in heart valves after 6, 24, or 48 h of cold storage. Moreover, immunohistochemistry showed that the marker for apoptosis activated caspase 3 and the marker for cell division Ki67 remained unchanged after 48 h of cold storage. Finally, quantification of fluorescing resorufin showed no statistically significant decrease in cellular metabolic activity in heart valves after 48 h of cold storage. We conclude that partial heart transplants remain viable after 48 h of cold storage. These findings represent the first step toward translating partial heart transplantation from the bench to the bedside because they have direct clinical implications for the procurement logistics of this new type of transplant. Congenital heart defects are the most common type of birth defects in humans. In North America, 7 in 1,000 live born children are affected . TreatmeConventional approaches to deliver growing heart valve replacement are based on tissue engineering or mechanical engineering but these approaches have failed in clinical translation –9. This Heart valve tissue from rats was obtained from hearts procured by the usual protocol for heart transplantation (IACUC protocol 2020-01093). Briefly Sprague Dawley rats  were anesthetized with isoflurane. A sternectomy was performed to access the heart. The animals were exsanguinated, the aorta was cross-clamped and the heart flushed with ice-cold University of Wisconsin solution . The hearts were then excised by dividing the inferior vena cava, left atrium, superior vena cava, pulmonary artery and aorta. The donor aortic valve was harvested from the donor hearts and stored in ice-cold University of Wisconsin solution until cellular analysis .Experience with conventional heart transplants shows that a cold-preservation time of 6 h has no effect on the growth or function of the transplanted valves , 15. TheTissue structure was analyzed by histology with hematoxylin and eosin stain, Masson trichrome stain, and immunohistochemistry for aSMA and CD31.Cellular apoptosis was analyzed by immunohistochemistry for activated caspase 3.Cellular division was analyzed by immunohistochemistry for Ki67.Cellular metabolic activity within aortic valve grafts was measured by quantification of fluorescing resorufin, which is produced by cellular reduction of resazurin. Whole aortic valve grafts were stored in University of Wisconsin buffer for 6, 24, and 48 h then rinsed in PBS and incubated in DMEM with 1% antibiotic/antimycotic solution and 10% AlamarBlue reagent  at 37 degrees Celsius for 1 h. Resorufin fluorescence was measured at an excitation wavelength of 545 nm with exposure time 1/15 s , and measured fluorescence intensity was normalized to tissue mass. Three replicate aortic samples were measured for each cold ischemia time period.Histology with hematoxylin and eosin stain and Masson trichrome stain revealed no morphological differences in heart valves after 6, 24, or 48 h of cold storage. The valve leaflets were structurally intact, and there was no evidence of edematous swelling . StructuImmunohistochemistry for activated caspase 3 showed that there is no increased level of apoptosis in heart valves after 48 h of cold storage . SimilarQuantification of fluorescing resorufin showed no statistically significant decrease in cellular metabolic activity in heart valves after 48 h of cold storage .Partial heart transplantation is a new concept to deliver growing heart valve implants for children. It readily translatable both from a surgical perspective and from a transplant immunology perspective. However, the detailed transplant biology for this new type of transplant remains unexplored.Here we show that the cellular viability of heart valve transplants remains stable within 48 h of cold storage. This finding has important clinical implications for the logistics of partial heart transplantation. Importantly, shipping of the donor tissue with a commercial courier likely is an option in the continental United States. This contrasts which conventional heart transplants, which require dedicated procurement teams to limit the cold storage time to 6 h. Moreover, the procurement radius for partial heart transplants is significantly expanded compared to conventional heart transplants.The current study is limited to an examination of cellular viability of the partial heart transplant donor grafts. In addition to decreased cellular viability during cold storage, ischemia reperfusion injury contributes to the success of transplantation. Therefore, future studies are necessary to investigate the effects of ischemia reperfusion injury on partial heart transplants and potentially identify specific ways to mitigate it.In conclusion, our findings that structural integrity and cellular viability persist in partial heart transplant grafts support the feasibility of partial heart transplantation to deliver growing heart valve replacements for children. Moreover, the data presented here will help with the design of the procurement protocol for a pilot clinical trial for heart valve transplantation.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.TKR discloses a preliminary patent relevant to partial heart transplantation. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Critical aortic stenosis (AS) of the fetal heart causes a drastic change in the cardiac biomechanical environment. Consequently, a substantial proportion of such cases will lead to a single-ventricular birth outcome. However, the biomechanics of the disease is not well understood. To address this, we performed Finite Element (FE) modelling of the healthy fetal left ventricle (LV) based on patient-specific 4D ultrasound imaging, and simulated various disease features observed in clinical fetal AS to understand their biomechanical impact. These features included aortic stenosis, mitral regurgitation (MR) and LV hypertrophy, reduced contractility, and increased myocardial stiffness. AS was found to elevate LV pressures and myocardial stresses, and depending on severity, can drastically decrease stroke volume and myocardial strains. These effects are moderated by MR. AS alone did not lead to MR velocities above 3 m/s unless LV hypertrophy was included, suggesting that hypertrophy may be involved in clinical cases with high MR velocities. LV hypertrophy substantially elevated LV pressure, valve flow velocities and stroke volume, while reducing LV contractility resulted in diminished LV pressure, stroke volume and wall strains. Typical extent of hypertrophy during fetal AS in the clinic, however, led to excessive LV pressure and valve velocity in the FE model, suggesting that reduced contractility is typically associated with hypertrophy. Increased LV passive stiffness, which might represent fibroelastosis, was found to have minimal impact on LV pressures, stroke volume, and wall strain. This suggested that fibroelastosis could be a by-product of the disease progression and does not significantly impede cardiac function. Our study demonstrates that FE modelling is a valuable tool for elucidating the biomechanics of congenital heart disease and can calculate parameters which are difficult to measure, such as intraventricular pressure and myocardial stresses.The online version of this article (10.1007/s10439-020-02683-x) contains supplementary material, which is available to authorized users. Congenital aortic stenosis (AS) carries a prevalence of 0.2–0.5 per 1000 live births.20Both the disease physiology and fetal heart intervention significantly alter the biomechanical environment of the fetal heart, which may influence its subsequent development. Studies in animal models have demonstrated that biomechanical aberrations can lead to cardiac maldevelopment and congenital heart malformations.To date, however, there have been few studies on the biomechanics of the fetal heart. Dewan et al. developed a finite element strain-based growth model for the fetal heart to test the hypothesis that restrictive mitral inflow could cause Hypoplastic Left Heart Syndrome (HLHS).Our strategy was to first develop FE models of the fetal LV myocardium based on clinical images of healthy fetal hearts, and subsequently modify these models to include various features of critical AS. Features investigated include AS, MR, LV hypertrophy, myocardial fibrosis, and cardiomyopathy.4D ultrasound images and valve Doppler velocities were acquired from cardiac imaging of three healthy fetuses at 22, 28 and 32 gestational weeks at the National University Hospital, Singapore. Procedures were approved by the Domain Specific Review Board under protocol 2014/00056, and informed consent was obtained from all participants. Retrospective Doppler velocity data and 2D B-mode images for an additional 32 fetal hearts with critical AS were acquired from the Kepler University Hospital (KUH), Austria. Procedures were approved under the KUH Institutional Review Board protocol #1009/2017.via published echo data with MRI ground truths. Figure 4D B-mode images were acquired in the Spatio-Temporal Image Correlation (STIC) mode. Next, semi-automatic segmentation of the myocardium was performed with a custom-written lazy-snapping algorithm and vascular modelling toolkit (VMTK) software at a time point slightly before the end diastolic phase. The segmentation surface was then smoothed with Geomagic Studio® , as previously described.W, given byC is defined as passive stiffness coefficient withThe mechanical model and FE modelling of the fetal LV was adapted from previous work,Eij with  ϵ  are components of the Green-Lagrange strain tensor E, with f, s, and n denoting the myocardial fiber, sheet and sheet normal directions, respectively.In Eq. , Eij witPast studies had derived varied conclusions about the passive stiffness of the fetal ventricular myocardium. McPherson et al.Pact, was prescribed to act in the local fiber direction using a published active contraction model,22ef and ef0 are, respectively, the local vectors defining the muscle fiber direction in the current and reference configurations, Tmax is the isometric tension as a result of the longest sarcomere length, and The active stress, Tmax, was assumed to be 60 kPa, as an appropriate interpolation between early fetal and adult data. Racca et al. measured fetal myocardium active tension and found that fetal hearts at 130 days and 134 days could generate 49.9 ± 9.3 kPa and 36.0 ± 12.1 kPa, respectively.Tmax in our fetal heart models of all ages. This was corroborated by difficulty in matching the target stroke volume and pressures in our simulations of the 32 week old fetal heart when we had assumed a higher peak active tension of 80 kPa or 100 kPa. We did not assume a variability of Tmax with gestational age due to the paucity of data. This simplified assumption is a limitation of the study.Peak myocyte active tension, Further details and values of parameters used are given in section S1 of the supplementary text.https://fenicsproject.org/). Segmented and smoothed LV models were discretized using quadratic