The main cardiac features of primary aldosteronism (PA) are impaired left ventricular (LV) diastolic function, and some articles also reported more cardiac fibrosis in PA patients. However, the correlation between LV dysfunction and diffuse myocardial fibrosis in PA remains unknown.We enrolled 84 PA patients and 28 essential hypertension (EH) patients in West China Hospital. Cardiac magnetic resonance imaging (CMR) contrast enhancement was arranged for all subjects. Postcontrast T1 time and left ventricular myocardial strains and strain rates were measured.76 PA patients and 27 essential hypertension (EH) patients were included in the final analysis. Blood pressure, LV mass indexes, and LV ejection fractions were comparable in both groups, while the global circumferential peak diastolic strain rate (PDSR) was lower  and the postcontrast T1 time was shorter  in PA patients than those in EH patients. Postcontrast T1 time (p = 0.01) was independently related to global circumferential PDSR after adjusting for age and duration of hypertension in PA patients. Furthermore, plasma aldosterone concentration was negatively associated with postcontrast T1 time  in PA patients.The global circumferential PDSR derived by CMR is decreased, and the diffuse myocardial fibrosis is increased in PA patients compared to those in blood pressure matched EH patients. The severity of cardiac diastolic dysfunction independently relates to the degree of diffuse myocardial fibrosis in PA patients, and the diffuse myocardial fibrosis may be caused by high PAC level.http://www.chictr.org.cn/listbycreater.asp, identifier ChiCTR2000031792. Primary aldosteronism (PA), characterized by the overproduction of aldosterone that seems autonomous from renin , is the It is well known that PA patients’ major cardiac damage is impaired left ventricular function , 11, leaCMR offers a non-invasive, highly accurate assessment of cardiac function and geometry, and contrast-enhanced T1 mapping can provide evidence of diffuse myocardial fibrosis , 20. PosFrom April 2018 to May 2019, 84 PA patients were recruited from the inpatient department of Endocrinology and Metabolism of West China Hospital. 28 EH patients were recruited from the medical examination center of West China Hospital. All the subjects were of Han ethnicity and between 22 and 78 years old. All the patients completed the initial screening test of the plasma aldosterone/renin ratio (ARR) for PA, plasma renin activity (PRA) <0.2 ng/ml/h was set as 0.2 for the calculation of the ARR to avoid inflation due to a very low denominator. According to the guidelines, before the initial screening, all the subjects had been on stable antihypertensive treatment with an α1-adrenergic receptor antagonist alone or verapamil sustained-release agent or hydralazine, and with normal serum potassium levels. The duration of stable antihypertensive treatment depended on the antihypertensive drugs the patients were taking. MR antagonists , potassium-sparing diuretics , and potassium-wasting diuretics  should be withdrawn for at least four weeks before ARR testing. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, renin inhibitors, dihydropyridine calcium channel antagonists, β-Adrenergic blockers, and central α-2 agonists  should be withdrawn for at least two weeks before ARR testing. The PA patients were further diagnosed by confirmatory tests of saline infusion and/or captopril challenge according to current guideline . The excThis study was revised and confirmed by the Ethics Committee of West China Hospital. Before the study, written informed consent was obtained from each individual. Our study was registered in the Chinese clinical trial registry (ChiCTR2000031792).Two trained staff members recorded the clinical characteristics of subjects with a standard questionnaire. Physical examination was performed on all the subjects, including body height, weight, waist circumference, and blood pressure. Body mass index (BMI) was computed as body weight in kilograms (kg) divided by height in meters squared (m2). The body surface areas were calculated as 0.0057 × height (cm) + 0.0121 × weight (kg) + 0.0882 for males and 0.0073 × height (cm) + 0.0127 × weight (kg) − 0.2106 for females. All patients underwent 24-hour ambulatory blood pressure monitoring three days before the CMR scan.After overnight fasting (≥8 h), venous blood samples were collected to measure plasma aldosterone concentration (PAC), PRA, and other biochemical parameters. Radioimmunoassay was used to measure PAC and PRA . Serum potassium, serum sodium, total cholesterol, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, pro-brain natriuretic peptide (pro-BNP), creatine kinase MB, troponin T, and myoglobin concentrations were measured for all patients using automated, standardized equipment by the Clinical Laboratory at West China Hospital.CMR was