Left ventricular diastolic dysfunction (LVDD) remains challenging to be assessed by echocardiography. We sought to explore the relationship between left atrial strain and left ventricular (LV) diastolic function in patients with normal left ventricular ejection fraction (LVEF) by invasive left-heart catheterization. 55 consecutive individuals with LVEF > 50% underwent LV catheterization. Standard transthoracic echocardiography was performed during 12 h before or after the procedure. Left atrial (LA) strain were obtained by speckle tracking echocardiography. When LVEF ≥ 50%, the group with elevated left ventricular end-diastolic pressure (LVEDP) (n = 35) showed decreased left atrial reservoir strain (LASr) , left atrial conduit strain (LASct) , left atrial contraction strain (LAScd)  and increased E/e′ ration. LVEDP negatively correlated with LASr , LASct  and LAScd , but not with E/e′. LASr, LASct and LAScd were all independent predictors of elevated LVEDP (p < 0.05), with a higher C-statistic for the model including LASr . The area under the curve (AUC) for LASr is 0.914 . In patients with normal LV ejection fraction, left atrial strain presented good correlation with LVEDP, and LASr was superior to LASct and LAScd to predict LVEDP. LA strain demonstrated better agreement with the invasive reference than E/e′. Left ventricular diastolic dysfunction is an independent predictor of all-cause mortality in the general population, even in the preclinical stage , and eviThe 2016 ASE/SCAI guidelines streamline the use of four variables into a single algorithm to assess LV diastolic function, while accuracy will be affected in the presence of pulmonary arterial hypertension, severe tricuspid valve lesions, and low right atrial and right ventricular filling pressure etc. . An accuBetween June 2018 and November 2019, we prospectively studied 55 patients with LVEF ≥ 50%  referred for left heart catherization, and echocardiography was completed within 12 h before or after catheterization. Patients with confirmed or suspected coronary artery disease underwent left heart catheterization. Those with Atrial fibrillation, ST-segment elevation myocardial infarction (STEMI), non-ST-segment elevation myocardial infarction (NSTEMI), moderate or greater tricuspid regurgitation, moderate or greater mitral regurgitation, any mitral or aortic stenosis, prosthetic valves, hemodynamic instability or poor echocardiography imaging were excluded. The study was approved by the institutional enrolling board of the first affiliated hospital of Soochow university.Echocardiographic measurements were performed by two board-certified echocardiographers blinded to the LVEDP who finalized each measurement by consensus. The two-dimensional echocardiographic imaging of all subjects was performed by GE Vivid E9 and GE Vivid E95 equipment (Norway) 2.5 MHz transducer. The LA dimension was measured in the parasternal long-axis view at the ventricular end-systole. Mitral diastolic inflow was interrogated using pulsed-wave Doppler from the apical four-chamber view at the level of the mitral leaflet tips. Mitral early diastolic peak (E-wave) and late peak (A-wave) velocities and E/A ratio were measured. In the apical two and four-chamber views including the entire left atrium, LAV was determined using biplane Simpson method at end-systolic frames just before mitral valve opening , at end-diastolic frames coincided with the R-wave on the electrocardiogram  and during mid-diastole phase which is before electrocardiographic P-wave . Values were then indexed to the body surface area . left atrial ejection fraction (LAEF) were calculated by LAVImax minus LAVImin. In addition, the septal mitral annulus early (E′) velocity was measured by tissue Doppler imaging, and the E/E′ ratio was calculated using a cutoff value > 15 to represent elevated LV filling pressure. LVEF was measured using Simpson’s method, which was used as a standard index of global LV systolic function. All echocardiographic measurements used in the analysis were averaged from 3 heart beats.The two-dimension strain analysis package available on the Echo PAC work station  was used to measure the LA strain and strain rate. Similar to the left ventricle, the complete myocardial region of interest (ROI) of the LA is defined by the endocardial border. An adjustable ROI with a default width of 3 mm is recommended. The user can adjust the size and shape to include the thickness of LA wall and to avoid including the pericardium. The software divided the atrial endocardium into six segments, poorly displayed segments were automatically rejected by the software and excluded from the analysis. The global longitudinal strain and strain rate curves were generated by the software for each apical view. The operator could repeat the imaging or change software parameters such as the width of the region of interest and the smoothing functions to obtain satisfactory tracking. Apical four and two-chamber views were obtained in three consecutive heart beats, and electrocardiograph was recorded in the meantime. The LA strain is defined as the absolute strain value in LA three phases, which includes reservoir strain in systole (LASr), conduit strain in early diastole (LASct) and contraction strain in late diastole (LAScd). LV end-diastole was defined as initial zero reference point. The respective strains are LASr, calculated as difference between onset of filling and end-diastole; LAScd, calculated as difference between onset of atrial contraction (before start of Doppler A-wave) and onset of filling; LASct, calculated as difference between end-diastole and onset of atrial filling. The global strain was calculated as the average of both respective values form both views. Fig. .Fig. 1LAA 6F pigtail catheter was placed in the left ventricle to obtain the invasive LV pressure. Excluding the unstable baseline of LV filling pressure, LVEDP was measured by mean values of 3–5 cardiac cycles. Image J was used to measure LVEDP at the beginning of QRS on Electrocardiography. A LVEDP value > 16 mmHg was defined as elevated LV filling pressure . LVEDP vAnalyses were performed using the SPSS 25.0. Continuous variables which are normally distributed are presented as mean ± SD. Variables that are not normally distributed will be presented as median with inter-quartile ranges (IQR = 25th–75th percentile). T test and Mann–Whitney U test was used for comparison of groups. Categorical variables are expressed as absolute numbers and respective percentages, categorical variables were compared with chi squared tests. LA strain and LV diastolic dysfunction parameters such as septal e′ velocity, lateral e′ velocity, E/e′, E/A, LAEF, tricuspid regurgitation velocity, LAVI and LVEDP were evaluated using univariate logistic regression analysis. Differences with p values less than 0.05 were considered significant. The independent predictive value of echocardiographic variables was evaluated in three different multivariate model. Predictors of elevated LVEDP with p value ≤ 0.12 in the univariate analysis and age, were included in multivariate models. In our three models, LASr LASct and LAScd were analyzed separately due to their multicollinearity, with other control variables the same. The C-statistic was calculated in each model, in order to allow comparison between them. Receiver operating characteristics (ROC) curves were created to compare the performance of multiple variables in determining increased LVEDP.Patients’ clinical characteristics and echocardiographic measurements are shown in Table The LA strain and LVEDP are correlated negatively: LASr , LASct , LAScd . No significant correlation was found between the LVEDP and E/e′ (p = 0.493). Figure The predictive values of LASr, LASct and LAScd were evaluated in three different multivariate logistic regression analyses Table , which cFigure Left atrial strain presents significant feasibility and reproducibility, which has recently emerged as a powerful assessment in evaluation of left ventricular diastolic dysfunction . We aim In the early phase of LVDD, reduced ventricular compliance and elevated LVEDP result in decreasing passive early transmitral diastolic flow, then atrial pump function enhances to compensate LV filling. As left ventricular distensibility declines further, atrial pressure rises to maintain cardiac output, which may blunt the compliance of the LA. LA function is impaired as a consequence of chronically elevated LVEDP and decreased LA compliance . This maMultiple recent studies have demonstrated the correlation between LA strain and hemodynamic parameters , 9, but Our study is consistent with the findings observed by Cameli and colleagues. They found that LASr was strongly negatively correlated with pulmonary capillary wedge pressure (PCWP) in patients with heart failure, which performed excellent sensitivity and specificity of 100% and 93% in assessing PCWP .Amita Singh et al. have reported that LASr could predict elevated filling pressure with high accuracy and identified a cutoff value for LASr , while wPoor correlation between E/e′ and LVEDP was observed in this study, which seems to contradict previous reports that E/e′ correlated with PCWP or LVEDP significantly , 14, 15.Our study showed that LAVI correlated with LVEDP poorly. LA dilatation usually implies the chronic, long-term elevation of LA pressure, and LAV can be normal in the early phase of LVDD , 19. ManCurrent echocardiographic parameters show moderate sensitivity in evaluating LVDD, with the presence and severity of LVDD failing to be determined for a significant proportion of patients. LA strain measured by speckle tracking echocardiography can reclassify patients even in the early phase of LVDD. LA strain also has advantages when diagnosing LVDD in mitral prosthesis, mitral annular calcification, bundle branch block, post-cardiac surgery and AF. LA strain, with high reproductivity and feasibility, is suggested to be incorporated into routine evaluation of LVDD, especially for patients who are classified in the indeterminate LVDD group using the conventional recommended algorithm.The sample size in this study is limited, so selection bias still exists, however increasing the number of individuals will reduce the selection bias. The study was conducted on patients from only one medical center, which might impact the population selected and, consequently, the variables analyzed. Left atrium imaging is difficult to obtain and the image definition is poor in some cases, and some echocardiographic images have poor repeatability in left atrial strain.For patients with normal LV ejection fraction, left atrial strain presented better correlation with LVEDP than E/e′. Moreover, LASr presented a better diagnostic value in predicting LVEDP than LASct and LAScd. It is suggested that left atrial strain should be used in diagnosis of LVDD.