tetrahedral elements, with at least 2500 elements, which was higher than past published work,FE modelling was performed using the open source library FEniCSvia ultrasound image tracking as described above and via FE simulations, and the resulting end-systolic geometry from both approaches were compared. Evaluation of the geometry match was conducted with the Iterative Closest Point algorithm in Geomagic Studio®,During FE model development and calibration, we attempted to achieve models with reasonable outputs that matched characteristics obtained from the ultrasound images and from available literature. Peak LV systolic pressures were compared to literature values, ventricular volumes were compared to LV geometries obtained from the ultrasound images. The myofiber angle model and the Windkessel model were manually adjusted until a satisfactory match was achieved. This volume comparison was conducted at end-systole, when LV deformations were at their maximum difference from the end-diastolic starting geometry. The starting geometry was propagated to end-systolic state Healthy fetal LV pressure data were adopted from Johnson et al.o denoted alignment to the circumferential axis, while 90o denoted alignment to the apical-basal axis. Our endo-to-epi angles were close to 120o. These values were similar to literature values. Garcia-Canadilla et al. measured endo-to-epi angles of − 50o to 100o for mid-2nd trimester human fetus.o to 60o for 14, 20 and 33 weeks old fetal hearts,o endo-to-epi angle difference.34The epi-to-endo myofiber angle that provided the best geometry match with ultrasound images were − 60° to 60° for the 32 weeks old fetal heart, –37° to 80° for the 28 weeks old heart, and –37° to 83° for the 22 weeks old heart, where 0The Windkessel model parameters that enabled the good match are given in supplementary Table S2 and S3. The heart rate used in 22, 28, and 32 weeks old hearts were 147, 154 and 127 beats/min, which were obtained from their subject-specific ultrasound images, and which fitted within variability range in the literature.47Aortic stenosis. To simulate this, we increased aortic flow resistance in the Windkessel model, and considered 3 levels of severity, a 3-fold, 10-fold, and 100-fold increase in aortic resistance, and denote these scenarios as “RAO*3”, “RAO*10”, and “RAO*100”, respectivelyAortic stenosis and mitral regurgitation. MR often accompanies fetal AS.6, 104, and 103 times that of the forward mitral inflow resistance as shown in Fig. MR106”, “RMR104”, and “RMR103”, respectively. The case of “RAO*100, RMR103” demonstrated valve velocities results that were close to clinical observations in our critical AS cases. This model was used as the baseline for modelling disease features 3–5 belowLV hypertrophy. Increased wall thickness can accompany critical AS.Endocardial Fibroelastosis. Endocardial fibroelastosis is commonly observed for fetal hearts with critical AS.via scaling of parameter C in Eq.  from the literature.l/d in the range of 1.5 to 17 and Re in the range 550 to 7000, and the conditions found in our study were within these ranges.From the FE and Windkessel model, flow at the valves was modelled as volume flow rates. However, valve flow is typically quantified as Doppler velocities in clinical measurements, and volume flow rate is difficult to measure directly, due to difficulties in accurately measuring valve orifice size and acquiring good Proximal Iso-velocity Surface Area (PISA) images. We thus adopted an empirical formulation to convert volume flow rate to flow velocities to enable clinical interpretations of our results. Valve volume flow rate data was converted to flow velocities mentclasspt{minimaThe thickness of the heart valves can be used to estimate the axial length of the orifice flow. We estimated the thickness of the aortic and mitral valves of fetal heart by first obtaining literature value of newborn heart valve leaflet thicknesses,Cd can be equated to pressures and flow rates via the Euler number (Eu),3),36u is average velocity within the orifice, which can be calculated from the volume flow rate and orifice size. Equation  conditions. The spatial strain pattern was largely similar between the healthy and diseased cases, but the magnitude was different and reduced with AS. Figure AO*100. With MR, this decrease in strain were less pronounced, which was similar to observations for stroke volume. Peak strains for all hearts are summarized in supplementary Fig. S1, and reflect largely the same trend as in Fig. Figures Stress in the myofiber direction generally increased with gestational age. From 22 to 32 weeks, this stress increased by 43.1% Fig. a. This iInterestingly, with AS and MR, the systole-diastole timing was changed, as could be observed from the flow rate waveforms across the valve Figs. a and 7b.AO*3 to RAO*10) led to an increase in aortic velocity, but at a more severe stenosis, increasing stenosis (from RAO*10 to RAO*100) led to a decrease in aortic velocity.The valve velocity estimated using the coefficient of discharge formulation is shown in Table We further found that the aortic velocities in our simulated stenotic cases were close to the mean of the peak aortic Doppler velocities measured for our diseased fetal heart cohort (2.35 m/s). However, for peak MR velocities, our simulation results showed a range from close to 0 m/s to less than 3 m/s, which were lower than that clinically measured in our diseased cohort (3.40 m/s). Further manipulation of the MR resistance could not increase mitral velocities above 3 m/s, unless thickening of the LV wall was modelled, as described in analysis below. We thus noted that LV remodelling, such as hypertrophy, appeared to be necessary to increase MR velocities above 3 m/s.Manual quantification of the LV free wall thickness  was conducted in 10 randomly selected cases from our KUH data set (average age = 28.0 ± 1.6 weeks). The free wall thickness was found to be 6.0 ± 1.1 mm, which is 105 ± 37% larger compared to value reportedAO*100, RMR103 are shown in Figs. The results of simulations with increased LV wall thicknesses for the case of RIt was noteworthy that, after simulations of multiple cardiac cycles, thicker wall simulation cases demonstrated a reduction of the overall LV lumen size compared to the baseline case before thickening. This occurs even though we have modelled thickening only in the epicardial direction as the initial condition. This is because thicker walls reduced LV compliance,We used stiffness changes as a model for fibroelastosis. Results are shown in Figs. Results of modelling with decreased LV contractility are shown in Figs. in vivo, such as myocardial stresses.In this study, we developed and calibrated FE models of healthy fetal hearts from 4D ultrasound images and Doppler velocity measurements, and then used them to investigate biomechanical changes during disease conditions associated with fetal AS. We could successfully calibrate the FE models, where healthy heart models showed stroke volume, chamber sizes, and LV geometry that agreed well with the same data obtained from clinical images. When we used the calibrated FE model to investigate diseased scenarios, we could capture systole-diastole timing alterations observed in clinical measurements in disease cases, and our simulated valve velocity results were close to these measurements. The observation of alteration of systole-diastole timing under critical aortic stenosis cases was also reported in the literature.The focus of our current work, however, was to investigate the individual effects of each of the disease features. For this reason, we did not study the interdependencies of the various features, and we used the healthy heart as a baseline for our investigation, instead of directly using the diseased heart anatomy and diseased myocardial characteristics as the baseline. This is also due to the lack of information of the diseased fetal myocardium. These are limitations of the current work that warrants future studies. However, the advantage of our chosen focus is that we can better understand the effects of each individual disease feature, which will be difficult with clinical or animal studies. Simulations results from the healthy baseline can also be helpful when considering the next question of how abnormal biomechanics can lead to pathological remodelling.From our results, we found that AS can elevate fetal LV peak systolic pressures significantly (10–20 mmHg), but MR can reduce this slightly. With these two disease features, we observed that aortic velocity could be elevated to 2–3 m/s, which was similar to that in our cohort of fetal hearts with critical AS. However, interestingly, the MR velocity could not be elevated above 3 m/s, while many cases in our cohort of fetuses with critical AS had velocities of above 3.5 m/s. We found that LV wall thickening was necessary to increase LV pressures further for MR velocities to be elevated to this level, suggesting that such clinical cases might have hypertrophy.Our simulations further showed AS decreases stroke volume and LV strains more readily than it decreased aortic flow velocity. In our most severe AS cases, stroke volume and strains were close to zero, but aortic velocities remained above 2 m/s. From our investigation, we found that further reduction of the aortic velocity was possible with further increase in the aortic resistance, and our simulations could produce aortic velocity that is close to zero if resistance was sufficiently high. From our clinical data samples, there were cases where the aortic velocity were less than 1 m/s, much lower than the average of the whole cohort.Another noteworthy finding was that AS caused LV strain to decrease much more in the circumferential direction than in the longitudinal direction. Consequently, while our normal hearts had longitudinal strains that were close to their circumferential strain, which was in agreement with a previous study,via myocardium deformations) to a sufficiently low pressure for mitral inflow to occur.Further, our simulations showed that they could capture the increase in the systole duration and decrease in the diastole duration observed in clinical AS cases. This was observed even without modulating the myocardial activation timing in our model. This phenomenon could be explained by the higher pressure in the LV associated with the disease, which required more time to decrease , and reduce myocardial strains and stroke volume. MR moderates these effects. LV hypertrophy significantly increased LV pressures, strains, and stroke volume and was found necessary to produce high MR valve velocities as measured in the clinic. Reduced contractility significantly decreased LV function, but increased passive myocardial stiffness had only modest effect on LV function and its biomechanical environment.Supplementary material 1 (DOCX 3544 kb)Supplementary material 2 (MP4 1161 kb)Supplementary material 3 (MP4 8235 kb)Below is the link to the electronic supplementary material.