performed with a 3.0 T MRI imager  using an eight-channel phased-array surface coil and prospective electrocardiographic triggering. Patients assumed a supine position, and ECG gating and respiratory gating were used throughout the scan. The cine images of the short-axis covering the LV and the long-axis  were obtained with a segmented balanced steady-state-free-precession sequence. The scanning parameters were TR/TE 3.4/1.3 ms, flip angle 50°, a field of view 320–340 mm, matrix size 256 × 144, and section thickness, 8 mm with no gap.Postcontrast T1 maps were acquired using modified look-locker inversion recovery sequence , which was recommended by the Society for Cardiovascular Magnetic Resonance . PostconAll imaging data of PA patients and EH subjects were uploaded to Argus software . Two experienced radiologists blinded to clinical data defined the end-diastole, end-systole, and delineated LV endocardial and epicardial borders Figure 2Normally distributed data were expressed as the mean (± SD) for continuous variables, and categorical variables were expressed as percentages. Skewed variables were logarithmically transformed before analysis and expressed as medians (interquartile ranges). The quantitative variables were compared using a t-test, while the qualitative variables were compared using the χ2 test. Univariable analysis was performed to discover the correlation of the global circumferential PDSR with postcontrast T1 time and other risk factors. The association of the global circumferential PDSR with postcontrast T1 time in PA patients was analyzed with the stepwise multivariate analysis. Variables included in the regression model were those parameters p ≤0.1 in univariable analysis. P ≤0.05 was considered statistically significant. Pearson’s analysis was used to test the relationship between PAC and postcontrast T1 time in PA patients. Analyses were performed with SPSS 17.0  for Windows.All patients successfully underwent CMR except for nine patients (eight PA patients and one EH patient) who had severe arrhythmia, causing ECG synchronization failure during the study session. Therefore, 76 PA patients and 27 EH patients were included in the analysis. CMR results for LV mass, volumes, function, and contrast-enhanced T1 mapping are summarized in To further identify the parameters affecting global circumferential PDSR in PA patients, we used univariate analysis to demonstrate the relationship between global circumferential PDSR and potentially related factors. Global circumferential PDSR statistically related to age , duration of hypertension  and postcontrast T1 time .Parameters that are p ≤0.1 Table 3 As showed above, the global circumferential PDSR was lower in PA patients than EH patients but not statistically related to PAC. However, Pearson’s analysis Figure 3Inter-observer variabilities of tissue tracking between two experienced radiologists were minimum, which were shown in To the best of our knowledge, this is the first study to demonstrate the relationship between CMR-verified cardiac diastolic dysfunction and diffuse myocardial fibrosis assessed by postcontrast T1 time in PA patients. Although there was no significant difference was found in systolic cardiac functions between PA and EH patients, the global circumferential PDSR was lower, the native-T1 and ECV were higher, and the post-T1 time was shorter in PA patients than in blood pressure matched EH patients. In PA patients, postcontrast T1 time independently related to global circumferential PDSR after adjusting for confounding factors in the multivariate regression analysis. Additionally, the postcontrast T1 time is reversely related to PAC. Our study implies that diffuse myocardial fibrosis, which may be caused by elevated PAC level, affects left ventricular diastolic function in PA patients.In the present study, we also found that the global circumferential PDSR is a more sensitive indicator for identifying the left ventricular dysfunction in PA patients than ejection fraction, PS, and PSSR. Catena found that PA patients had lower left ventricular diastolic function than EH patients but no systolic function differences with echocardiographic measurements , which wDiastolic dysfunction plays a causative role in the process of cardiac failure . In one Several studies have demonstrated that PA patients have increased fibrosis than healthy volunteers , 35 and We speculate that the different salt consumption of included patients may explain the different myocardial fibrosis results in PA patients in different research. From a rat model of hyperaldosteronism, the myocardial fibrosis only developed in rats with high salt intake , and AngCMR-verified diffuse myocardial fibrosis was proved to associate with diastolic dysfunction in heart failure , hypertrOur study had some limitations. The myocardial biopsy is the gold standard for the diagnosis of cardiomyopathy. Considering its invasiveness and financial cost, we did not have histological evidence of myocardial fibrosis to validate the results of T1 mapping. Furthermore, because this was a single-center study, there is a need for multicenter, large-scale trials to confirm our findings.The global circumferential PDSR derived by CMR is decreased, and the diffuse myocardial fibrosis is increased in PA patients compared to those in blood pressure matched EH patients. The severity of cardiac diastolic dysfunction independently relates to the degree of diffuse myocardial fibrosis in PA patients, and the diffuse myocardial fibrosis may be caused by high PAC level.