In non-haemodialysis (HD) patients, increased epicardial adipose tissue (EAT) thickness was significantly associated with adverse cardiovascular (CV) events. This study was designed to investigate whether EAT thickness was a useful parameter in the prediction of adverse CV events in HD patients. In addition, we also evaluated the major correlates of EAT thickness in these patients. In 189 routine HD patients, we performed a comprehensive transthoracic echocardiographic examination with assessment of EAT thickness. The definition of CV events included CV death, non-fatal stroke, non-fatal myocardial infarction, peripheral artery disease, and hospitalization for heart failure. The follow-up period for CV events was 2.5 ± 0.7 years. Thirty-one CV events were documented. The multivariable analysis demonstrated that older age, smoking status, the presence of diabetes mellitus and coronary artery disease, and low albumin levels were independently correlated with adverse CV events. However, increased EAT thickness was not associated with adverse CV events (P = 0.631). Additionally, older age, female sex, low haemoglobin, and low early diastolic mitral annular velocity were correlated with high EAT thickness in the univariable analysis. In the multivariable analysis, older age and female sex were still correlated with high EAT thickness. In conclusion, high EAT thickness was associated with older age and female sex in the multivariable analysis in our HD patients. However, EAT thickness was not helpful in predicting adverse CV events in such patients. Further large-scale studies are necessary to verify this finding. Cardiovascular (CV) disease is the leading cause of mortality in haemodialysis (HD) patients6. Previous studies demonstrated that EAT was significantly correlated with body fat measurement, CV risk factors, and dialysis dose in patients with HD7. In non-HD patients, increased EAT thickness was significantly associated with left ventricular diastolic dysfunction and the severity of coronary artery disease8 and was a useful parameter in predicting adverse CV events10. However, no study has examined the ability of EAT thickness in predicting adverse CV events in HD patients. Hence, this study was designed to investigate whether EAT thickness was a useful parameter in the prediction of adverse CV events in patients with HD. In addition, we also evaluated the major correlates of EAT thickness in these patients.Epicardial adipose tissue (EAT) represents a real and unique visceral fat deposit of the heart in terms of the size of its adipocytes, biochemical composition, and metabolic activity. EAT has a significantly higher rate of lipolysis and lipogenesis than other visceral fat depots. Because there is no discrete barrier between EAT and the adjacent myocardium, EAT interacts locally with the coronary arteries and the myocardium through paracrine or vasocrine pathways. Increased EAT thickness is strongly associated with visceral obesity, metabolic syndrome, diabetes mellitus, CV disease, and subclinical atherosclerosis at multiple locations11. There were significant differences in age, diastolic blood pressure, and percentage of males between patients with EAT thickness ≦5.0 mm and >5.0 mm. In addition, our study patients had a wide left ventricular ejection fraction (LVEF) range of 32–80%.The study population included 189 regular HD patients , and the mean age was 61 ± 12 years. Table Table The follow-up period for CV events was 2.5 ± 0.7 years in all patients. Thirty-one CV events were documented during the follow-up period, including hospitalization for heart failure (n = 5), myocardial infarction (n = 7), stroke (n = 4), peripheral artery disease (n = 5), and CV deaths (n = 10). A Cox proportional hazards regression analysis for CV events is shown in Table 12.The intraobserver and interobserver mean percent errors for measurement of EAT thickness were 7.1 ± 10.1% and 8.3 ± 12.1%, respectivelyOur present study examined the ability of EAT thickness to predict adverse CV events in HD patients. We found that EAT thickness was not helpful in predicting adverse CV events in such patients.In Table 14. Previous studies showed that hypertension patients with high EAT thickness (>7 mm) were older5, EAT thickness increased as age increased in the general population9, and age had a positive correlation with EAT thickness in patients with coronary artery disease3. We similarly demonstrated that old age was significantly associated with increased EAT thickness in HD patients.Ageing greatly changes the distribution, mass, and function of adipose tissue and causes increased infiltration and redistribution of fat into non-adipose tissue such as muscle, liver, and heartet al. found that female sex had a negative correlation with EAT thickness in the general population9. Jeong et al. showed that sex had no correlation with EAT thickness in patients with coronary artery disease3. In the present study, in contrast, we found that female sex had a positive correlation with EAT thickness in HD patients. The reason for this inconsistent result was not clear and might be partially explained by the different study populations. A previous study demonstrated that ageing could result in increased redistribution of fat into non-adipose tissue, and it was more pronounced in women than in men13. This redistribution of fat into the heart as an ageing process might be more marked in HD women than in HD men.Mahabadi 17. In contrast to previous studies, BMI was not correlated with EAT thickness in our study. BMI could estimate the overall fat status but did not reflect body fat distribution18. Hence, the association between BMI and EAT thickness might be influenced by different patient groups.EAT deposition was found to be strongly associated with measures of obesity and insulin resistance and had a significant correlation with BMI in non-HD patients8. In addition, Lin et al. found that EAT thickness was significantly independently associated with left ventricular diastolic dysfunction in patients undergoing peritoneal haemodialysis19. In the present study, we also found that EAT thickness had a significant correlation with E’  in the univariable analysis.Increased EAT thickness was demonstrated to be significantly associated with left ventricular diastolic dysfunction in subjects with metabolic syndrome, even after adjusting for other risk factors12. EAT is a source of several pro-inflammatory, inflammatory, and pro-atherogenic cytokines that influence heart function22. In addition to its correlation with left ventricular diastolic function23, EAT thickness was high in several cardiac diseases, such as coronary artery disease and chronic heart failure25. EAT thickness was reported to be a useful predictor of clinical outcomes and provided incremental prognostic value over traditional CV risk factors28. Christensen et al. demonstrated that high levels of EAT were associated with the composite of incident CV diseases and mortality in patients with type 2 diabetes26. In contrast to Christensen’s patients with homogeneous disease, our HD patients had various different pathologies resulting in ESRD and a wide LVEF range (32–80%), indicating inhomogeneous left ventricular systolic function. This diverse patient cohort might cause the discrepancy between our findings and those of other studies. In fact, our results demonstrated that traditional CV risk factors, including diabetes, hypertension, current smoking, and hyperlipidaemia, were not associated with EAT thickness, and comorbidities, such as coronary artery disease, stroke, and chronic heart failure, were also not associated with increased EAT thickness. Furthermore, EAT thickness was not helpful in predicting adverse CV events in our patients. No association of EAT thickness with traditional CV risk factors and comorbidities might partially explain why EAT thickness was not a useful CV outcome predictor in the present study.EAT is the true visceral fat deposit of the heart and accounts for approximately 20% of total heart weight25. Second, EAT thickness averaged from the values measured at the end-systole and end-diastole might provide more comprehensive results than that measured only at the end-systole or end-diastole. However, we only measured EAT thickness at end-systole in the present study. Third, the results might be different if EAT thickness was averaged from the values measured from parasternal long and short axis views. We only measured EAT thickness from the parasternal long axis view, while parasternal long and short axis measurements were reported to be similar31. Fourth, the majority of our patients had long-term use of antihypertensive medication. For ethical reasons, we did not withhold these drugs. Hence, we could not exclude the impact of these medications on the present findings. However, we adjusted for the use of antihypertensive medicines in the multivariable analysis. Fifth, using the stpower cox command, we found that the estimated power was only 0.4879, which was lower than 0.8. Hence, our study was clearly underpowered and unable to conclusively assess the correlation between EAT thickness and CV outcomes in HD patients. Finally, because there were many variables in the analysis with only 31 outcomes, the chance findings and restricted power should be taken into consideration.Several limitations existed in our study. First, EAT thickness was measured by echocardiography in the present study but not by computed tomography or magnetic resonance imaging. Hence, we could not evaluate the ability of EAT thickness measured by computed tomography or magnetic resonance imaging to predict adverse CV events in our HD patients. However, EAT thickness measured by echocardiography was reported to have a good correlation with EAT measured by computed tomography and magnetic resonance imagingIn HD patients, high EAT thickness was associated with older age, female sex, low haemoglobin, and low E’ in the univariable analysis. After multivariable analysis, increased EAT thickness was significantly correlated with old age and female sex. However, EAT thickness was not helpful in predicting adverse CV events in our HD patients. Further large-scale studies with a longer follow-up period are necessary to verify this issue.The study was performed in a regional hospital of southern Taiwan since April 2014. All routine HD patients at our dialysis clinic were enrolled. Six patients who did not want to undergo echocardiographic examination and 4 patients with atrial fibrillation were excluded. Finally, 189 patients were enrolled in this study. The study protocol was approved by our institutional review board committee (KMUH-IRB-20170200). All clinical investigations were conducted according to the related guidelines and regulations. Informed consent was obtained from all study patients.Our study patients received their routine HD (3 times/week) using a Toray 321 machine . Every haemodialysis session was conducted around 3–4 hours using a dialysate flow of 500 mL/min and a dialyzer with a blood flow rate of 250 to 300 mL/min.32. LVMI was calculated by dividing left ventricular mass by body surface area. Biplane area-length method was used to measure left atrial volume33. LAVI was calculated by dividing left atrial volume by body surface area. The mean value of these echocardiographic parameters from 3 consecutive cardiac beats was used for later analysis.Using VIVID 7 , the echocardiographic examination was performed by one well-trained cardiologist who was blind to the original patient characteristics according to a standardized protocol. The lateral and septal E’ were measured using pulsed tissue Doppler imaging from apical 4-chamber view. The average value of lateral and septal E’ was used for later analysis. Modified Simpson’s method was used to measure LVEF. Devereux-modified method was used to measure left ventricular mass34. The mean value of 3 consecutive cardiac beats was used for later analysis.From the parasternal long axis view, EAT thickness was measured from the free wall of right ventricle. EAT was recognized as an echo-free space located between the visceral pericardium and the outer wall of the myocardium on 2-dimensional echocardiography. In order to standardize the measuring point, the aortic annulus was used as an anatomical reference. EAT thickness was measured perpendicularly on the free wall of right ventricle at end-systole for 3 consecutive cardiac beatsThe raw echocardiographic data were stored and then analysed offline using EchoPAC software .35.Age, sex, current smoking history, and comorbidities were acquired from medical records or interviews with patients. BMI was calculated by dividing the square of height in metres by weight in kilograms. Laboratory data were checked from fasting blood samples and acquired within 1 month of enrolment. Stroke was defined as a history of cerebral bleeding or infarction. Coronary artery disease was defined as a history of typical angina with a positive stress test, old myocardial infarction, angiographically documented coronary artery disease, or previous angioplasty or coronary artery bypass surgery. Heart failure was defined based on Framingham criteriaCV events were defined as peripheral artery disease, hospitalization for heart failure, non-fatal stroke, non-fatal myocardial infarction, and CV death. Hospitalization for heart failure was defined as admission due to dyspnoea with chest radiographic evidence of pulmonary congestion and treatment with intravenous diuretics. The stroke diagnosis was confirmed by clinical evaluation of a neurologist combined with computed tomographic or magnetic resonance imaging findings. CV events were determined and judged by two cardiologists with disagreements resolved by a third cardiologist from the hospital course and medical record. If patients suffered from several CV events, only the first event was coded. However, if patients expired after episodes of heart failure, stroke, myocardial infarction, or peripheral artery disease during the same admission, they were coded as CV deaths. Study patients reaching the end points were followed until the first episode of adverse CV events. The other subjects were followed until March 2017.Study data were expressed as the percentage or mean ± standard deviation. Independent samples t test and Chi-square test were used to compare the continuous and categorical variables between groups, respectively. The association between two continuous variables was analysed by a bivariate correlation method (Pearson’s correlation). Multivariable linear regression analysis was employed to find the determinants of EAT thickness. We chose age, sex, comorbidities, antihypertensive medication, and important clinical, laboratory, and echocardiographic parameters in the univariable linear analysis. The significant variables in the univariable linear analysis were selected for multivariable linear analysis. Time to adverse CV events and covariates of risk factors were modelled using a Cox proportional hazards model. Similarly, the significant variables in the univariable analysis were selected for multivariable analysis. Statistical evaluation was performed using SPSS 22.0 software . All tests were 2-sided, and the level of significance was established as P < 0.05.