By echocardiography, 8 cases of congenital heart disease were found in 4 combined MMA patients (5.3%) including ventricular septal defect (n = 2), atrial septal defect (n = 3), patent ductus arteriosus (n = 1) and coronary artery-pulmonary artery fistula (n =2). Pulmonary hypertension (n = 2) and hypertrophic cardiomyopathy (n = 1) in combined subtype were also noted. Moreover, echocardiographic parameters were analyzed by multiple regression to clarify the influence of different subtypes on cardiac function. It was found that the left ventricular mass index (LVMI) was significantly reduced only in combined subtype . For left ventricle, the mitral E' velocity was significantly reduced , the global longitudinal strain (GLS) was the same , suggesting weakened left ventricular diastolic and systolic functions in both subtypes. For right ventricle, only in combined subtype, the tricuspid E' velocity was significantly reduced , and the tricuspid annular plane systolic excursion (TAPSE) was the same , suggesting impaired right ventricular systolic and diastolic function. In conclusion, isolated and combined types showed different pattern of cardiac dysfunction, specifically the former only affected the left ventricle while the latter affected both ventricles. And it is necessary to perform echocardiographic screening and follow up in both MMA subtypes.Methylmalonic acidaemia (MMA) has been reported to be associated with cardiovascular involvement, especially for the combined type with homocystinuria. We have screened 80 control subjects and 99 MMA patients (23 isolated type and 76 combined type) using electrocardiograph and echocardiography. 32 cases (34%) of ECG changes were found including sinus tachycardia ( MMACHC  is a class of diseases due to various inherited autosomal recessive gene defects, which result in impaired function of methylmalonyl-CoA mutase (MCM) or impaired intracellular cobalamin (Cbl) transport and processing , 2. ClinMMACHC , which iThis disease has a broad spectrum of clinical manifestations. Most patients suffer from nervous system impairment and extranervous system involvement. Currently, cardiovascular involvement has begun to draw attention as an increasing number of cases have been reported in combined type, especially CblC patients. The first CblC patient with cor pulmonale as a complication was reported by Brandstetter et al. in 1990 . ProfitlCardiomyopathy has been observed in many inherited metabolic diseases, such as Anderson-Fabry disease , as cardCurrently, no studies have investigated the cardiac function of MMA patients in the stable stage. Echocardiography has been a useful and non-invasive tool to measure cardiac structure, function and haemodynamic. Tissue Doppler imaging can provide an assessment of myocardial systolic and diastolic function in both ventricles , and a nHence, we organized a screening of the cardiovascular system to assess cardiac function and clarify the incidence of congenital heart disease (CHD), cardiomyopathy and PAH in MMA patients and explore the difference between the subtypes.From April 2019 to August 2019, we organized cardiovascular system screenings in three areas of China  for MMA patients who were recruited at local tertiary hospitals . During consultation, clinical information was collected, such as the diagnosis (isolated or combined type) according to blood tandem mass spectrometry and urinary gas chromatography, genetic diagnosis, and others.The control group consisted of age- and gender-matched children who were referred for a pediatric cardiology consultation at XinHua Hospital. The inclusion criteria included minor clinical symptoms (innocent murmur) and normal results on electrocardiography (ECG) and conventional echocardiography. The exclusion criteria included children with a disease or undergoing a treatment that may affect heart function.Height and weight were measured in all subjects. For subjects aged over 3 years old, blood pressure (BP) and heart rate (HR) was measured during rest using an Omron HBP-1,300 professional blood pressure monitor   in the sStandard 12-lead ECG was performed with the subject in the supine position, and the results were analyzed by a professional medical officer.Transthoracic echocardiography examinations were performed by a single senior echocardiologist using a CX 50 ultrasound system . Image acquisition was conducted including M-mode, spectral Doppler flow, tissue Doppler imaging (TDI) , 21, andTR) was quantified if present. The pulmonary arterial systolic pressure (PASP) was calculated by the modified Bernoulli equation, and PAH was diagnosed if PASP >40 mmHg  was measured using M-mode in the parasternal short-axis view. The LV mass (LVM) was calculated by Devereux's formula , and theAll of the following parameters were measured three times in independent cardiac cycles and averaged: the LV early and late diastolic mitral inflow velocity (LV E/ LV A), and peak early diastolic velocity (LV E') at the lateral segment of the mitral annulus; the mean velocity of circumferential fiber shortening corrected for cardiac frequency (mVCFc) and myocardial performance index (MPI); the right ventricular (RV) peak early diastolic velocity (RV E') and early systolic velocity (RV S') measured at the lateral segment of the tricuspid annulus; and the tricuspid annular plane systolic excursion (TAPSE) measured along its longitudinal plane from end-diastole to end-systole.STE analysis was performed using commercial QLAB version 10.5 software . The region of interest was anchored as the endocardium in end-diastole, and their longitudinal strain during a heartbeat was detected by the software. The global longitudinal strain (GLS) of the left ventricle was then calculated from the 17-segment model.UK−WHO application (version 2.0.1) with references, including the Neonatal and Infant Close Monitoring Growth Chart, the UK WHO 0–4 years' growth chart, and the UK Growth chart  and Graphpad Prism 12.0). Continuous variables are presented as the mean ± SD, and categorical variables are presented as frequencies or proportions. To minimize the influence of age, height, weight and body mass index (BMI) were converted to a Z score using the Growth Charts.0. Contith chart . CompariP = 0.001) and BMI Z score  were decreased in both types of MMA patients, which was consistent with their limited developmental state. The heart rate of patients was elevated compared with that of controls .A total of 99 patients and 80 control subjects were recruited in this study, with 23 isolated MMA and 76 combined MMA; of them, 84 patients underwent genetic testing and variant identification, and all identified combined MMA patients were the CblC type . The basOn ECG, 94 patients have been examined and detailed parameters were listed in P < 0.001; LVIDS: 22.2 ± 3.2 vs. 22.2 ± 6.0 vs. 19.8 ± 4.1, P < 0.001), indicating a hypogenetic heart in this group, while the LVMI showed no difference between them. The LVEF was within normal range in three groups, although MMA patients had higher LVEF than controls . The other two traditional systolic function indexes, LVFS and mVCFc, were not significantly different among three groups, while GLS, a new sensitive index, was reduced in MMA patients . This indicator suggested impaired myocardial systolic function. The ratio of LV E/A, an index reflecting LV diastolic function, showed significant reduction in patients compared with control subjects , which was consistent with the LV E' velocity .P < 0.001), while another systolic index RV S' showed a different tendency . As for diastolic function, there was no significant difference in RV E' among three groups.For the right ventricle, the TAPSE, an index of RV systolic function, showed a significant reduction in combined type compared to the others , P = 0.036] combined ; LVIDS: isolated  combined , while LVMI showed significant reduction only in combined type . LVEF still remained elevated , and GLS reduced  in both MMA groups. Although the ratio E/A showed no more difference, the LV E' velocity still showed significant reduction in both MMA groups . As for right ventricle, only combined type had significant reduction in TAPSE , and RV E' .During our echocardiography examination, 8 combined MMA patients with cardiovascular involvement were noted, accounting for 10.5% of this population, and their detailed information was listed in Patient 1 had a muscular VSD with a diameter of 1.8 mm and a CA-PAF. Patient 2 had a ASD and a PDA. Patient 3 had two ASDs  and a VSD, which were responsible for the enlargement of the LV and required an interventional operation for defect closure. Patient 4 had a CA-PAF, and his left coronary artery was slightly enlarged, with a diameter of 3.13 mm. Patient 5 had a relatively thick interventricular septum for her age as the IVS during systolic phase was 7.16 mm and the Z score was +1.52.Patient 6 presented at 3 months of age with jaundice and failure to thrive and had shown progressive cyanosis since 1.5 years of age. He was admitted at 2 years and 3 months of age due to oedema and worsening cyanosis. The CblC type was diagnosed genetically with variants (c.609G>A/c.80A>G). Echocardiography revealed PAH (WHO FC IV) with a PASP of 96 mmHg and a significantly dilated right ventricle. With treatment with PAH-targeted drugs and hydroxocobalamin, this patient gradually recovered and showed no recurrence of PAH during follow-up.Patient 7 was admitted at 6 years of age due to systemic hypertension, haematuria, proteinuria, and anemia to a local hospital, and echocardiography revealed LV hypertrophy, and enlargement, impairment of global LV systolic , and diastolic function with no signs of PAH, which was probably secondary to the systemic hypertension and anemia. This patient was then transferred to a higher level hospital and diagnosed with the CblC type harboring heterozygous variants (c.80A>G/c.217c>T). Renal biopsy revealed endocapillary proliferative glomerulonephritis. After treatment with antihypertensive drugs, nephroprotective agents and hydroxocobalamin, control of this patient's blood pressure was achieved, with improved cardiac function and negative conversion of haematuria and proteinuria.Patient 8 first showed narcolepsy, vomiting, jaundice, anemia and dyspnoea at 4 years of age and was then diagnosed with the CblC type harboring variants (c.609G>A/c.80A>G). 