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 the Ethics Committee of West China Hospital. The patients/participants provided their written informed consent to participate in this study.FZ designed research, acquisition, and analysis of data, writing the manuscript. TW, WW, and SW collection of data. WC analysis of the data. HT, TC, and JS designed research. YR designed the study, revising the manuscript, and final approval of the manuscript submitted. All authors contributed to the article and approved the submitted version.This study was supported by West China Hospital, Sichuan University (Grant Nos. ZYGD18022 and 2018HXFH009), Department of Science and Technology of Sichuan Province  and Health Department of Sichuan Province (Grant No. 20PJ047).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The relationship between LV ECVF and O2Pulse following thoracic radiotherapy has not been explored.Radiation-induced myocardial fibrosis increases heart failure (HF) risk and is associated with a restrictive cardiomyopathy phenotype. The myocardial extracellular volume fraction (ECVF) using contrast-enhanced cardiac magnetic resonance (CMR) quantifies the extent of fibrosis which, in severe cases, results in a noncompliant left ventricle (LV) with an inability to augment exercise stroke volume (SV). The peak exercise oxygen pulse  measurement. Multivariable-analyses were performed to identify factors associated with O2Pulse normalized for age/gender/anthropometrics.Patients who underwent thoracic radiotherapy for chest malignancies with significant incidental heart dose (≥5 Gray (Gy), ≥10% heart) without a pre-cancer treatment history of HF underwent cardiopulmonary exercise testing to determine O2 was 1376 [1057–1552] mL·min− 1, peak HR = 150 [122–164] bpm, resulting in an O2Pulse of 9.2 [7.5–10.7] mL/beat or 82 (66–96) % of predicted. The ECVF, LV ejection fraction, heart volume receiving ≥10 Gy, and NTproBNP were independently associated with %O2Pulse (P < .001).Thirty patients  were included. The peak VO2Pulse is inversely associated markers of diffuse fibrosis (ECVF), ventricular wall stress (NTproBNP), radiotherapy heart dose, and positively related to LV function. Increased LV ECVF may reflect a potential etiology of impaired LV SV reserve in patients receiving thoracic radiotherapy for chest malignancies.In patients with prior radiotherapy heart exposure, %-predicted OThe online version contains supplementary material available at 10.1186/s40959-021-00127-6. Incidental cardiac radiation exposure following anti-cancer thoracic radiotherapy treatment increases risk of heart failure (HF) in a dose-dependent manner  with a p2) divided by the heart rate (HR) at peak exercise. Through deduction of the Fick equation, the peak oxygen pulse can accurately serve as a noninvasive estimate of the LV SV response to exercise in both healthy subjects and HF patients ), cancer type , prior chemotherapy including type and dose, presence of anemia, and current beta-blocker and/or angiotensin-converting enzyme inhibitor (ACEI)/ angiotensin receptor blockers (ARB) defined per medical record review and patient interview. Due to the likelihood of coexistent chronic obstructive pulmonary disease (COPD) in chest tumor patients the presence of COPD was also considered based upon Global Initiative for Chronic Obstructive Lung Disease criteria from pre-exercise spirometry . PhysicaRadiation dose calculation was performed based on a volumetric computed-tomography (CT) data set obtained during the pre-radiotherapy treatment planning session. A single radiation oncologist (E.W.) performed quantification of total radiation dose and heart volumes exposed. The heart was manually contoured on each CT-slice generating 3-dimensional structures using treatment planning software . After radiation beam definition and target dose calculation, mean cardiac radiation dose (MCRD) was determined for the whole organ volume as well as using dose-volume histograms to generate %volumes (V) of the heart receiving ≥5, 10, 20, 30, 40, and 50 Gray (Gy), respectively.2 obtained during the final 30-s of exercise was used to define peak VO2. The peak exercise respiratory exchange ratio (RER) was