Several studies indicate that fatty replacement of myocardium occurs after left ventricular myocardial infarction. Magnetic resonance imaging can readily identify the location and morphology of both fatty tissue and myocardial infarction and may have the ability to non-invasively identify fatty replacement within infarcted regions. Fat deposition may impair global and regional cardiac function as well as the electrical activation of the heart.Twenty-five patients  with documented prior myocardial infarctions and ten normal volunteers (age: 63 ± 10 yrs) underwent MR imaging on a clinical 1.5 T scanner using precontrast fat-water separated (Dixon) and late gadolinium-enhanced infarct imaging. Myocardial infarct location and size were assessed using the full width half maximum (FWHM) infarct sizing algorithm applied to the late gadolinium-enhanced images. Fat-water separation was performed using a three-point Dixon reconstruction from in- and opposed-phase gradient-echo images (Echo times (TEs) = 4.8, 7.2, 9.6 ms). Fat segmentation was performed on a slice by slice basis using a signal intensity threshold set two standard deviations above the noise level. Volumes of myocardial late gadolinium-enhancement and fat deposition were compared using a Student's t-test. Precontrast infarct location and detection was compared with late gadolinium-enhanced infarct imaging using a seventeen segment model.Subjects with prior myocardial infarction had a 68% prevalence of fat deposition 17/25). In subjects without a history of myocardial infarction, fat deposition and late gadolinium-enhancement were not detected (0/10). In the patients with fat deposition, the fat volume was 19.6 ± 19 ml (range: 1.7–62.6 ml) vs late gadolinium-enhancement volume of 30 ± 15 ml (range: 9.6–59.2 ml). The volumes of late gadolinium-enhancement and fat deposition were statistically different (p = 0.01). Of the 425 myocardial segments, 156 (37%) had late gadolinium-enhancement and 76 (18%) had fat deposition. 65 segments (15%) had both fat deposition and late gadolinium-enhancement, while 91 segments (21%) had late gadolinium-enhancement and no fat deposition. 11 segments (2.6%) had fat deposition and no late gadolinium-enhancement, but all 11 segments had adjacent myocardial segments with late gadolinium-enhancement. Figure 7/25. In Fatty replacement of myocardium after myocardial infarction is common and can be readily identified using fat/water separation MR imaging. The clinical significance and biologic mechanism of fatty deposition in infarction remain to be determined.


CES) and area strain (AS) with higher rates of increase in males, end-diastolic (ED) and ES wall thickness  with higher rates of increase in females, and reductions in ED and ES wall stress indices  with higher rates of increase in females. Females exhibited greater ED curvedness, CES, σi,ED and AS than males, but smaller WTED and WTES. Age × gender interaction was not observed for any parameter. This study establishes age and gender specific reference values for 3D LV regional parameters using CMR without additional image acquisition.Curvature-based three-dimensional cardiovascular magnetic resonance (CMR) allows regional function characterization without an external spatial frame of reference. However, introduction of this modality into clinical practice is hampered by lack of reference values. We aim to establish normal ranges for 3D left ventricular (LV) regional parameters in relation to age and gender for 171 healthy subjects. LV geometrical reconstruction and automatic calculation of regional parameters were implemented by in-house software (CardioWerkz) using stacks of short-axis cine slices. Parameter normal ranges were stratified by gender and age categories . Our software had excellent intra- and inter-observer agreement. Ageing was significantly associated with increases in end-systolic (ES) curvedness ( The spatially spread-out 2D image slices constitute a sparse sampling of LV geometry and can neither capture changes in LV deformation in their entirety nor account for through-plane displacements. To comprehensively quantify LV geometry and longitudinal changes associated with remodeling in disease or with ageing, three-dimensional (3D) techniques potentially offer greater sensitivity and precision. This will be particularly helpful for the challenging task of quantitative characterization of LV geometry alterations among non-diseased healthy male and female subjects of various age groups, who do not exhibit gross LV remodeling.Structural and functional changes occur in the left ventricle (LV) during disease processes and over the course of chronological ageing. Cardiac magnetic resonance (CMR), specifically Simpson’s method employing phasic endocardial border contouring of a stack of parallel LV short-axis two-dimensional (2D) cine CMR images, is long regarded as the gold standard for quantification and assessment of global LV function and volumes due to its superiority over other modalities like echocardiography in terms of imaging quality, accuracy and reproducibility. Current CMR feature tracking (FT) techniques allow characterization of LV regional —and when aggregated, global— function, but are ultimately still based on tracking of 2D cine CMR images, commonly the LV basal, mid-cavity and apical short-axis slices2, heart failure (HF)3, myocardial infarction5 and hypertrophic cardiomyopathy6, as well as predominant right ventricular pathology such as repaired tetralogy of Fallot7. In this study, we hypothesize that our 3D technique can be applied in healthy cohorts to characterize gender- and age-related differences in LV geometry. Our results will provide reference values for the 3D characterization technique which will facilitate future clinical applications in healthy cohorts for both genders across various age groups.In our previous studies, regional ventricular curvedness, thickness, curvature-based wall stress index and area strain were automatically evaluated from 3D reconstructed LV geometry in diverse of LV pathologies such as ischemic dilated cardiomyopathy8: ≤44 years (30/36), 45–64 years (16/22), 65–74 years (30/23) and 75–84 years (7/7).The analysis cohort comprised 171 subjects without prior history of cardiovascular disease, hypertension, dyslipidemia or diabetes, and with LV ejection fraction (EF) ≥ 50% on CMR. Demographic data were collected at the time of imaging. In the evaluation of age-related characteristics, subjects were stratified into the four age (M/F) groups based on definitions of young, mid-age, young-old and medium-old by the Department of Statistics Singapore9. As expected, systolic blood pressure was significantly higher in the 65–74 years and 75–84 years age categories than the ≤44 years and 45–64 years categories. LV EDV index and ESV index were significantly smaller in the 75–84 years age group than the other three groups . There was a significant trend towards increased LV mass-to-volume ratio with increased age (P = 0.017). Sex-specific comparison of demographics are tabulated in Table P < 0.05). Heart rate and LV EF did not differ significantly between males and females .Table CED and CES), wall thickness at ED and ES (WTED and WTES), curvature-based wall stress index at ED and ES , peak systolic wall stress (σES), and area strain (AS). Detailed computations of these parameters are given in Methods section.Segmented LV endocardial and epicardial contours of the stack of LV short-axis images from QMass  were imported into our in-house software (CardioWerkz) to reconstruct the 3D LV geometry. Figure CES, σi,ED, σi,ES, σES and AS . There were significantly higher CES and AS for those aged 75–84 years compared with the other three age groups (P < 0.05). The 45–64 years, 65–74 years and 75–84 years age groups showed significantly lower σi,ES compared with the ≤44 years age group. Shaded error plots (mean ± SD) for CED, CES, WTED, WTES, σi,ED, σi,ES, σES and AS for individual LV wall segments among the age groups are given in Figure 3D regional parameters for the four age groups are tabulated in Table CED, CES, σi,ED and AS were significantly larger in females  compared with males  . No significant differences were seen for σi,ES and σES between genders . Gender comparisons of CED, CES, WTED, WTES, σi,ED, σi,ES, σES and AS in individual LV segments are presented in Figure CED and CES, showed significant differences at the following segments: basal anterior (Segment 1); inferior, inferior lateral and anterior lateral (Segments 4–6); mid anterior septal (Segment 8); inferior lateral (Segment 11); and apical anterior (Segment 13) . For wall thickness, females exhibited significantly thinner myocardial walls than males at both ED and ES for all segments  except for apical inferior at ES phase. For σES, with the exception of basal anterior septal (Segment 2) and mid inferior (Segment 10), no differences were found at other segments or aggregated values at basal, mid-cavity and apical levels. The basal and mid-cavity anterior lateral segments, and the apical lateral segment, had the largest σES. There were no differences between males and females in AS, with the exception of the apical septal segment (Segment 14).Comparisons of 3D regional parameters between males and females are presented in Table CED (P = 0.0067), CES (P = 0.0001) and AS (P < 0.0001) increased significantly with age, while σi,ED (P = 0.0160) and σi,ES (P = 0.0011) decreased with age. Results of male vs female comparisons of ANOVA least squares means are as follows: CED , CES , σi,ED  and AS  were significantly lower in males than females; conversely, WTED  and WTES  were significantly higher in males than females. No gender differences were found in least squares means  for σi,ES  or σES . Figure CED, CES, WTED, WTES, σi,ED, σi,ES, σES and AS vs gender stratified by age group. Only in the ≤44 years group did females have significantly higher CED and CES than males. Except for the 75–84 years group, females had significantly smaller WTED and WTES and larger σi,ED than males in the other three age groups. Increased AS was observed in females for the ≤44 and 45–64 years groups (P < 0.05). Age × gender interactions were non-significant for all parameters, indicating relative constancy in differences between males and females across age categories. No significant differences were detected among age categories with respect to WTED (P = 0.626) and WTES (P = 0.133), indicating no significant effect of age on wall thickness. Significant differences in σES were observed among the four age groups (P = 0.0051), while associations with age (P = 0.348) and gender differences (P = 0.808) were non-significant. Plotted in Figure CED, CES, WTED, WTES, σi,ED, σi,ES, σES and AS vs