1 month later, this child was transferred to the ICU due to the sudden onset of respiratory failure. He presented with hypovolemic shock and decompensated metabolic acidosis, and fibreoptic bronchoscopy with bronchoalveolar lavage indicated alveolar haemorrhagic syndrome (AHS). Echocardiography revealed moderate PAH with a PASP of 62 mmHg and LV enlargement with impaired mobility. In addition, a venous thrombus was detected in the left superficial jugular vein. With aggressive symptomatic treatment and hydroxocobalamin, this patient was rescued.MMACHC variant, c.80A>G. In addition, only patient 6 had mild PAH, while the others showed no signs of PAH at the time of echocardiography.As mentioned above, patients 6–8 shared a common According to our study, the heart was smaller in both MMA subtypes, as the LVIDD and LVMI were lower in the patients than the control subjects, this may play a role in their increased heart rate as higher frequency was required to fulfill their physiological need for circulating a sufficient blood volume.In terms of systolic function, the LV GLS showed a reduction of 1.4 and 1.1% in isolated MMA and combined MMA group, respectively, indicating impaired systolic function, although the EF was increased in all MMA patients. This inconsistency may be due to the cubed method that presumes the heart as a cube which is not an accurate model. In addition, we have analyzed the relationship of GLS and age in different groups  by lineaAlthough the pathophysiology of this disease remains unclear, there are several explanatory hypotheses, including direct toxicity of excess metabolites , enhanced oxidative stress and mitochondrial disorders , 25–27. For combined MMA patients, extra mechanisms relating homocysteine may be involved. Hyperhomocysteinaemia can induce endothelial-myocyte uncoupling by matrix metalloproteinase activation and subsequent interstitial fibrosis accumulation, and this uncoupling leads to impaired diastolic relaxation , 31. In In our study, combined MMA patients showed a much higher incidence of CHD of ~5.3% compared to that of 8.98 per 1,000 live births in the general population in China .MMACHC gene itself has shown tissue-specific expression in the developing heart in mouse embryos, indicating its involvement in cardiac development  to methionine (Met) catalyzed by methionine synthase is greatly impaired, causing disturbance or disruption of the Met-Hcy-SAM pathway. S-adenosylmethionine (SAM) is an important methyl group donor and participates in various methylation reactions, including DNA and histone methylation , 35. A gelopment . An MMACoduction .MMACHC c.80A>G variant  , 41, 42, variant . Our groThe mechanism was suspected to be hyperhomocysteinaemia-related thrombotic microangiopathy (TMA), as thrombi were detected in pulmonary vessels and on renal biopsy, and homocysteine was recognized as a risk factor for arteriosclerosis and thrombosis in adults. However, there was controversy as thrombosis was not found in all patients with PAH, and some patients presented with interstitial lung disease or pulmonary vessel abnormalities , 43, 44.MMACHC c.80A>G variant, extra attention should be paid to signs of PAH.Isolated and combined MMA groups showed different pattern of cardiac function impairment, in which the former only affected the left ventricle while the latter affected both ventricles, and affected ventricle exhibited both systolic and diastolic function impairment. In addition, there was a relatively high incidence of CHD in combined MMA group, and we recommended that combined MMA patients should undergo routine cardiovascular examinations. For patients carrying the The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Ethics Committee of Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.YW, KS, and LH contributed equally to the study and conceived and designed the study. YL and LY prepared an analytical plan, analyzed data, and drafted the initial manuscript. RS was involved in the clinical data collection. SH and BZ were involved in the electrocardiography. YW performed the echocardiography examinations. All authors have reviewed and revised the manuscript, approved the final manuscript as submitted, and agreed to be accountable for all aspects of the work.This work was supported by the Program of Shanghai Municipal Health Commission (No. 202040160) and the Program of Shanghai Municipal Commission of Health and Family Planning (No. 201840347).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


This study aimed to determine native T1 and extracellular volume fraction (ECV) in distinct types of myocardial disease, including amyloidosis, dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), myocarditis and coronary artery disease (CAD), compared to controls.We retrospectively enrolled patients with distinct types of myocardial disease, CAD patients, and control group (no known heart disease and negative CMR study) who underwent 3.0 Tesla CMR with routine T1 mapping. The region of interest (ROI) was drawn in the myocardium of the mid left ventricular (LV) short axis slice and at the interventricular septum of mid LV slice. ECV was calculated by actual hematocrit (Hct) and synthetic Hct. T1 mapping and ECV was compared between myocardial disease and controls, and between CAD and controls. Diagnostic yield and cut-off values were assessed.A total of 1188 patients were enrolled. The average T1 values in the control group were 1304 ± 42 ms at septum, and 1294 ± 37 ms at mid LV slice. The average T1 values in patients with myocardial disease and CAD were significantly higher than in controls . Native T1 of the mid LV level and ECV at septum and mid LV with actual and synthetic Hct of patients with myocardial disease or CAD were significantly higher than in controls.Although native T1 and ECV of patients with cardiomyopathy and CAD were significantly higher than controls, the values overlapped. The greatest clinical utilization was found for the amyloidosis group.The online version contains supplementary material available at 10.1186/s12872-021-02086-3. Cardiac magnetic resonance (CMR) has been increasingly used for the assessment of patients with suspected or known heart disease. Late gadolinium enhancement (LGE) can illustrate myocardial fibrosis. The common type of fibrosis detected by LGE is replacement fibrosis which happened after myocardial injury . T1 mappThe primary objective of this study was to determine T1 values and ECV in distinct types of myocardial disease, including amyloidosis, dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), myocarditis, and coronary artery disease (CAD) compared to controls. The secondary objective was to determine the diagnostic yield and cut-off values of T1 and ECV for differentiation of myocardial disease and CAD compared to controls.This study was approved by the Siriraj Institutional Review Board (SIRB) of the Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand. According to committee of SIRB, consent to participate was not required due to the retrospective nature of this study. The study was conducted in compliance with the principles of the Declaration of Helsinki, International Conference on Harmonization Good Clinical Practice guidelines on non-interventional studies. Patients who underwent clinical stress/viability protocol of CMR 3 Tesla with routine T1 mapping at Siriraj Hospital during July 2017 to December 2019 for clinical indication were enrolled. Subjects were categorized based on CMR findings into the myocardial disease group, the CAD group, or the control group. The myocardial disease group included patients diagnosed with amyloidosis, DCM, HCM, or myocarditis.We used established criteria in combination with CMR criteria for the diagnosis of amyloidosis , DCM 1515, HCM , acute aFigure 2, flip angle 20°, SENSE 2, and slice thickness 10 mm) [2, flip angle 15°, SENSE 2.5, and slice thickness 8 mm) to assess LGE. Post contrast T1 mapping was performed.MR imaging examinations were performed using a commercial Ingenia 3.0T MR system . The routine