defined as the ratio between the peak carbon dioxide production divided by the peak VO2. Predicted peak VO2 was calculated according to the reference equations proposed by Wasserman and colleagues which take into account age, gender, and anthropometric  differences  due to potential non-Gaussian distributions. Chi-square tests were performed to assess differences between nominal variables including Fisher’s exact test for variables with cell count frequencies < 5. Spearman’s rank test was used for univariate analysis of associations between continuous clinical characteristics, radiotherapy, CMR, and CRF variables. The Mann-Whitney U test was performed to compare differences between groups based upon categorical variables and peak oxygen pulse values < 85% or ≥ 85% of predicted  and LV E2 was 1376 (1057–1552) mL·min− 1 with a peak HR of 150 (122–164) bpm resulting in a peak exercise O2 pulse of 9.2 (7.5–10.7) mL/beat that was 82 (66–96)% of predicted values. Table 2Pulse was evaluated as a continuous variable according to nominal clinical characteristics there were significant differences with respect to smoking status, diabetes, obesity, cancer type, COPD, ACEI/ARB use, and sex. There was not a significant difference between %O2Pulse and race, hypercholesterolemia, hypertension, anemia, beta-blocker use, or prior receipt of chemotherapy.Thirty patients  underwent evaluation. The peak VO2 was moderately-reduced (62% of predicted) compared to normalized values. The peak exercise %O2pulse demonstrated a significant positive correlation with the peak VO2  and a significant inverse relationship with the cardiac biomarker NTproBNP . The peak %O2Pulse and peak VO2 were positively associated with FACT-G7 scores  reflecting higher CRF correlated with higher QOL.Table 2Pulse was not significantly associated with age, physical activity levels, rest or maximal HR or blood pressures. From a chronicity perspective, there was not a significant association between %O2Pulse achieved and time from cancer diagnosis or completion of chemotherapy or radiotherapy.The peak exercise %On = 12 [41%]) of subjects exhibiting qualitative evidence of LGE with post-contrast CMR. Analysis of CMR variables with peak exercise %O2Pulse demonstrated a negative correlation with the composite LV ECVF , a positive correlation with LVEF  . There was no significant correlation between the %O2Pulse and native T1 , post-contrast T1 , or %LGE burden . Similarly, there was no significant difference between dichotomous qualitative presence of LGE and %O2Pulse (P = 0.99).Cardiac magnetic resonance variables of interest are detailed in Table r = − 0.51, P = 0.006), peak VO2 , cancer type  and use of angiotensin blockade  , MCRD or V5-50Gy heart doses , age (P > 0.136), presence of COPD (P = 0.190), or prior chemotherapy use (P = 0.278).The global LV ECVF demonstrated significant relationships with LVEF . Additionally, all %-volumes of the heart receiving between V5-V50Gy of radiotherapy demonstrated a negative association with peak %O2Pulse . Total prescribed radiotherapy dose was not associated with %O2Pulse .The total prescribed radiotherapy dose was 60.0 (48.0–60.4) Gy, MCRD 5.6 (3.7–17.8) Gy, and the %-volume of heart exposed to V5Gy was 39.5 (15.8–80.5)%, V10Gy 19.3 (8.8–67.3)%, V20Gy 7.0 (1.2–35)%, V30Gy 2.5 (0–15)%, V40Gy 1.0 (0–7.8)%, and V50Gy 0 (0–3)%, respectively. There was a negative correlation between the MCRD and the peak %O2Pulse was restricted to those chemotherapy agents wherein at least 20% of the cohort received that agent. The doses of the chemotherapy agents analyzed included paclitaxel , carboplatin , cyclophosphamide , and doxorubicin , which were not significantly associated with peak %O2Pulse. Supplemental Table Due to the heterogeneity of chemotherapy use, comparison with peak %O2, LV ECVF, and NTproBNP  in block-1 of the multivariate model with an adjusted-R2 of 0.394.In the multivariate model, significant nominal-level clinical predictors of %O2Pulse.When evaluating radiotherapy dose parameters, collinearity diagnostics revealed significant multicollinearity between the MCRD and V5-V50Gy doses. Due to this finding, the cardiac V10Gy was the only radiotherapy variable entered into the multivariate model as it had the highest univariate relationship with %Oβ = −.281, P = 0.049), LVEF , cardiac V10Gy , and NTproBNP  were retained in the model as independent predictors of %O2Pulse while cancer type was removed from the model. The overall-model fit demonstrated an adjusted-R2 of 0.732.In block-2 of the multivariate model, cancer type (block-1) was added to the significant univariate continuous predictors: LV ECVF, LVEF, cardiac V10Gy, and NTproBNP into a stepwise analysis. The LV ECVF  was inversely associated with a CMR-derived marker of diffuse myocardial fibrosis (LV ECVF), ventricular wall stress (NTproBNP), cardiac radiation dose, and