age stratified by gender showing 95% confidence intervals and prediction intervals.Table P < 0.05 for both genders). However, only females had significant positive association with age for LV mass-to-volume ratio . Correlation of CES with age was higher for males than females , while negative association of σi,ES with age was more pronounced in females than in males . Correlation between wall thickness and age was higher in females vs. males at both ED  and ES . No significant correlation was observed between σES and age in either males or females . For AS, males were more correlated with age than females .We also investigated associations of age and gender vs LV function and 3D regional parameters, and the correlation coefficients are given in Table CED, CES, WTED, WTES, σi,ED, σi,ES, σES and AS, respectively. Intra-observer intraclass correlation coefficient (ICC) and coefficient of variation (CV) were 0.949–0.993 and 3.3–8.8%, and inter-observer ICC and CV were 0.924–0.991 and 3.9–10.1%. Both intra- and inter-observer variability have small biases and limits of agreement.Table Our study establishes the age- and gender-specific CMR reference ranges for 3D regional LV curvedness, thickness, wall stress index and area strain that can be automatically calculated from the reconstructed LV geometry. Age was positively associated with curvedness and area strain more in males, while negatively correlated with wall stress index more in females. On average, females exhibited significantly greater curvedness, wall stress index and area strain, but reduced wall thickness compared to males. Peak systolic wall stress showed no gender differences across the entire cohort or among age groups, and was not associated with age. Importantly, age × gender interaction effects were non-significant for all parameters.10. In Hindieh, et al.10, discordant measurements between TTE and CMR in maximal LV wall thickness at the parasternal long- and short-axis views were present in a significant subset of HCM patients because of TTE technique limitations. CMR has been shown to be superior to TTE in measuring LV chamber dimensions and wall thickness owing to image quality and accuracy with better reproducibility than TTE11. CMR 2D normal values for ED wall thickness were established from 300 participants (ages 45–94) free of cardiovascular disease in the Multi-Ethic Study of Atherosclerosis (MESA) cohort, and measurements were performed on both cine short- and long-axis images using QMass V.7.2 12. Compared with their results, our wall thickness values tended to be smaller. The discrepancy could be explained by: (1) LV wall thickness increases with aging, and participants in their paper were middle-aged or older compared with our relatively younger cohort ; (2) participants in the MESA study had larger LV mass index  on average compared with our Asian cohort 13; and 3) variations in measurement methodology. In our study, wall thickness was computed from a 3D reconstructed LV model and is the mean of the wall thicknesses of all points within the segment. The wall thickness is defined as the length of a ray with origin at a point of interest on the endocardial surface that is directed towards, and terminates at its intersection with the epicardial surface, and is neither dependent on the location of a center point nor imaging frame of reference2. This ray is not in the same plane as, and is always shorter than the distance measured on, standard 2D short- and long-axis slices. It approximates the “true” wall thickness in 3D space, and unlike 2D measurements, is independent of inaccuracies in slice positioning. Therefore, as suggested by Kawel, et al.12, it is critical to report the measurement technique along with the measured parameters. In addition, from the 16 segment plots in Figure 12.Regional parameters derived from the reconstructed LV geometry can provide new insights into the local mechanics that are not apparent from the 2D approach. Transthoracic echocardiography (TTE) is the standard and commonest clinical imaging modality for measuring LV wall thickness at the ED phase from the left parasternal long-axis view, but it is highly dependent on imaging plane obliquity, acoustic window and operator14. In pulmonary hypertension patients, the ratio of IVS curvature and free wall curvature at the ES phase by the three-point arc method was used to predict right ventricular (RV) systolic pressure15. Several shape descriptors have been proposed to characterize and quantify the differential properties of surfaces. The most common ones —first mentioned by Koenderink and Van Doorn16— are Gaussian curvature (K = k1k2), mean curvature [H = (k1 + k2)/2] and curvedness H measured on 3D echocardiography (3DE) has been proposed by Addetia, et al.17 to discriminate normal pressure from right ventricular pressure overload in pulmonary arterial hypertension patients, and normal 3DE values of RV regional curvature indices were established by the same group18. In a retrospective study of 416 inpatients using 2DE and 3DE, regional curvature H provided additional mortality risk prediction beyond global longitudinal strain and LV EF19. A serious limitation of curvature analysis is that H will be zero at the saddle point even when the surface is curved. Similarly, Gaussian curvature K is zero at the parabolic line on a toroidal surface even as the surface is actually curved2. In contrast, point curvedness is zero only when the surface is flat, and varies monotonically with the magnitude of surface curve characteristics. In Maffessanti, et al.20, curvedness, normalized to instantaneous LV size, was calculated using prototype software  and compared between segments for subjects with normal LV function (n = 14), dilated cardiomyopathy (n = 15) and ischemic heart failure (n = 15) using CMR images. The study size does not permit the determination of normal ranges of curvedness parameters. In contrast, our study, which recruited equal proportions of healthy male and female subjects stratified by age, is sizeable and able to establish gender- and age-specific normal ranges. Our results show that curvedness at ES is positively associated with age, indicating that the endocardial surface at the ES phase becomes more spherical during the ageing process.2D curvature has been proposed for characterizing LV local shapes in different HCM subtypes using independent coordinates method21. Numerous formulas have been proposed to evaluate wall stress that assume the LV as an ideal spherical, spheroidal or ellipsoidal shape25. Some of these geometrical limitations can be overcome by finite element analysis (FEA) which is a numerical and engineering technique for solving complicated structural problems. The characteristics of wall stress have been applied in translational research to analyze LV mechanics27. From the curvature-based wall stress index formula, increases in curvedness and wall thickness with ageing (decrease of radius-to-thickness ratio R/WT) will contribute to decreases in wall stress index, which is what we show in Table r = −0.213 for σi,ED and r = −0.331 for σi,ES). However, for peak systolic wall stress σES, which incorporates systolic blood pressure into the ES wall stress index, no association with age was found. Across each age group, σES first decreased in the 45–64 years age group due to the decrease in radius-to-thickness ratio, then increased in the 65–74 years group because R/WT is counterbalancing the somewhat elevated systolic blood pressure. Even though there was no clinical history of hypertension in the study population, σES eventually dropped in the 75–84 years group. However, σES exhibited no significant differences between males and females for all subjects, which implies that σES can be thought of as an intrinsic contractility index that is independent of gender that can potentially be helpful for longitudinal and/or therapeutic monitoring in disease applications.LV wall stress is proportional to wall radius and inversely proportionate to wall thickness according to Laplace’s lawAS reflects endocardial surface deformation during contraction and relaxation and integrates the regional changes from the circumferential, longitudinal and radial directions. Previous 3D echocardiography studies used percentage change in area from the original dimensions to quantify AS29. In contrast, our calculation was based on the natural log (ln) function of the ratio of surface area at ES and ED4. We found a significant gender difference in AS with greater deformation magnitude in females and greater rates of increase with age in males (r = 0.362). A similar trend was found for peak systolic longitudinal strain evaluated by CMR feature-tracking (CMR FT)30, an emerging technique for quantitating myocardial deformation in both clinical and research settings. Normal strain ranges using this approach have been presented32, however, only 2D basal, mid-cavity and apical LV short-axis slices were used to calculate global circumferential and radial strains, and only three standard LV long-axis views for global longitudinal strain. Hyperelastic warping is another technique employed to characterize cardiac motion and function measurement in finite deformation continuum mechanics and image-based data33, and this method has been applied to characterizing pulmonary hypertension36 and heart failure with preserved ejection fraction37. Strain measurements from this technique are based on the reconstruction of a 3D biventricular model that can extract circumferential, longitudinal and radial strains for the LV, RV and septum simultaneously.Area strain P ≤ 0.008). Both ED and ES curvedness in the HF patient groups were smaller than in the normal references and decreased from HFpEF to HFmrEF to HFrEF, implying that the LV was becoming flatter with decrease in LV EF. LV myocardial wall was thicker in HF patient groups than normal group, and ES wall thickness increased from Control to HFrEF to HFmrEF to HFpEF. With the progressive reduction of EF, HF patients had a propensity for higher wall stress index at ES and peak systolic wall stress, with trend HFpEF to Control to HFmrEF to HFrEF. The HFrEF stress was about twice that in Controls and around 2.7 times that in HFpEF. This can be explained as follows: the normal or near normal chamber size and increased wall thickness relative to chamber dimension in HFpEF patients (concentric remodeling) resulted in reduced wall stress relative to Control. In contrast, in HFrEF, there is LV chamber dilatation (eccentric remodeling), with increase in LV radius38. However, the decrease of AS was from Control to HFpEF to HFmrEF to HFrEF. Moreover, HFmrEF and HFrEF were significantly different from Control, HFpEF and each other. The bar graphs in Figure