CMR protocol included black blood axial plain images, steady-state free precession (SSFP) cine images of standard long-axis, 2-chamber, 3-chamber, 4-chamber views, and native modified Look-Locker inversion recovery (MOLLI) T1 mapping. Native T1 mapping was performed in mid-diastole with breath-holding technique and using MOLLI in a single mid-ventricular short axis slice . Routine T1 relaxation maps were also obtained using IntelliSpace Portal (version 9). The region of interest (ROI) was drawn in the myocardium of the mid left ventricular (LV) short axis slice, in the myocardium at the interventricular septum of mid LV slice and the left ventricular blood pool. Native T1 and ECV values were derived from pre- and post-contrast T1 mapping. Greyscale and color mappings were displayed with software default color scheme Fig. A. The miThe actual Hct value was determined either on the day of or within 6 months of the CMR study. For patients without blood sampling, ECV was calculated using a synthetic Hct value that was derived from the relationship between hematocrit and the longitudinal relaxation rate of blood according to the formula: Synthetic Hct = 869.7 × (1/T1blood)-0.071 [t-test. For comparison of two and more than two normally distributed variables, Student’s t-test and one-way analysis of variance (ANOVA) was used, respectively. Sensitivity, specificity, diagnostic accuracy, positive predictive value (PPV), negative predictive value (NPV), area under the curve (AUC), and cutoff values of native T1 and ECV values to distinguish between controls and the 5 evaluated heart diseases were calculated using receiver operating characteristic (ROC) curve analysis. Comparison of diagnostic yield for detecting diseased cases was performed by the McNemar’s test. Comparison of native T1 and ECV between 2 different regions of interest was performed using Pearson’s correlation coefficient. Bland-Altman plot, which was used to determine the level of test-retest reliability , was performed using MedCalc statistical software program . Statistical significance was defined as a p-value less than 0.05.Statistical analysis was performed using SPSS Statistics version 18 . Normally distributed data are reported as mean plus/minus standard deviation (SD), and categorical data are given as number and percentage. Differences in the average T1 and ECV values between control group and diseased groups were evaluated using independent samples We enrolled 2840 patients who underwent routine CMR T1 mapping protocol , and for all septum native T1 values (p < 0.001). The native T1 values and ECV between myocardial disease and CAD and controls are shown in Fig. The average native T1 value and ECV are presented in Tables p < 0.001) and septum ECV values , similar to the comparisons for native T1 value. Similar findings were demonstrated for remote area of CAD groups versus controls. The results of ROC curve analysis to evaluate for the ability of ECV to differentiate each myocardial disease subgroup and CAD from controls are presented in Table There were 909 patients who had actual Hct, and their ECV values were calculated using both actual Hct and synthetic Hct. There were 279 patients who did not have actual Hct, so their ECV values were calculated using only synthetic Hct. Statistical analysis showed significant difference between the control group and the myocardial disease group for all mid LV ECV values (The relation of native T1 (at mid LV) and ECV values (at mid LV using synthetic Hct) among the different groups are demonstrated in Fig. proportion of diseased cases that missed diagnosis by using native T1 cut-off. The results showed that the diseases that missed diagnosis by native T1 can be diagnosed by the cut-off of ECV data using actual Hct in 0% of amyloidosis, 28.8% of DCM, 12.2% of HCM, 25.0% of myocarditis, and 34.0% of CAD. If we used cut-off of ECV data using synthetic Hct, the diseases that missed diagnosis by native T1 can be diagnosed in 0% of amyloidosis, 53.6% of DCM, 25.0% of HCM, 10.0% of myocarditis, and 41.9% of CAD.Sensitivity analysis was performed for the assessment of diagnostic yield results that might be influenced by the low prevalence of disease by propensity score matching of case and control at 1:1 ratio. Cases and controls were matched for age, gender, clinical presentation,and cardiovascular risk factors. The results of native T1 and ECV are shown in Additional files p < 0.001). The calculated ECV compared between mid LV and septum native T1 when using actual Hct showed a statistically significant correlation , and significant correlation was also found for ECV by synthetic Hct . The calculated mid LV ECV by actual Hct and synthetic Hct showed statistically significant correlation , and a significant correlation of both approaches was also found for septum ECV .The average native T1 compared between different measurement approaches (ROI drawn in mid LV myocardium and septum) showed a statistically significant correlation  cardiac amyloidosis that had definite cardiac involvement by endomyocardial biopsy, and in AL cardiac amyloidosis patients with uncertain or absent cardiac involvement by echocardiogram. Native T1 CMR was observed to be more sensitive than other methods for detecting cardiac amyloidosis . The diap < 0.001), and between healthy heart patients and HCM patients (p = 0.035). The AUC for the DCM group was 0.814 (p < 0.001), and the AUC for the HCM group was 0.688 (p = 0.067) [In the present study, native T1 mapping was found to be an effective test for differentiating between controls and DCM with good diagnostic accuracy, specificity, and NPV, but not for sensitivity and PPV. The possible reason for limited sensitivity and PPV may be related to the accuracy of co-registration of thin-wall myocardium in DCM cases that is subjected to a potential measurement errors . For dif= 0.067)  which isp = 0.003) for mid LV native T1, and with an AUC of 0.752 (p < 0.001) for septum native T1. Both ROI approaches showed high specificity and NPV, but limited sensitivity and PPV. However, we were not able to determine if native T1 mapping could distinguish between acute and convalescent myocarditis due to the small sample size in the acute myocarditis group (n = 2). Hinojar, et al., reported native T1 to be an independent discriminator between healthy patients and myocarditis patients, as well as for differentiating between acute and convalescent stage of myocarditis with high diagnostic accuracy, PPV, and NPV. The mean native T1 value was found to be higher in both the acute and convalescent myocarditis groups than in the healthy patient group [Myocarditis patients usually have nonspecific signs, symptoms, and laboratory findings. Myocarditis is often diagnosed by exclusion of other cardiac causes. The diagnosis of myocarditis by CMR often requires multiple techniques, including early gadolinium enhancement, T2W, and LGE imaging. Updated recommendations of CMR criteria using novel CMR techniques, such as T1 mapping, T2 mapping, T2W image, and ECV, have more diagnostic accuracy . The prent group . The difIn the CAD group, native T1 mapping test showed statistical significance in remote myocardium (excluding scarred segment) for mid LV short-axis approach and septal approach. The present study’s CMR imaging analysis protocol for the CAD group excluded subdivision segment with scar for native T1 analysis since the scar area since the scar would markedly increase native T1. However, lipomatous changes within the scar may decrease native T1 . PreviouNative T1 myocardium has acquisition without gadolinium-based contrast agent, which is an important advantage for patients with significant renal impairment who may be at increased risk for nephrogenic systemic sclerosis. The calculated ECV from T1 mapping reduces the variability of test results because of calculation from the ratio of change in myocardial T1 relative to blood pool T1 pre- and post-contrast . The advThe value of calculated ECV using actual Hct and synthetic Hct in each group showed concordant results with high degree of agreement which supported the report of the synthetic Hct formula by Fent, et al., .This study has some mentionable limitations. Firstly, no healthy volunteer data were included in this study. Patients having clinical indication for CMR without evidence of ischemia or infarction was used as the control group. It has been shown that patients with suspected CAD and negative adenosine CMR had an excellent prognosis with no major adverse cardiac event during follow up . ResultsThere were some strengths of this study. First, we reported data on a large number of patients. Second, we are the one of the few studies  that repAlthough native T1 and ECV of patients with cardiomyopathy and CAD were significantly higher than controls, the values overlapped. The greatest clinical utilization was found for the amyloidosis group.Additional file 1. Cutoff values from receiver operating characteristic (ROC) curve analysis of native T1 in myocardial disease and CAD Case: control (1:1).Additional file 2. Cutoff values from receiver operating characteristic (ROC) curve analysis of mid LV short-axis ECV in myocardial disease and CAD (1:1).