positively related to cardiac function (LVEF). This demonstrates a potential mechanistic relationship between the effects of thoracic radiotherapy on myocardial function and tissue composition  and its resulting influence on cardiac reserve measured via peak exercise %O2Pulse. Although the adverse effects of thoracic radiotherapy on late CVD/HF risk are well-known optimal methods for screening to detect subclinical cardiac dysfunction and the role of advanced imaging or exercise testing remain understudied [In this cross-sectional analysis of patients with significant incidental heart exposure following thoracic radiotherapy without an established history of CVD or HF, we found peak exercise %Orstudied , 23.2 following thoracic radiotherapy driven primarily by impaired diastolic reserve [2, however, oxygen pulse was not reported [2 [We recently observed reductions in peak VO reserve , 24. Inc reserve . Work ha reserve . Takagi  reserve . Althougreported . Similarreported . In a prorted [2 .2 that by its nature corrects for HR and when further corrected for age, sex, and anthropometrics can differentiate cardiac from noncardiac causes of exercise intolerance [2 pulse is associated with risk for sudden cardiac death, fatal coronary heart disease, CVD, and all-cause mortality [2Pulse provides additive predictive accuracy to intermediate-range peak VO2 (10–14 mL·kg− 1·min− 1) for mortality risk assessment in HF patients [2 pulse over peak VO2 for predicting clinical HF events particularly when it’s normalized for body mass [2 and higher incidence of the composite endpoint  [2, VE/VCO2 slope) CTHF was associated with a higher risk of death and the composite endpoint.The peak oxygen pulse is an expression of peak VOolerance , 32. Theortality –35. Morepatients ; some reody mass . Althougimplant) . Further2 [In oncological surgery patients, an abnormal exercise oxygen pulse response has been associated with increased mortality, neoadjuvant treatments, and was a strong independent predictor of post-operative cardiopulmonary complications even surpassing peak VO2 –39. Coll2), presence of anemia, or COPD were not significant predictors of %O2Pulse in the current study. Unfortunately, the influence of peripheral oxygen extraction was not directly assessed in the current study. Future studies should explore the relationships of radiotherapy dose to specific cardiac substructures with %O2Pulse and LV ECVF for a more precise mechanistic understanding of radiotherapy-related cardiac dysfunction [The limitations of this study are its small-sample size, single-center, and cross-sectional nature, limiting the findings to hypothesis generating rather than definitively establishing causality and require further exploration. Another limitation is that evaluation of the oxygen pulse is complex, as it depends upon many factors such as fitness, body mass, and is also significantly influenced by arterial oxygen supply and peripheral oxygen extraction. However, in the current study normalization of the oxygen pulse reported as a %-predicted value accounted for the influences of age, sex, and anthropometrics. Furthermore, arterial oxygen supply  may provide mechanistic insight into the causes of exercise intolerance in the cancer survivor following thoracic radiotherapy, suggesting that an expansion of myocardial LV ECV may be contributing to the inability to increase LVSV during exercise leading to reductions in exercise capacity. Although requiring further study, our findings indicate reductions in %O2Pulse may represent subclinical reductions in stroke volume that is associated with elevations in LV ECVF. This may allow early detection of radiotherapy-related myocardial dysfunction prior to the onset of overt HF thus opening the door to prophylactic therapeutic interventions.A multimodality noninvasive assessment, including myocardial tissue composition (using contrast-enhanced CMR to derive LV ECVF) and assessment of cardiac reserve (using CPET to determine the normalized peak exercise %OAdditional file 1.Additional file 2.Additional file 3.


Left ventricular (LV) diastolic dysfunction is an acknowledged peri-operative risk factor that should be identified before surgery. This study aimed to evaluate a simplified echocardiographic method using e’ and E/e’ for identification and grading of diastolic dysfunction pre-operatively.Ninety six ambulatory surgical patients were consecutively included to this prospective observational study. Pre-operative transthoracic echocardiography was conducted prior to surgery, and diagnosis of LV diastolic dysfunction was established by comprehensive and simplified assessment, and the results were compared. The accuracy of e’-velocities in order to discriminate patients with diastolic dysfunction was established by calculating accuracy, efficiency, positive (PPV) and negative predictive (NPV) values, and area under the receiver operating characteristic curve (AUROC).