To demonstrate the clinical utility of normal reference values for curvature-based LV parameters, three patient groups —HF with reduced EF ; mid-range EF  and preserved EF — were evaluated using the 3D regional analysis described in this study. Comparisons of demographics and regional parameters in each group against the normal reference values are presented in Table 9. As such, it would not be surprising if reference ranges for curvedness-based parameters were to differ between ethnic groups. Fortunately, curvedness and the derived parameters can be determined expeditiously with post-processing of standard cine CMR images, and can therefore be applied retrospectively to extant research or clinical image repositories to generate references ranges in different populations and/or diverse disease states.These reference values were derived from a multi-ethnic Singaporean cohort with predominant Chinese ethnicity, which may limit the generalizability of the indices to Western populations. Our group has previously demonstrated that standard CMR parameters like chamber volumes and mass derived from a predominantly Chinese population were different than Western norms42 and deep learning techniques45 may reduce processing time, is the next logic step. One of the limitations in our current reconstruction approach is the omission of the true apex (Segment 17 on the standard nomenclature) as it cannot be easily identified using the short-axis images due to thick (10 mm) slice acquisition. This may potentially lead to underestimation of LV volume. Another limitation concerns the tracking of LV chamber height, which shortens from ED to ES. LV chamber height is measured using the line joining the LV apex to the midpoint of the straight line connecting the two atrioventricular junctions, which assumes that the base of the LV is a flat plane orthogonal to the image defined solely by the two atrioventricular junction points. In reality, the LV basal surface is non-planar and the mitral valve is saddle-shaped. In our study, endocardial and epicardial borders at the base of the LV were manually contoured on short-axis cine CMR images, which is the routine in research and clinical laboratories. The left atrium (LA)-LV and LV-Aorta (AO) intersections are almost tangential to, and frequently not well-defined on, LV short-axis planes. A more optimal approach would be to reconstruct a whole heart model with the left atrium (LA) and aorta (AO) intact, and then to subsequently isolate the LV by truncating at the mitral annular and aortic planes. In a prior work, we acquired a series of 18 rotational slices at 10° angular equidistance in the LV long axis —the line extending from the LV apex to the center of mitral valve orifice— that depicts the mitral valve and annulus comprehensively46. Future work will be to develop an algorithm to construct a composite 3D LV+LA+AO geometric model using 18 rotational slices as the reference, and to compare volumetric measurements with the LV models reconstructed from routine CMR images.The sample size in the 75–84 years group was smaller than the other age groups owing to challenges in recruiting older subjects free of cardiovascular diseases, hypertension, diabetes and dyslipidemia. In the present study, manual delineation of endocardial and epicardial contours at ED and ES was needed to generate inputs for 3D geometric reconstruction, which is manually intensive. Incorporation of automatic segmentationet al.18. However, acquisition of 3D RV echocardiographic data sets is quite challenging and often hampered by varying degrees of anterior wall dropout17. Using routine CMR to reconstruct 3D RV geometry and performing curvedness analysis has been reported in our prior study7. A future study will establish normal ranges of RV regional deformation using the same stacks of LV short-axis cine CMR images, which also cover the RV chamber, combined with automatic segmentation of RV endocardial contours48.One attractive feature of our CardioWerkz software is that it does not require additional image acquisition and only uses short- and long-axis CMR images acquired in routine clinical practice. The short-axis contours used for LV function measurements can be directly imported into CardioWerkz for LV regional parameter evaluation permitting retrospective study of various cohorts. The relatively complex structure of the RV has rendered it less studied compared with the LV. Normal values of RV regional curvature indices using 3D echocardiography have been established by Addetia, AS for healthy subjects across a broad age spectrum, and investigated the associations with age and gender. Our approach is highly reproducible and automatic apart from contour extraction. The parameters in this study may shed light on the LV regional deformation with ageing.We have established normal values for 3D regional curvedness, wall thickness, wall stress index and Between July 2011 and July 2016, 444 healthy asymptomatic subjects (age range 20–87) without known cardiovascular disease were recruited from the community to undergo CMR. Those with prior history of hypertension, dyslipidemia, diabetes mellitus, and detected to have LV ejection fraction (EF) < 50% on CMR were excluded from analysis, leaving a final study sample of 171 subjects. The study was conducted in accordance with the Declaration of Helsinki and approved by the SingHealth Centralized Institutional Review Board. Written informed consent was obtained from all subjects.49 and prior hospitalization with primary diagnosis of HF. Exclusion criteria for HF included specific subgroups of HF  and isolated right heart disease.As a clinical application of our normal ranges, we also included three heart failure (HF) patient groups —HF with reduced EF ; mid-range EF  and preserved EF . Inclusion criteria of HF required the presence of signs or symptoms of HF based on modified Framingham criteiraAll subjects underwent CMR on a 3.0 Tesla system  with a dStream Torso coil. Contiguous end-expiratory breath-held balanced fast field echo short-axis cine images covering the LV from base to apex were acquired along with routine 2-, 3- and 4-chamber long-axis cine images. Typical sequence parameters were: TR/TE 3/1 ms, flip angle 45°, slice thickness 10 mm for both short- and long-axis with 0.6 mm × 0.6 mm to 1.1 mm × 1.1 mm in-plane spatial resolution, pixel bandwidth 1797 Hz, field of view 280–450 mm, and frame rate was 30 frames per cardiac cycle.Commercially available software QMass  was used for standard volumetric analysis. LV endocardial and epicardial contours were delineated manually at end-diastole (ED) and end-systole (ES) for each short-axis slice to determine LV end-diastolic volume and end-systolic volume, stroke volume (SV) and EF. Papillary and trabeculae muscles were included in the chamber volume calculation. LV mass was estimated at the ED phase as  × 1.05 g/ml. LV endocardial and epicardial contours in the remaining time phases were automatically tracked for each short-axis slice and manually corrected where needed.50; up-sampling of both endocardial and epicardial short-axis contours using a Bézier fitting algorithm to facilitate smooth surface reconstruction; and reconstruction of both LV endocardial and epicardial surfaces in the form of unstructured triangular meshes. Additionally, for LV endocardial surface meshes, we generated 1-to-1 correspondence between the mesh at ED phase and the mesh at ES phase by enforcing identical connectivity information and number of vertices using a radial basis function morphing approach51. Details of the reconstruction approach and methodology can be found in our previous publications7. The LV endocardial mesh is then partitioned into 16 segments  based on the American Heart Association recommendation52 to compute all 3D regional parameters5.Segmented LV endocardial and epicardial contours of the stack of LV short-axis images from QMass were imported into our in-house software  to reconstruct the 3D LV geometry. CardioWerkz is a proprietary in-house developed software comprising a suite of algorithms for geometrical reconstruction of the left heart and its subsequent analysis. The workflow for the reconstruction process and the ensuing computation of associated 3D regional parameters is illustrated in Figure C) measures the degree of curvature at a given point, and how it deviates from flatness on a surface. It was calculated using the formula16Curvedness  and ES (WTES) for each segment were calculated using a previously derived formula2. Thick-walled elliptical and spherical models53 had been proposed for calculating pressure-normalized wall stress, obviating the need for invasive LV pressure measurement. In the current study, the curvature-based wall stress index σi, was determined from the inner radius of curvature (R) and wall thickness WT2:where et al.22, peak systolic wall stress (σES) was calculated asSP denotes peak systolic ventricular blood pressure (= 0.9 × systolic blood pressure)54 and σi,ES is the curvature-based wall stress index computed at ES by Eq. (2.Following Grossman AS) was defined as4SAED and SAES are endocardial surface areas at ED and ES phases, respectively.Area strain is a quantitative strain measurement that incorporates endocardial wall strains in the circumferential, longitudinal and radial directions, and reflects the aggregate deformation of the LV endocardial surface with contraction and relaxation. The area strain . All continuous variables were presented as mean ± standard deviation (SD). Associations between continuous variables were investigated using regression and correlation (Pearson). Comparisons of means between two independent groups were investigated using the two-sample t test. Comparison of means in three or more groups was investigated by one-way analysis of variance (ANOVA) with Bonferroni correction. Correlations of CMR measurements with gender and age were analyzed using a two-way analysis of variance model with factors age category , gender (M/F), and age × gender interaction. F-tests were performed to test for significant differences in age category and gender main effect means, and for age × gender interaction effects.P < 0.05.Inter- and intra-observer reproducibility were assessed in 20 randomly chosen subjects via intraclass correlation coefficient (ICC), Bland-Altman analysis and coefficient of variation (CV). For inter-observer variability, LV endocardial and epicardial contours were segmented by a second independent observer (SL) blinded to the first observer’s results, and a second segmentation was made by the primary observer (XZ) one month after the initial segmentation to assess intra-observer variability. Statistical significance was set at Supplementary information.