Purpose: In recent years, cardiac magnetic resonance (CMR) has been used to assess LV diastolic function. In this systematic review, studies were identified where CMR parameters had been evaluated in healthy and/or patient groups with proven diastolic dysfunction or known to develop heart failure with preserved ejection fraction. We aimed at describing the parameters most often used, thresholds where possible, and correlation to echocardiographic and invasive measurements. Methods and results: A systematic literature review was performed using the databases of PubMed, Embase, and Cochrane. In total, 3808 articles were screened, and 102 studies were included. Four main CMR techniques were identified: tagging; time/volume curves; mitral inflow quantification with velocity-encoded phase-contrast sequences; and feature tracking. Techniques were described and estimates were presented in tables. From published studies, peak change of torsion shear angle versus volume changes in early diastole (−dφ′/dV′) , early peak filling rate indexed to LV end-diastolic volume <2.1 s−1 , enlarged LA maximal volume >52 mL/m2, lowered LA total (<40%), and lowered LA passive emptying fractions (<16%) seem to be reliable measures of LV diastolic dysfunction. Feature tracking, especially of the atrium, shows promise but is still a novel technique. Conclusion: CMR techniques of LV untwisting and early filling and LA measures of poor emptying are promising for the diagnosis of LV filling impairment, but further research in long-term follow-up studies is needed to assess the ability for the parameters to predict patient related outcomes. Impaired diastolic filling of the heart is a well-recognized cause of heart failure (HF), but it has proven difficult to measure and diagnose accurately. A reference standard is the finding of invasively measured increased mid- or end-diastolic (EDP) left ventricular (LV) filling pressure, but an invasive measurement in all patients has never been a realistic option. Furthermore, it is desirable to identify patients in earlier stages of impaired diastolic heart function before LV diastolic pressures are elevated, and thus while it may still be possible to reverse ventricular remodeling. Most studies on LV diastolic dysfunction have relied on echo- and tissue-Doppler interrogation of mitral valve diastolic inflow patterns and relaxation of LV myocardium. Echo-Doppler is versatile, and a high number of echo-determined parameters have been related to different aspects of diastolic (dys-)function, but there is overlap with normal values, and cut-off values for diastolic dysfunction have been difficult to establish. Partly due to this difficulty in assessing diastolic function, the term “HF with preserved ejection fraction” (HFpEF) was coined in the 1990’s. However, the term has not been altogether helpful, as it may result in a pooling of very different patient populations , which mCardiovascular magnetic resonance (CMR) has not traditionally been considered a technique to evaluate diastolic dysfunction but may have an important role in acquiring accurate measures due to its high spatial resolution. Thus, CMR is a reference technique for three-dimensional coverage of volumes of the LV and left atrium (LA) in addition to the evaluation of myocardial composition, mass, and function. Previous reviews of CMR assessment of diastolic dysfunction, including expert opinions and state-of-the-art papers ,10,11, hThe PubMed.gov , EMBASE.com , and Cochrane.org  databases were searched in June 2021. The following terms were used in the systematic search strategy: “CMR” OR “cardiovascular magnetic resonance” OR “magnetic resonance” OR “MRI” OR “magnetic resonance imaging, cine” OR “magnetic resonance imaging” AND “peak diastolic strain rate” OR “diastolic function” OR “myocardial tagging” OR “heart failure with preserved ejection fraction” OR “HFpEF” OR “atrial function” OR “left atrial size” OR “LA size” OR “left atrial volume” OR “LA passive emptying fraction” OR “left atrial passive emptying fraction” OR “left ventricle peak filling rate” OR “LV Peak filling rate” OR “LA volumes” OR “filling pressures” OR “transmitral flow” OR “diastolic dysfunction” OR “diastolic filling” OR “heart failure, diastolic” OR “diastole” OR “atrial function”. The search was fitted to the three databases individually.1 cine sequences  produce slightly lower LV volumes than the currently applied steady-state free precession cine images and were excluded. Reference lists of previous systematic reviews were screened for original studies and studies not identified by the initial database search. The protocol has been published on PROSPERO (CRD 42016051982) .We included original studies where CMR had been used to evaluate global LV diastolic function in human adults using 1.5T or 3.0T magnetic resonance systems. We excluded studies on patients with LV ejection fraction (EF) <45%, studies on regional diastolic function, and studies on patients with valve disease other than isolated aortic valve stenosis (AS) where diastolic dysfunction becomes important. CMR studies of indirect aspects linked to diastolic dysfunction  were excluded since these have been extensively reviewed elsewhere and may not necessarily indicate diastolic dysfunction in all cases. Case reports, conference abstracts, descriptive studies where no values were presented, non-English publications, pediatric or pregnant patient groups, congenital heart disease, and studies focusing on atrial function and not ventricular function, including patients with atrial fibrillation, were excluded. The older TAfter the initial search, duplicates were removed, and remaining articles were screened by title and abstract. We reviewed the full text of all potentially eligible articles. To provide normal reference values, we included studies on healthy young controls and studies on healthy elderly subjects (for age-related LV stiffness), as well as patients with hypertension, diabetes, ischemic heart disease, isolated significant AS, and diagnosed conditions often associated with increased LV mass/LV stiffness: hypertrophic cardiomyopathy (HCM), cardiac sarcoidosis, and cardiac amyloidosis. Echo-Doppler and/or invasive measurements of diastolic function were included for comparison with CMR. Reported echo-Doppler parameters were compared to 2016 American Society of Echocardiography and The European Association of Cardiovascular Imaging criteria where possible .,90.21,90LA feature tracking is a promising technique, although, thus far, studies are few. Data processing is simple and fast, and reproducibility is good, making it an appealing technique. Reduced LA reservoir function seems to differentiate patients from healthy controls . EstimatEighteen studies were identified with more novel and less well-established techniques, including atrioventricular motion assessment, LA transit time, blood velocity mapping, 4D flow kinetic energy, and vortex formation analysis ,112,113.−1. Further changes of ePFR during diastolic stress testing with glycopyrrolate, demonstrated ePFR decreasing in the elderly but increasing in the young, underlining the usefulness of “diastolic stress-testing”. However, further studies including cardiovascular outcome and validation against established measurements of diastolic dysfunction are needed. For LA parameters, a maximal LA volume >52 mL/m2 and a lowered LA total (<40%) and passive emptying fractions (<16%) can be considered signs of diastolic dysfunction.Our systematic literature search revealed several promising CMR techniques for assessing LV diastolic dysfunction, but still very few studies were found with comparisons to established measures of diastolic dysfunction, notably invasive or echo-Doppler. Furthermore, few CMR studies exist with clinical outcomes. Tagging and feature tracking (both LV and LA strain measurements) hold promise, the former especially addressing the first ATP-dependent active LV relaxation, but studies are still few and require further investigation to improve the standardization of analysis and reporting and to establish age-related changes. For -dφ′/dV′ ≥6.2, both specificity and sensitivity are high for severely compromised LV diastolic filling. Initial promising findings will require further studies to improve standardization of analysis and reporting and to establish age-related changes. Due to the lower temporal resolution of CMR in comparison with echo-Doppler, CMR velocity-encoded phase contrast assessment of E/A or E/e′ ratios does not appear to offer any improvement over echo-Doppler unless an adequate echo-window cannot be obtained or unless internal validation of signs of diastolic dysfunction is needed in CMR studies performed for other reasons. For CMR to become of value in the study of diastolic function, it would be important to use it for the parameters for which it has a comparative advantage for improving echo-Doppler. For both LV filling and LA emptying parameters, age-related normal values are well-established and must be considered with respect to what normal aging-related stiffening of the LV can account for. An LV early peak filling rate (ePFR), especially when indexed to LVEDV, reflects diastolic dysfunction with abnormal function indicated by a value of <2.1 ± 0.8 sConclusively, CMR, especially if incorporating the determination of LV myocardial mass and fibrosis, may offer the possibility of reclaiming the term “diastolic dysfunction” from “heart failure with preserved ejection fraction” in order to study the specific mechanisms and to explore mechanisms and treatments. However, in order to do so, further validation against well-established echo-Doppler and/or invasive determination of LV diastolic pressures or large clinical outcome studies are now firmly needed.