− 1) had an AUROC of 0.901 (95%CI 0.840–0.962), with a PPV of 55.2%, a NPV of 90.9% and a test efficiency of 0.78.Comprehensive assessment established diastolic dysfunction in 77% (74/96) of patients. Of these, 22/74 was categorized as mild dysfunction, 43/74 as moderate dysfunction and 9/74 as severe dysfunction. Using the simplified method with e’ and E/e’, diastolic dysfunction was established in 70.8% (68/96) of patients. Of these, 8/68 was categorized as mild dysfunction, 36/68 as moderate dysfunction and 24/68 as severe dysfunction. To discriminate diastolic dysfunction of any grade, e’-velocities (mean < 9 cm sThe results of this study indicate that a simplified approach with tissue Doppler e’-velocities may be used to rule out patients with diastolic dysfunction pre-operatively, but together with E/e’ ratio the severity of diastolic dysfunction may be overestimated.NCT 03349593. Date of registration 21/11/2017. https://clinicaltrials.gov.Clinicaltrials.gov, Identifier: The online version contains supplementary material available at 10.1186/s12871-022-01642-4. Diastolic dysfunction is a common and often underestimated pathology, referring to abnormalities of left ventricular (LV) relaxation, compliance and filling, regardless of LV systolic function –3. DiastPoint-of-care transthoracic echocardiography (TTE) has been shown to have incremental value on clinical management in anesthesiology and intensive care, providing crucial hemodynamic information on cardiac disease and in situ knowledge of volume status –11. Howen = 30), and 100 patients were included after obtaining written consent. Moreover, patients with severe calcification of the mitral annulus or signs of significant mitral valve regurgitation , arrythmias, i.e., atrial fibrillation/flutter, multiple supraventricular or ventricular extrasystoles in preoperative ECG and/or during TTE scanning and poor acquisition quality in apical four-chamber windows were excluded . The collection of data was carried out between 2017 and 12-01 and 2018-11-30. On the study days, when resources were available, 130patients, ≥18 years of age, scheduled for ambulatory surgery were assessed for eligibility for the study. Due to the surgery schedule, the first patients on each study day were excluded . Informed, signed consent was obtained from all participants. The study was registered prior to patient enrollment at Clinicaltrials.gov . The study adheres to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines.− 1 + E/e’ ≤ 8 = grade I and normal filling pressures, ii) e’ < 9 cm s− 1 + E/e’ 8 to 14 = grade II and elevated filling pressures and iii) e’ < 9 cm s− 1 + E/e’ ≥ 14 = grade III and elevated filling pressures [The conventional pre-operative fasting period was applied to all patients . All echocardiographic examinations were performed 1–2 h before anesthesia and surgery by a specialist sonographer (LL) or a clinical cardiac physiologist (TM) accordingly to guidelines , 18 withressures . Estimatressures , 20. Theressures .Fig. 2Th− 1 [P values > 125 ng L− 1 [Patient history was taken, with a focus on dyspnoea and exercise tolerance . New York Heart Association (NYHA) Functional Classification was established. Non-invasive blood pressure was measured in a supine position. Blood samples for myocardial damage (high-sensitive troponin I (hs-TnI)) and dysfunction (NT-proBNP) were collected and we classified plasma concentrations for hs-TnI ≥5 ng L− 1  respecti ng L− 1  as incre ng L− 1 .− 1 and normal LV diastolic function at 11 cm s− 1 . Test efficiency , sensitivity, specificity, negative predictive value (NPV) and positive predictive value (PPV) were calculated from the cross-tabulations. Levene’s test and Kolmogorov-Smirnov test were applied to analyze the equality of variances respective normality of data. Student’s t test and ANOVA was used to compare mean values, and p-values < 0.05 were considered statistically significant. Receiving operating characteristic curves were calculated to determine accuracy and represented as area under the receiving operating characteristic curve (AUROC). The most optimal cut-off of the mean values for e’ to discriminate LV diastolic dysfunction was established by use of Youden’s method (Youden index = sensitivity + specificity − 1). Binominal data was analyzed with Chi-square/Fisher’s exact tests and correlation between the variables reported by the Phi coefficient (φ) when appropriate.The study data was analyzed with SPSS . The study sample size was calculated to a minimum of 57 individuals for the hypothesized area under the receiver operating characteristic curve at 0.725, null hypothesis at 0.5, a ratio of negative/positive cases at 2, α 0.05, and a power of 0.8 (power = 1-β = 0.8). Moreover, for a comparison of average e’ velocities, the sample size was