To investigate the influence of respiratory distress syndrome management on clinical and echocardiographic parameters used for hemodynamic evaluation in ≤ 32- week newborns.Thirty-three ≤ 32-week newborns were prospectively evaluated and subjected to invasive mechanical ventilation. The need for exogenous surfactant and clinical and echocardiographic parameters in the first 24 hours of life was detailed in this group of patients.2O versus 9 (6.2 - 12) cmH2O; p = 0.04]. A negative correlation was found between the mean airway pressure and velocity-time integral of the pulmonary artery , right ventricular output  and measurements of the tricuspid annular plane excursion . A negative correlation was found between the number of doses of exogenous surfactant and the right ventricular output  and pulmonary artery velocity-time integral .The mean airway pressure was significantly higher in newborn infants who required inotropes [10.8 (8.8 - 23) cmHIn ≤ 32-week newborns under invasive mechanical ventilation, increases in the mean airway pressure and number of surfactant doses are correlated with the worsening of early cardiac function. Therefore, more aggressive management of respiratory distress syndrome may contribute to the hemodynamic instability of these patients. The immediate postnatal period is marked by important cardiopulmonary changes. In preterm infants with a gestational age of less than 32 weeks, the immaturity of several organs may affect this physiological transition, and a need for respiratory and hemodynamic support is common. Treatment consists of pulmonary recruitment by applying positive airway pressure through noninvasive or invasive ventilation associated or not associated with the use of exogenous surfactant.Infant respiratory distress syndrome (RDS) is one of the main causes of morbidity in these patients. Surfactant deficiency, which is characteristic of developing lungs, causes alveolar collapse, which manifests as respiratory discomfort during the first hours of life. In turn, the excessive use of positive airway pressure causes adverse effects, such as increased pulmonary vascular resistance, reduced pulmonary perfusion and venous return and a low cardiac output.The use of positive airway pressure facilitates the establishment of a functional residual capacity, decreases pulmonary vascular resistance and may increase pulmonary venous return, thereby favoring systemic output. therefore, gaining a better understanding of the interaction between respiratory support and cardiac function is essential. Additionally, establishing whether the echocardiographic changes are transient and typical of perinatal cardiorespiratory adaptation or secondary to respiratory management of the patients is important.A low systemic output and decreased superior vena cava (SVC) flow are associated with an increased risk of intraventricular hemorrhage in preterm infants;The objective of the present study was to evaluate the influence of RDS management, comprising ventilatory support and pulmonary surfactant replacement, on clinical and echocardiographic parameters used for hemodynamic evaluation of ≤ 32-week newborns in their first 24 hours of life.Instituto da Criança of the Hospital das Clínicas of Faculdade de Medicina of the Universidade de São Paulo between August 2016 and March 2018. The Research Ethics Committee of the institution approved the research project (CAPPesq report: 1531501), and informed consent forms were signed by the legal guardians.A prospective cross-sectional study was performed on a convenience sample of preterm infants admitted to the Neonatal Center of the th week of gestation. Patients with congenital malformations, newborn infants who did not have an echocardiogram within the first 24 hours of life and those whose caregivers did not consent to the study were excluded.Newborn infants born with a gestational age ≤ 32 weeks who underwent invasive mechanical ventilation for RDS treatment within their first 24 hours of life were included. The gestational age was determined by obstetric ultrasound performed up to the 20 greater mean airway pressure (Paw) in cmH2O during the first 24 hours of life; need for administration of exogenous surfactant and the number of doses ; presence of hypotension ; and use of inotropic agents.The following clinical parameters were investigated: exposure to antenatal corticosteroids; presence of fetal distress; weight at birth; gestational age; sex; Score for Neonatal Acute Physiology Perinatal Extension, version II (SNAPPE II); A Logiq-e®  portable ultrasound with a multifrequency transducer (6S) from 5 to 7.5MHz was used for morphological and functional cardiac evaluation by a team composed of three experienced echocardiographers who were blinded to the patient's clinical parameters. The cavity measurements and cardiac function evaluation were performed according to the 2010 guidelines of the American Society of Echocardiography (ASE).An echocardiogram was performed in the first 24 hours of life. This period was chosen because it is considered to have the highest risk for the occurrence of low output related to the transitional phase of circulation in the preterm newborn. Measurements of the tricuspid annular plane systolic excursion (TAPSE) and mitral annular plane systolic excursion (MAPSE) allowed calculation of the z-scores of these parameters for each patient.The diastolic and systolic diameters of the left ventricle were measured in M mode, which allowed calculation of the fractional shortening (ΔD) and left ventricular ejection fraction (LVEF) using the Teichholz method.The velocity-time integrals for the pulmonary artery flow (VTIPA) and SVC were obtained using Doppler. To estimate the VTIPA, the Doppler sample was placed in the right ventricular outflow tract (RVOT) in the parasternal short axis view just below the pulmonary valve plane. The VTI of the VSC was estimated by placing the Doppler sample at the entrance of the vena cava in the right atrium in the subcostal section view. The maximum diameter of the RVOT was measured using a two-dimensional, parasternal, short axis view. In contrast, the mean SVC diameter was recorded as mode M in the parasternal view of the RVOT.The right ventricular output (RVO) was calculated according to the following formula:With the following units: VTI in cm; outlet diameter in cm; weight in kg; and π = 3.14.The SVC flow (SVCF) was calculated using the following formula:With the following units: VTI in cm; diameter of the outflow tract in cm; weight in kg; and π = 3.14. LVEF 55%, RVO 150mL/kg/minute, pulmonary VTI 7cm, MAPSE z-score < -2, TAPSE z-score < -2 and SVCF 40mL/kg/minute.The cut-off points used to categorize the echocardiographic parameters of cardiac function as normal (no dysfunction) or reduced (with dysfunction) were ΔD 28%,shunt from left to right.The RVO was used to avoid overestimating the systemic output given the likelihood of a patent ductus arteriosus on the first day of life with a In the statistical analysis, the qualitative variables were described as absolute frequencies and percentages. Quantitative variables were described using summary statistics  and the median, minimum and maximum.To assess the correlation between the MAP and Paw and the echocardiographic measurements, Spearman's correlation coefficient (r) was used. The comparison of Paw between the groups with and without dysfunction was performed using the nonparametric Mann-Whitney test. The association between the number of doses of exogenous surfactant and the presence of cardiac dysfunction was assessed using the Kruskal-Wallis test. The significance level was set as p < 0.05. The data analysis was performed using the IBM Statistical Package for Social Sciences for Windows, version 20.0.A total of 33 preterm infants on mechanical ventilation for treatment of RDS were studied, including 63.6% males and 36.4% females. The means (± SDs) for gestational age, weight and SNAPPE II were 27.8 (± 1.9) weeks, 958 (± 332) grams and 39.5 (± 20.6), respectively. Fetal distress occurred in 33.3% of the cases, and 78.8% of the fetuses were exposed to antenatal corticosteroids.2O (minimum of 6.2 and maximum of 23cmH2O). Four patients were treated with high-frequency ventilation by interrupting flow. A total of 32 patients were given at least one dose of exogenous surfactant.The median of the mean Paw was 9.2cmH2O versus 9 (6.2 - 12) cmH2O, with p = 0.04.Hypotension was diagnosed in 11 (33%) patients; a total of 8 (24%) patients were given inotropes  in the first 24 hours of life. No significant correlation was found between the MAP and mean Paw value . The mean Paw was higher in those that required inotropes: 10.8 (8.8 - 23) cmHThe echocardiogram was performed within a median of 20 hours of life (minimum of 7 and maximum of 24 hours). No significant association was detected between the echocardiographic measurements and fetal distress or use of antenatal corticosteroids. Additionally, no correlation was found between the MAP and echocardiographic parameters of cardiac function . A negatThe mean Paw values were higher in patients with cardiac dysfunction based on the following parameters: ΔD < 28%, LVEF < 55%, VTIPA < 7cm and RV < 150mL/kg/minute .A negative correlation was noted between the number of exogenous surfactant doses and the RVO  and VTIPA  measurements. A higher number of surfactant doses was used for patients with cardiac dysfunction based on the following echocardiographic parameters: VTIPA < 7cm, RV < 150mL/kg/minute and TAPSE z-score < -2 .The present study demonstrated the impact of respiratory management on the hemodynamic status of ≤ 32-week newborn infants using not only clinical parameters (MAP and need for inotropic drugs) but also bedside echocardiographic parameters of cardiac function.Increases in the mean Paw indicated worsening of right and left cardiac functions as evaluated by echocardiography and a greater need for hemodynamic support with inotropic drugs. In a more recent study, de Waal et al. demonstrated a reduction of the RVO after an increase in the positive end-expiratory pressure (PEEP) but not of the systemic output estimated by the SVCF.Other authors have described a worsening of myocardial function in patients with moderate to severe respiratory failure. In 1996, Evans and Kluckow showed a reduction in the output of both ventricles that was associated with an increased severity of respiratory failure and the frequency of low output (< 150mL/kg/minute) of the LV and RV with the increase in the mean Paw. we were able to demonstrate an association between the reduction of these left cardiac function parameters and an increase in the mean Paw in our sample.Although the ΔD and LVEF measurements are less reliable in neonates ,In the present study, the negative correlations between the mean Paw and the VTIPA, RVO and TAPSE measurements and the higher frequencies of a VTIPA < 7cm and RV < 150mL/kg/minute with the increase in the mean Paw reinforce the influence of the latter parameters on the RV. Since a