Radiofrequency catheter ablation (RFA) is the most effective method of supraventricular tachycardia therapy. Recurrent supraventricular tachycardia causes systolic dysfunction and dilated cardiomyopathy. The aim of this study was to evaluate the long-term alterations of atrial and ventricular functions after RFAof typical atrioventricular nodal reentrant tachycardia (AVNRT).This cross-sectional study included 55 consecutive patients with symptomatic drug-resistant AVNRT who had had an invasive electrophysiology study and RFA. Speckle-tracking–based echocardiographic assessment was performed shortly before and 1 year after the operation. Left ventricle (LV) and right ventricle (RV) peak systolic strain (PSS) and atrial strain measurements were performed.RFA successfully eliminatedtachyarrhythmia in all patients. LV apical 4-chamber PSS –20.8% (–24.7 to –16.0) vs. –22.8% , LV apical 2-chamber PSS –21.5% (–26.8 to –10.1) vs. –22.0% , LV global PSS –20.4% (–26.4 to –14.4) vs. –23.0% , RV global PSS –26.0% (–30.0 to –18.0) vs. –26.5% , and peak left atrial longitudinal strain 41.0% (19.0–71.8) vs. 54.0%  were significantly improved 1 year after RFA.RFA of AVNRT not only provides relief of palpitations but also improves cardiac functions. Radiofrequency catheter ablation (RFA) is an effective and accepted treatment strategy in supraventricular tachyarrhythmias [1–3]. Recurrent supraventricular tachycardia may cause systolic dysfunction and dilated cardiomyopathy [4]. RFA could improve ventricular functions in patients with arrhythmic cardiomyopathies [5]. Speckle tracking echocardiography techniques, including strain, strain rate (SR), and torsion measurements, provide more precise assessment of systolic and diastolic function of the heart than conventional parameters [6]. We have shown previously that RFA of atrioventricular nodal reentrant tachycardia (AVNRT) improved left atrial functions soon after the procedure [7]. However, to our knowledge, reports of the long-term alterations of cardiac functions after AVNRT RFA are lacking in the literature. We aimed to assess the long-term variation of atrial and ventricular functionsafter RFA AVNRT by usingspeckletracking echocardiography.This was a cross-sectional study including 55 successive patients who underwent an invasive electrophysiology study and RFA between April 2018 and August 2018 due to symptomatic drug-resistant typical slow-fast AVNRT.Patients with atrioventricular block, atrial tachycardia, atrioventricular reentrant tachycardia, paroxysmal atrial fibrillation,bundle branchblock, chronic renal failure (estimated glomerular filtration rate <60 mL/min/1.73m2), hypertension, a history of coronary artery disease, left ventricular hypertrophy, heart failure with reduced ejection fraction, diabetes mellitus, or moderate to severe valvular heart disease were excluded from the study. The study protocol was approved by our university ethics committee. This study conforms to the principles of Helsinki Declaration. Written informed consent was obtained from all patients.A Vivid E-9 cardiovascular ultrasound system  was used for transthoracic echocardiographic examination. Echocardiography assessment was performed 24 h before and 1 year after the RFAoperation. Atrialelectromechanical coupling times, left ventricularpeak systolic strain (LVPSS), and right ventricle peak systolic strain (RVPSS) measurements were evaluated [8]. The images were acquired at a frame rate of 70–100 frame/s. Modified biplane Simpson’s method was used for the evaluation of the left ventricular ejection fraction.The apical 4-chamber view was selected for the evaluation of left atrial deformation; peak positive longitudinal strain at the reservoir phase was determined. Right and left ventricular global longitudinal peak systolic strains were measured. EchoPAC dimension 2010 software  was used by 2 experienced cardiologists to analyze echocardiographic data. The measurements of left atrial and right ventricular speckle tracking imaging are shown in Figures 1a and 1b, consecutively. Conventional electrophysiology study and RFA were performed on all patients [9]. Antiarrhythmic drugswerestopped for more than 7 days prior to RFA and discontinued thereafter. Conventional quadripolar catheter , decapolar coronary sinus catheter , His catheter , and ablation catheter  were introduced. A Micropace electrophysiology recorder and stimulator  was used for programmed stimulation techniques. Typical slow-fast AVNRT was diagnosed and ablated according to standard criteria [9]. After the administration of 1 mg i.v. atropine, programmed stimulation protocols were repeated after RFA in order to confirm elimination of tachyarrhythmia. To standardize the frequency of AVNRT episodes,we used a scale based on history of AVNRT occurrence . The distribution of continuous variables was evaluated with the Shapiro–Wilk test. Continuous variables were expressed as mean ± standard deviation or median (minimum-maximum), whichever was appropriate. To analyze dependent variables,the Wilcoxon signed rank test was used. Bland–Altman and intraclass observer agreement tests were used for the evaluation of inter- and intraobserver agreement. A two-tailed P < 0.05 was considered statistically significant. IBM SPSS 21.0 was used for statistical analysis .Programmed electrical stimulation induced AVNRT in all patients. RFA successfullyeliminated AVNRT in all patients and recurrence was not observed. Thirty-three patients were using beta blockers and 22 patients were using calcium channelblockers before the RFA. After the RFA, no patient used any antiarrhythmic drug.The mean age of the patients was 35.67 ± 6.95 years and the mean body mass index was26.48 ± 2.54 kg/m². Clinical characteristics of the patients are presented in Table 1. The duration of palpitations was 10 (2–20) years and the scale of AVNRT occurrence was2 (1–3). Apical 4-chamber LVPSS –20.8% (–24.7 to –16.0) vs. –22.8% , apical 2-chamber LVPSS –21.5% (–26.8 to –10.1) vs. –22.0% , apical long axis LVPSS –19.2% (–21.9 to –15.6) vs. –21.7% , global LVPSS–20.4% (–26.4 to–14.4) vs. –23.0% , global RVPSS–26.0% (–30.0 to –18.0) vs. –26.5% , peak left atrial longitudinal strain 41.0% (19.0–71.8) vs. 54.0%  were significantly improved 1 year after RF catheter ablation (Table 2). Left ventricle diastolic filling velocities and left atrial volume index were also significantly improved after the procedure.Intra- and interobserver variability wereevaluated from echocardiographic data of 12 patients. To analyze interobserver variability, the second operator, who was unaware of the previous measurements, analyzed the data 2 weeks later. Two weeks after that analysis, the first operator repeated the analysis to evaluate intraobserver variability as well. The intra- and interobserver correlation of coefficient for assessment of A4C-S, A2CS, LVG-S, RV-G-S, and LA-S-r were not significantly different. A Bland–Altman graphic of apical 4-chamber peak systolic strain measurement, left ventricle global peak systolic strain measurement, right ventricle global peak systolic strain measurement, and left atrial peak systolic strain measurement are shown in Figures 2a–2d successively. We found that RFA of AVNRT has long-term restorative effects on cardiac functions, as demonstrated via speckle tracking echocardiography.RFA is the first-line therapy of AVNRT [1–3]. Recurrent AVNRT attacks may causeventricular dilatation and arrhythmic cardiomyopathy . Myocyte loss, elongation, myofibril misalignment, and breakdown of extracellular matrix architecture were demonstrated on the cellular level [10–13].Atrial fibrillation causes atrial stunning, which ameliorates progressively after restoration of normal sinus rhythm[14]. Tachycardia attacks raiseatrial pressure, resulting in fibrosis of the atrium. Compared to atrioventricular reentrant tachycardia and atrial tachycardia, atrial pressure increase is much more prominent in AVNRT [15]. It has been shown that left atrial functions improved after RFA, along with left atrial volume reduction in atrial fibrillation/flutter patients [10–12]. Recurrent AVNRT attacks increase atrial pressure, leading to elevated atrial wall stress, which causes negative remodeling and systolic impairment [15]. Therefore, termination of AVNRT may restoreatrial and ventricular functions. Reduction of the left atriumdiameter was shown after RFA of AVNRT and AVRT . Similarly, we found that left atrial volume was decreased after RF catheter ablation.We have recently shown that RFA of AVNRT restored left atrial functions shortly after the procedure[7]. However, long-term outcomes of AVNRT RFA on cardiac mechanics are lacking in the literature. To our knowledge, this is the first study evaluating the long-term alterations of cardiac functions after RF ablation of AVNRT. We found that peak left atrial longitudinal strain, as well as interatrial and intraatrial electromechanical coupling times, were significantly improved after RFA.Lelakowski et al. showed that RFA improves left ventricular systolic and diastolic functions in patients with AVNRT [17]. Jimbo et al. reported that termination of AVNRT with RFA led to reduction of atrial dimensions and significantly improved exercise capacity [17]. The increase of exercise capacity wasprobably due to improved diastolic and systolic functions. Duszanskaet al. studied the variation of left ventricle systolic and diastolic functions by conventional echocardiographic parameters after AVNRT RFA. They found that successful RFA of AVNRT ameliorated left ventricle systolic and diastolic functions 6 months after the operation [18]. Similarly, we found that cardiac functions were ameliorated after RFA; however, we examined the cardiac function with speckle tracking echocardiography, a more accurate method. Additionally, our study examined the long-term effects of RFA. The evaluation of atrial functions with speckle tracking echocardiography allows assessment of entire elements of atrial functions . Additionally, assessment of left ventricle functions by speckle tracking echocardiography allows detection of even subtle changes. Fishberger et al. reported that an improvement was observed in left ventricular myocardial mechanics after the RFA of ectopic atrial and permanent junctional reciprocating tachycardia. However, they did not study patients with AVNRT[19]. We found that left atrial functionsand left ventricular functionssignificantly improved after successful RFA, as assessed by speckle tracking echocardiography.The perinodal area is an important locus of parasympathetic innervation of the heart. This area is rich in vagal fibers. Previous studies have demonstrated thatheart rate increased after RFA [20]. This increase was associated with parasympathetic withdrawal. Similarly, this partial parasympathetic withdrawal may increase both sympathetic tone and inotrophy. There are some limitations of this study. First, this study is relatively small in scale. MRI is a useful tool for detection of fibrosis, which is an important component of arrhythmic cardiomyopathy. Unfortunately, we did not perform an MRI study to detect fibrosis. Second, we included only patients with typical slow–fast AVNRT; however, atypical AVNRT and the left variant have the same mechanisms as typical AVNRT. Similar improvement in cardiac functions is expected to be present in atypical and left variant AVNRT cases. In conclusion, RFA of AVNRT not only provides relief of palpitations but also improves cardiac functions.This study conforms to the principles of the Helsinki Declaration. All patients gave informed consent. This study was approved by the Clinical Studies Ethical Committee of Kahramanmaraş Sütçü İmam University with a protocol number of 19 (28.02.2018).