calculated to overall 56 patients minimum with expected e’ mean velocities for LV diastolic dysfunction at 8.0 cm s1–m2)/(m1+m2)/2 x 100%” was used, where m1 and m2 are mean values of the first and the second measurements of one investigator (TM), or the first measurements between the two investigators (TM and LL).As a measure of reproducibility, intra- and interobservation variability was controlled based on repeated measurements of 13 randomly selected cases. To calculate intra- and interobservation variability, the equation “variability % = ) and had to a greater extent ongoing treatment with beta-blockers (p = 0.004), diuretics (p = 0.001), or combination treatment with beta-blockers, angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers calcium channel blockers or diuretics (p = 0.002). Overall LV ejection fraction and mean arterial blood pressure (MAP) did not differ between the groups . NT-proBNP was higher among patients with diastolic dysfunction compared with patients without dysfunction . In addition, high-sensitive troponin I values were higher in diastolic dysfunction compared with patients with normal diastolic function   of patients. Of these, 22/74 was categorized as a grade I (mild) dysfunction, 43/74 as a grade II (moderate) dysfunction and 9/74 as a grade III (severe) dysfunction . At the cut-off value < 9 cm s− 1, mean e’-velocities had a sensitivity of 82.2%, a specificity of 72.7%, a PPV of 55.2% and NPV of 90.9% to recognize patients with diastolic dysfunction , and mild correlation with symptomatic diastolic dysfunction . No correlation could be found between e’ < 9 cm s− 1 and asymptomatic diastolic dysfunction  or with low exercise capacity (MET < 4), φ = 0.175, p = 0.088). e’-velocities alone could discriminate patients with diastolic dysfunction (p < 0.001), but not between different grades of diastolic dysfunction (p = 0.198).Using the simplified method Fig. , diastolon Table . A moderp = 0.053) and AUROC 0.781 , respectively.In addition, mean e’ velocities and mean E/e’ ratio ability to discriminate lower grade of diastolic dysfunction  from higher grade (moderate and severe) were AUROC 0.615 , 21/52 (40%) were hypovolemic. There was no difference in tissue Doppler e’-velocities between patients without and with hypovolemia (euvolemia (n = 45); hypervolemia (n = 7)) and hypovolemia (n = 42), . In addition, no difference in e’-velocities were observed between euvolemia and hypovolemia, or euvolemia and hypervolemia .Overall, 43.7% (42/96) of patients had signs of hypovolemia based on the inferior vena cava assessment . In this study cohort, there was no difference in prevalence of hypovolemic state between patients with or without diastolic dysfunction, The intra- and interobservation variability for this cohort has been published in a previous study . The intThis prospective observational study investigated a simplified method with e’ and E/e’ for assessing diastolic function, and the results showed that regardless of which method used (comprehensive or simplified assessment), a high prevalence of diastolic dysfunction was found. Patients with comorbidities including hypertension, ischemic heart disease, chronic kidney disease, bronchial asthma, as well as patients with increased age, low exercise capacity, and smoking were more likely to have diastolic dysfunction. This is in line with previous reports exploring risk factors for diastolic concerns . The pro− 1 may be used to discriminate both symptomatic and asymptomatic patients with diastolic dysfunction from patients without these concerns [Furthermore, the results are in line with previous studies and indicate that e’-velocities with a cut-off at 9 cm sconcerns , 14. HowRegarding the use of E/e’ for assessing filling pressures, previous evidence is somewhat conflicting , 25. In Diastolic dysfunction is initially often asymptomatic, but is still associated with an increased morbidity and all-cause mortality , adverse− 1, i.e., well below the concentration used to diagnose myocardial infarction [− 1, but the study sample size was too small to evaluate significance of hs-TnI for cardiac risk assessment. In addition, the aim of this pre-operative study was to evaluate the accuracy of e’ and E/e’ in order to identify and grade diastolic dysfunction, and no intra- and postoperative data were analyzed. Hence, association between e’-velocities and/or E/e’ and intra-operative hemodynamic stability and postoperative outcome was not assessed in this study.This single-centered observational study had a rather small sample size and despite a consecutive unselected enrollment, a vast majority of the included patients were women . This may have affected the prevalence of diastolic concerns but should not have a negative effect on the assessment of the evaluated methods per se. Larger, multi-centered studies evaluating e’ and E/e’ as a