strong correlation exists between the VTIPA and RVO and the former is simpler to measure because it does not require calculation, measuring this parameter to quickly estimate the systolic function of the VD may be an interesting approach.,21 However, hypoxemia secondary to respiratory failure may have a direct effect on the increase in pulmonary vascular resistance and can lead to some degree of subendocardial ischemia, which causes impairment of myocardial function.The effect of the mean Paw on the RVO is most likely due to reduced venous return. Additionally, Vitali et al. did not observe changes in ventricular function measurements 2 hours after surfactant administration but described an improvement in the output of both ventricles and the TAPSE 24 hours later. In fact, the administration of exogenous surfactant is followed by pulmonary recruitment, which results in a reduction of pulmonary vascular resistance. Therefore, the following outcomes would be expected: an increase in the right ventricular output due to a reduced afterload and possibly a decrease in systemic perfusion due to an increase in left-to-right shunting through the ductus arteriosus, which usually is patent on the first day of life in preterm infants.The finding of the inverse association between the number of surfactant doses and the presence of a VTIPA < 7cm and RV < 150mL/kg/minute differed from observations in the literature. Sehgal et al. reported an increase in the RVO and a reduction in the LV output after surfactant was given in the first hour of life.In the present study, the worst cardiac function was exhibited by patients who used a greater number of surfactant doses and could be explained, in part, by two factors. First, we can assume that newborn infants requiring two or more doses of surfactant have more severe respiratory failure; second, in our sample, all patients who received more than one dose of surfactant were on mechanical ventilation at the time of the echocardiogram. Therefore, the hemodynamic repercussions of mechanical ventilation may have prevailed over the effects of exogenous surfactant on pulmonary compliance and vascular resistance.The study has some limitations, such as the relatively small number of newborns. In addition, the type of ventilation used (four patients received high-frequency flow interruption ventilation) and the mean Paw may have favored the presence of cardiac dysfunction.The fact that the patients were evaluated at only one time point (within the first 24 hours of life) should also be emphasized. During this period, preterm infants are prone to myocardial dysfunction.In newborn infants with a gestational age ≤ 32 weeks under invasive mechanical ventilation, more aggressive management of respiratory distress syndrome seems to exert a negative effect on echocardiographic parameters of cardiac function, particularly the right ventricle. New multicenter studies with a larger number of patients should be conducted to improve treatment strategies for this group of patients.


NCT03042104, NCT03094143, and NCT02436655.With the increasing prevalence of aortic stenosis (AS) due to a growing elderly population, a proper understanding of its physiology is paramount to guide therapy and define severity. A better understanding of the microvasculature in AS could improve clinical care by predicting left ventricular remodeling or anticipate the interplay between epicardial stenosis and myocardial dysfunction. In this review, we combine five decades of literature regarding microvascular, coronary, and aortic valve physiology with emerging insights from newly developed invasive tools for quantifying microcirculatory function. Furthermore, we describe the coupling between microcirculation and epicardial stenosis, which is currently under investigation in several randomized trials enrolling subjects with concomitant AS and coronary disease. To clarify the physiology explained previously, we present two instructive cases with invasive pressure measurements quantifying coexisting valve and coronary stenoses. Finally, we pose open clinical and research questions whose answers would further expand our knowledge of microvascular dysfunction in AS. These trials were registered with  The seminal 4-group classification of coronary microvascular dysfunction proposed in 2007 placed aortic stenosis (AS) into a category with other myocardial diseases, both primary and secondary . The impUniquely among our organs, the heart must pump its own blood supply and cannot meaningfully augment oxygen extraction, implying that only increased supply can match increased need. Wall stress, contractility, and heart rate account for most myocardial oxygen consumption. The law of Laplace informs us that wall stress is directly proportional to pressure and to radius but inversely proportional to thickness. AS increases wall stress through elevated afterload, and, in response, the heart compensates through increased wall thickness. In other words, left ventricular (LV) hypertrophy offsets pressure overload to reduce wall stress and thereby oxygen requirements. However, LV hypertrophy brings its own disadvantages, namely, diastolic dysfunction, insufficient capillary density , and difAs a semiquantitative and practical metric of coronary supply versus myocardial demand, a unitless index has been proposed using pressure measurements . The areAlthough commonly considered as a single “myocardium,” the subepicardial and subendocardial layers display distinct patterns of blood flow with differential sensitivity to pathology. On the one hand, the subepicardium faces generally low pressures from the pericardial space and thoracic cavity throughout the cardiac cycle, while, on the other hand, the subendocardium experiences generally low LV filling pressures during diastole that rise dramatically during systole. Even under normal conditions, the LV pressures during systole compress the subendocardium and redistribute flow to midmyocardial and subepicardial layers , a phenoTo apply these principles of supply versus demand to aortic stenosis, consider the animal model in 2), undergoing invasive hemodynamic study, average DPTI/SPTI of 0.34 with net lactate extraction at baseline 85 beats/minute fell with isoproterenol stress to DPTI/SPTI of 0.16 and switched to net lactate production at 113 beats/minute [In many ways, s/minute . These os/minute .Unfortunately, our intuitive notion of “resistance” gained from daily life and basic electrical circuits often provides a suboptimal analogy for understanding myocardial behavior. As a result, much of the literature on “myocardial resistance” must be reviewed with caution or at least through the lens of a more sophisticated understanding. This section discusses key points relevant to understanding the concept as it applies to AS since the general topic goes beyond the scope of this review.During baseline or resting conditions, myocardial flow remains relatively stable over a wide range of perfusion pressures  via a la2 = 64% of the variation can be explained).Animal models of supravalvular aortic stenosis inform us about its effects on myocardial resistance. Compared to normal dogs, animals with LV hypertrophy after 8–10 months of aortic banding displayed a more shallow slope (less flow for the same coronary pressure) but also a higher wedge pressure  as depicSeveral aspects add further complexity to this vasodilated relationship between flow and pressure. First, inotropic (dobutamine and exercise) and chronotropic stimulation can change the slope by about 20% in addition to increasing the wedge pressure , 20. ThiBefore presenting existing resistance data in humans with AS, several points deserve to be mentioned. First, two main invasive techniques exist to measure coronary flow (Doppler flow velocity and bolus thermodilution), thereby introducing heterogeneity in the literature. Encouragingly, vasodilatory hyperemia to enable either technique appears safe in patients with severe AS based on 40 reports from 1820 patients over 3 decades as summarized in While severe AS by itself can be sufficient to explain symptoms of heart failure or angina, due to a supply-demand mismatch discussed above, epicardial coronary disease of angiographic significance can be seen in 40% to 75% of these patients . Due to Superimposing a coronary stenosis on severe AS exacerbates the supply/demand mismatch. A fixed epicardial stenosis produces a pressure loss that increases with flow but has separate contributions from viscous  and separation  components. Based on the discussion of myocardial resistance in the prior section, the existing data support an increase in hyperemic flow after TAVI due to a change in the myocardial load line. This change occurs both via a reduction in wedge pressure, largely mediated by its direct correlation with LV filling pressures , 19 thatIn contrast to inferences regarding the mechanisms in The proposed model in A review not only provides an opportunity to look backward and synthesize existing knowledge but also offers the possibility to identify gaps that remain and how they might be filled in the future. On a basic level, measuring in humans the changes seen in animal models  regardinApart from a confirmation of translational animal physiology and conceptual insight, what clinical advantages might come from such data? Currently, we do not understand when to treat mixed coronary disease and AS, and in some cases, FFR values fall after TAVI, particularly when previously in the 0.75 to 0.85 range . If we uAs a final sign of our yet incomplete knowledge of the coronary microcirculation in aortic stenosis, a clinical case is considered in However, extensive workup revealed a calcified bicuspid aortic valve with moderate-to-severe stenosis at baseline, rising to a mean gradient of 90 mmHg during intravenous dobutamine infusion with a SAVI of 0.51 . A calcified mid-LAD stenosis had an FFR of 0.64 during intravenous adenosine with a focal pressure jump. An analysis of DPTI/SPTI  showed a potential drop to 0.10 during peak stress, entering the region that has been associated with net lactate production in a small human study . TherefoNCT03042104, NCT03094143, and NCT02436655), what should we currently do with such patients who nevertheless exhibit extreme hemodynamic derangements? Can we expect that the reduction in sudden death seen in a small trial of SAVR for asymptomatic yet severe AS (mean gradient 63 mmHg) [Should we understand this case as a profound challenge to the relevance of hemodynamic physiology reviewed in this article? Or does it indicate that patient symptoms (or their lack) as well as standard noninvasive testing often tell us at most a modest amount regarding physiologic severity, thereby necessitating routine quantification? While awaiting the results of ongoing randomized controlled trials of TAVI in severe yet asymptomatic AS   will be