Trials.gov records to identify eligible trials. The primary endpoints were cardiovascular death/hospitalization for heart failure (CV death/HHF), cardiovascular death, and hospitalization for heart failure. Secondary endpoints included hypoglycemia, volume depletion, urinary tract infection, left ventricular ejection fraction (LVEF), and NT-proBNP. Nine randomized controlled clinical trials were included. Dapagliflozin was reported to significantly decrease CV death/HHF (relative risk (RR): 0.75; 95% confidence interval (CI): 0.68–0.84), CV death , and HHF . There was no effect on hypoglycemia , volume depletion , urinary tract infection , LVEF , or NT-proBNP . The risk of CV death/HHF, CV death, and HHF was lower among patients receiving dapagliflozin than patients receiving placebo.Sodium-glucose cotransporter-2 (SGLT2) inhibitors represent newly developed oral antidiabetic drugs that are practiced for type 2 diabetes mellitus management and may decrease the risk of the first hospitalization in heart failure. The activity of SGLT2 inhibitors is not related to glucose, and the effectiveness and safety of SGLT2 inhibitors in individuals with chronic heart failure (CHF) remain unclear. We systematically retrieved PubMed, Cochrane Library, Embase, NCKI, VIP, Wanfang Data, and Clinical Despitenagement . Resultsnagement –9. Recennagement –12. ReceTrials.gov that were published before November 30, 2020, which contained one or more of the following keywords: dapagliflozin; Forxiga; Chronic Heart Failure; Myocardial Failure; Right-Sided; Systolic Heart Failure.; Sodium-Glucose Transporter 2 Inhibitors; -2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol/BMS-512148; Heart Decompensation; Left-Sided; Heart Failure.We systematically retrieved records from PubMed, Cochrane Library, Embase, NCKI, VIP, Wanfang Data, and ClinicalNo language restrictions were imposed. Besides, references from retained articles were manually searched to find other potentially pertinent data. The protocol was registered with PROSPERO (CRD42020215216).  Inclusion criteria:  All studies are randomized controlled trials (RCTs). The included patients conform to the following criteria: evidence of structural heart disease and manifestation of circulating congestion, age ≥18 years old, ejection fraction ≤50%, New York Heart Association (NYHA) class ≥ I, and NT-proBNP ≥ 600 pg per milliliter .  Exclusion criteria:2, systolic blood pressure <95 mm Hg, acute or previous myocardial infarction, moderate-to-severe liver, and kidney dysfunction.  Observational studies, diagnostic studies, and animal experiments were excluded, type 1 diabetes mellitus, estimated glomerular filtration rate (eGFR) <30 ml/min/1.73 m  All articles were independently reviewed using predefined inclusion and exclusion criteria. Initial inclusion/exclusion of articles was based on titles and abstracts, followed by full-text review in cases of uncertainty. Studies with a follow-up time of <12 weeks were excluded, as well as those that did not report any events of interest. In cases where several publications were based on a single study, we selected the RCT that included the longest follow-up time. Any discrepancies regarding inclusion or exclusion were settled by discussion. If any doubts remained, the third investigator (Qiang Su) made the final decision.Two researchers (Cai Ru-ping and Xu Yu-li) used standardized forms to collect data in duplicate. In cases of discrepancy, all authors discussed the results and established a consensus. The primary endpoints were acquired from the original published manuscript: cardiovascular death/hospitalization for heart failure (CV death/HHF), cardiovascular death, and hospitalization for heart failure; secondary endpoints: hypoglycemia, volume depletion, urinary tract infection, left ventricular ejection fraction (LVEF), and NT-proBNP. For each study, we searched the registration number, the type of the study, the data source of the primary endpoint, the drugs received by the control group, the follow-up time, and the dose (mg) of dapagliflozin. For the experimental group and control group in each study, we collected baseline characteristics .The consistency of the RCTs was measured using the prejudice risk evaluation method described in Cochrane Handbook 5.1.0 , and thep value was used for finding out heterogeneity between studies, and p < 0.1 represented a significant degree of heterogeneity. I2 > 75%, I2 > 50%, and I2 > 25% represented high, moderate, and low heterogeneity between studies, respectively. Where there was statistical homogeneity between the studies , the fixed-effect model was used; else, the model of random effects was adopted. We will have subgroups about the effect of heart function on results.Meta-analysis was implemented using RevMan 5.3 software. Relative risk (RR) was used for the analysis of efficacy, while each effect size was denoted as a 95% confidence interval (CI). A Through electronic retrieval, we identified and reviewed 1021 studies from the aforementioned sources as shown in The trials which were included in the study were published before May 1, 2020. The duration varies from 12 weeks to 4 years. Baseline characteristics by CHF patients are summarized in I2 = 0%; p=0.46). Using a model of random effects, we demonstrated that dapagliflozin highly decreased the prevalence of CV death/HHF   .I2 = 0%; p=0.75), and using a random-effect model, we demonstrated that dapagliflozin significantly reduced cardiovascular deaths   .I2 = 0%; p=0.44), and using a random-effect model, we demonstrated that dapagliflozin significantly reduced hospitalization for heart failure , and p < 0.00001)  .p=0.3) (p=0.11) (p=0.55) (p=0.82) (p=0.09)  , volume (p=0.11) , and uri(p=0.55) . LVEF (W(p=0.82)  and NT-p(p=0.09)  were notI2 = 0; p=0.74), and when a model of random effects was employed for analysis, we found that difference among the three groups was not statistically significant   . The posI2 = 0; p=0.39), and when a model of random effects was employed for analysis, we found that difference among the three groups was not statistically significant   . The posp=0.04) and heterogeneity (p > 0.1). It shows that these two studies [After excluding 2 studies , 15, we  studies , 15 are β-cell function [SGLT2 inhibitors, which act independently of insulin, selectively inhibit SGLT2 in the kidney and block the reabsorption of glucose, thereby lowering blood glucose levels. This process does not depend on insulin resistance and function . Recent function , 21–23. β-hydroxybutyrate. Cardiac uptake of carbohydrates  was shown to be reduced, while uptake of the total β-hydroxybutyrate and ketone bodies was enhanced in diabetic patients when they were compared with nondiabetic patients. Consequently, ketone bodies may be used as a source of energy moderately substituting glucose in patients with diabetes [The efficacy of dapagliflozin on the heart may be based on its ability to decrease preload of the heart by natriuresis and diuresis  and to ddiabetes –28. Thisdiabetes . Howeverdiabetes . SGLT2 idiabetes .In this meta-analysis, we quantitatively analyzed the efficacy and safety of dapagliflozin for the management of chronic heart failure. We showed that dapagliflozin can significantly decrease the frequency of cardiovascular death/hospitalization for heart failure, cardiovascular death, and hospitalization for heart failure. Furthermore, it improves survival and reduces the need for hospitalization. This suggests that dapagliflozin may provide an extra treatment option for patients with chronic heart failure in addition to ACEIs, ARNIs, beta-blockers, and MRAs. In summary, patients with HF should be treated with a combination of the following four drugs as early as possible: an ARNI, beta-blocker, MRA, and SGLT2 inhibitor. Volume depletion, hypoglycemia, and urinary tract infections are not affected by dapagliflozin. In the past, it was believed that patients with poorer heart function and left ventricular ejection fraction had a worse prognosis. However, subgroup analysis showed surprising results: the effect of dapagliflozin was not affected by heart function grades and LVEF. The positive effect of dapagliflozin in heart failure has nothing to do with the degree of heart function and LVEF. Therefore, dapagliflozin treatment is applicable in patients with mild and severe HF. Besides, dapagliflozin decreased the risk of death and deteriorating the HF and relieved symptoms among different ages of people . Some reAlthough dapagliflozin treatment carries several advantages, it also leads to some adverse reactions in clinical practice. Diabetic ketoacidosis (DKA) is a common complication in patients with diabetes, which is more common in patients with T1D than T2D patients. Several SGLT2 inhibitors have been FDA approved for the management of T1DM in the EU and Japan, but they have not yet been approved in the United States and China. In March and July 2019, respectively, sotagliflozin and dapagliflozin were rejected by the FDA for the treatment of T1DM, and in March 2020, empagliflozin was rejected because a higher number of patients in the experimental group developed DKA compared with that of the placebo group , 39. BesThis study has some limitations. The population that met the inclusion criteria was HFrEF and HFmrEF patients, and patients with preserved ejection fraction heart failure (HFpEF) may not be eligible for this drug. In this study, males accounted for 77% of the population, and black patients accounted for only 5.7%, which might affect the generalizability of the study data. However, to obtain further robust evidence to guide clinical practice, more extensive, multicenter, and high-quality clinical research must be performed.We assessed the incidence of cardiovascular death/hospitalization for heart failure, cardiovascular death, and hospitalization for heart failure in patients with heart failure. Dapagliflozin significantly decreased the incidence of CV death/HHF (relative risk (RR): 0.75; 95% confidence interval (CI): 0.68–0.84), CV death , and HHF .