Coronary heart disease (CHD) is an important cause of chronic heart failure, and chronic heart failure is also a serious complication in the end stage of coronary heart disease. At present, there is no specific treatment plan. Shenfu injection has advantages in the treatment of heart failure in patients with coronary heart disease, but there is a lack of standard clinical study to verify this. Therefore, the purpose of this randomized controlled trial is to evaluate the efficacy and safety of Shenfu injection combined with furosemide in the treatment of chronic heart failure in patients with coronary heart disease.This is a prospective randomized controlled trial to study the efficacy and safety of Shenfu injection combined with furosemide in the treatment of coronary heart disease and chronic heart failure. This study will be approved by the clinical research ethics committee of our hospital. The patients will be randomly divided into two groups according to 1:1:(a) Shenfu injection combined with furosemide group and (b) simple furosemide group. Standard treatment for 7 days followed up for 30 days at the same time, pay attention to its efficacy and safety indicators. The total effective rate of cardiac function improvement, left ventricular ejection fraction (LVEF), N-terminal pro-brain natriuretic peptide (NT-pro BNP), 6-minute walk test (6-MWTD), and adverse reactions will be observed. Data will be analyzed using the statistical software package SPSS version 25.0 .This study will evaluate the efficacy and safety of Shenfu injection combined with furosemide in the treatment of coronary heart disease with chronic heart failure. The results of this experiment will provide a clinical basis for Shenfu injection combined with furosemide in the treatment of coronary heart disease and chronic heart failure.doi: 10.17605/OSF.IO/27FPM Despite the continuous improvement of treatment, chronic heart failure remains a disease with poor prognosis. In 5 years of observation, the mortality rate was 50%. The most important cause of chronic heart failure is coronary heart disease. At the same time, chronic heart failure is one of the most serious complications of coronary heart disease.Chronic heart failure is a common clinical syndrome characterized by dyspnea, fatigue, and signs of volume overload, which may include peripheral edema and pulmonary rales. which can reduce the number of readmissions associated with heart failure through appropriate fluid retention management. In the clinic, the most commonly used diuretic in patients with heart failure is loop diuretic furosemide (furosemide). However, some studies have pointed out that furosemide has no positive effect on the prognosis of patients, and may even be related to an increased risk of hospitalization, all-cause mortality, and cardiovascular mortality.In order to improve the symptoms and exercise abilities in patients with chronic heart failure, the guidelines developed by the European Heart Association recommend the use of diuretics, According to the theory of TCM, the main cause of chronic heart failure is deficiency of heart Qi caused by Qi deficiency and blood stasis. Shenfu Injection (SFI) is a kind of special traditional Chinese medicine extracted from ginseng and aconite, which has the function of invigorating Qi and promoting blood circulation. SFI has shown a variety of pharmacological activities, including increased blood pressure and enhanced myocardial contractility. It has been used in China for the treatment of cardiovascular disease patients with reliable efficacy for many years. At present, there are no studies on the efficacy and safety of Shenfu injection combined with furosemide in the treatment of coronary heart disease with chronic heart failure. Therefore, we intend to evaluate the efficacy and safety of Shenfu injection combined with furosemide in the treatment of coronary heart disease and chronic heart failure through this randomized controlled trial.In recent years, Chinese medicine has shown great advantages in the treatment of chronic heart failure.22.1 Its flow chart is shown in Figure This is a prospective randomized controlled trial to study the efficacy and safety of Shenfu injection combined with furosemide in the treatment of coronary heart disease with chronic heart failure. This study will follow the Consolidated Standards of Reporting Trials (CONSORT).2.2The protocol will be in accordance with the Helsinki Declaration and approved by the Clinical Research Ethics Committee of our hospital. This experiment has been registered in the open science framework (OSF) (registration number: doi: 10.17605/OSF.IO/27FPM). Before randomization, all patients will sign a written informed consent. and they can freely choose whether to continue the trial at any time.2.3 Doppler echocardiography indicated that the left ventricular ejection fraction was less than 50%;③ The age was 40 to 79 years; ④ New York Heart Association (NYHA) grade III–IV; ⑤ No myocardial infarction and angina pectoris occurred in the past month.Inclusion criteria: ① meet the diagnostic criteria of coronary heart disease, the patients had occlusive myocardial infarction, and the stenosis rate of the main branch of the coronary artery (at least one branch) is more than 50%;) ② meet the diagnostic criteria for chronic heart failure.Exclusion criteria: ① Patients with heart failure induced by other diseases such as congenital heart disease; ② Complicated with other serious diseases such as malignant tumor; ③ Other heart diseases such as severe arrhythmia; ④ Complicated with serious mental illness; ⑤ Patients with drug allergy or contraindications in this study; ⑥ Unable to understand the study protocol or unwilling to participate in the study after explanation.2.4This study is a pilot clinical trial. The calculation of the sample size will be based on a drop-out rate of 20% in the clinical study, and 0.025% of the sample size will be taken as 90%, which is calculated to include 110 patients. The patient will randomly select any number from 001 to 110 from the sealed envelope and is assigned to the observation group (odd) and the control group (even) according to the parity of the number.2.5In this study, patients who meet the criteria will be screened through pre-hospital recruitments and in-hospital inpatients. The patients and their families will approve the study program and sign the informed consent form. The observation group will receive SFI  combined with furosemide injection , while the control group will only receive furosemide injection . Patients in both groups will receive the same routine care and drug treatment, such as angiotensin converting enzymeinhibitiors (ACEIs) or angiotensin II receptor blockers (ARBs). If necessary, the attending physician can adjust the plan according to the patient's condition, and all interventions will be recorded in detail for final result analysis. We will set up a special drug manager, and the nurse will be responsible for preparing the medicine, preparing the solution, and using the disposable optical infusion device to infuse the corresponding numbered patients. Therefore, the study is not blind to nurses, but to researchers, patients, and statisticians. All patients will receive intravenous injections once a week. The health status of each patient will be evaluated before and after treatment, including efficacy and safety indicators, and all patients will be followed up for 30 d by telephone or outpatient clinic. Follow-up will include cardiovascular events and rehospitalization.2.61.), Excellent: heart failure was essentially ameliorated or the NYHA classification increased by at least 2 levels; Valid: NYHA classification increased by 1 level; Invalid: NYHA classification remained the same before and after the treatment. Worsened: NYHA classification decreased by at least.Main outcome measures: ① total effective rate of cardiac function improvement , Interleukin-6(IL-6), and 6-minute walk test.Secondary outcome measures: left ventricular ejection fraction (LVEF), N-terminal pro-brain natriuretic peptide (NT-pro BNP), tumor necrosis factor-3.Adverse reactions, including abnormal liver and kidney function and any discomfort during treatment .2.7Data will be collected before treatment, 72 hours after treatment, and at the end of treatment according to evaluation criteria. After 30 days of treatment, outpatient or telephone follow-up will be conducted for each patient. Detailed follow-up information can not be collected to record the reasons for loss of follow-up information. All data will be collected by one or two assistants. Personal information about potential and registered participants will be collected, shared, and kept in a separate storeroom to protect confidentiality before, during, and after the trial. Access to the database will be limited to the researchers of this research group.2.8P < .05, the difference will be statistically significant.Data will be analyzed according to the full analysis set principle. Fisher exact test and the Mann–Whitney U test will be performed for comparison of both groups, for categorical variables and continuous variables, respectively. When 3 Patients with coronary heart disease are affected by coronary arteriosclerosis, stenosis, or obstruction for a long time, which can easily cause myocardial ischemia damage, lead to heart failure, and increase mortality. Integrated traditional Chinese and Western medicine treatments are a hot spot in modern medicine.Chronic heart failure is the main cause of hospitalization in the elderly worldwide, with high mortality, and has a negative impact on the quality of life in patients. Animal studies have shown that Shenfu injection can reduce tumor necrosis factor in the blood of rats with heart failure -α (TNF-α). The therapeutic mechanism may be related to the reduction of apoptosis and the inhibition of related factors. A randomized controlled study confirmed that Shenfu injection can significantly improve the clinical symptoms and myocardial tolerance of patients with congestive heart failure in the acute phase, without adverse reactions. Since there is no standard clinical study to evaluate the efficacy of Shenfu injection combined with diuretics in the treatment of chronic heart failure in patients with coronary heart disease, we intend to evaluate its efficacy and safety through prospective randomized controlled trials.As a traditional Chinese medicine, Shenfu injection has long been used in the treatment of coronary heart disease and heart failure in China, and has achieved good results.This study also has some limitations. Due to the short planned follow-up time, we cannot understand the impact of long-term efficacy. Therefore, we may extend the follow-up time if necessary. At the same time, due to the influence of treatment methods, this study cannot be strictly double-blind, which may have a certain impact on the results.Data curation: Yibing Gao, Ying Gao.Funding acquisition: Xiao Tan.Investigation: Ying Gao.Resources: Rong Zhu, Xiao Tan.Software: Rong Zhu.Supervision: Yibing Gao, Rong Zhu.Writing – original draft: Yibing Gao, Ying Gao.Writing – review & editing: Yibing Gao, Xiao Tan.