point-of-care assessment of diastolic dysfunction and the association with post-operative outcome, are warranted. All examinations were conducted by expert sonographers to minimize diagnostic bias and a high reproducibility was obtained. In addition, only four patients were excluded due to unusable image quality. The accuracy of evaluated tests may decrease with a less experienced observer, and this may decrease the applicability of the study results. In this study, the diagnosis and grading of diastolic dysfunction were conducted with the recommended parameters from 2009 American Society of Echocardiography (ASE) guidelines , with thfarction , 42. MosThe results of this study indicate that a simplified approach with tissue Doppler e’-velocities may be used to rule out patients with diastolic dysfunction pre-operatively, but together with E/e’ ratio the severity of diastolic dysfunction may be overestimated.Additional file 1: Supplementary file 1. PRICES checklist.Additional file 2: Supplementary file 2. Classification of diastolic dysfunction with two guidelines and simplified method.


Background: The detection and localization of electrophysiological substrates currently involve invasive cardiac mapping. Electrocardiographic imaging (ECGI) using the equivalent dipole layer (EDL) method allows the noninvasive estimation of endocardial and epicardial activation and repolarization times (AT and RT), but the RT validation is limited to in silico studies. We aimed to assess the temporal and spatial accuracy of the EDL method in reconstructing the RTs from the surface ECG under physiological circumstances and situations with artificially induced increased repolarization heterogeneity.Methods: In four Langendorff-perfused pig hearts, we simultaneously recorded unipolar electrograms from plunge needles and pseudo-ECGs from a volume-conducting container equipped with 61 electrodes. The RTs were computed from the ECGs during atrial and ventricular pacing and compared with those measured from the local unipolar electrograms. Regional RT prolongation (cooling) or shortening (pinacidil) was achieved by selective perfusion of the left anterior descending artery (LAD) region.Results: The differences between the computed and measured RTs were 19.0 ± 17.8 and 18.6 ± 13.7 ms for atrial and ventricular paced beats, respectively. The region of artificially delayed or shortened repolarization was correctly identified, with minimum/maximum RT roughly in the center of the region in three hearts. In one heart, the reconstructed region was shifted by ~2.5 cm. The total absolute difference between the measured and calculated RTs for all analyzed patterns in selectively perfused hearts (n = 5) was 39.6 ± 27.1 ms.Conclusion: The noninvasive ECG repolarization imaging using the EDL method of atrial and ventricular paced beats allows adequate quantitative reconstruction of regions of altered repolarization. Early risk stratification of patients with functional arrhythmogenic substrates may help to reduce mortality caused by arrhythmias. However, the detection and localization of these substrates is not easy and currently involves invasive mapping . To adapt this assumption to the gradually occurring repolarization phase, Geselowitz has shown that considering a nonuniform dipole layer with a strength that is proportional to the local transmembrane potentials (TMPs) at the myocardial surface allows the inclusion of the complete cardiac cycle .3, 0.4 PO4, 11.1 glucose, pH = 7.35–7.45). By the cannulation of the left anterior descending artery (LAD), selective perfusion of the LAD region and the remaining heart was achieved. After a period of normal perfusion, hearts were selectively perfused with ice-cooled perfusion fluid, creating temperature differences of up to 8°C. In addition, hearts 1 and 2 were LAD-perfused with pinacidil . Measurements were performed during atrial (cycle length (CL): slow = 600–700 ms, fast = 400–450 ms), right ventricular , and left ventricular  pacing. Intervention measurements were performed during atrial pacing.Heart explantation was performed on four male pigs  that had been premedicated, anesthetized, intubated, and artificially ventilated. The animals were heparinized , blood was collected, and ventricular fibrillation (VF) was electrically induced to avoid coronary air embolism. After explanation, the hearts were connected to a recirculatory Langendorff perfusion setup with 1:1 blood-Tyrode's mixture kept at 37.5°C (Tyrode's solution (mM): 155.5 Na, 4.7 K, 1.45 Ca, 0.6 Mg, 136.5 Cl, 27.0 HCOA total of 50 plunge needles  were placed in all regions in the heart, allowing the recording of unipolar transmural electrograms. Pacing hooks for stimulation were placed on the left atrium and RV and LV epicardium. In addition, temperature sensors were placed on both the LAD- and aorta-perfused regions. Then, a cylindrical, fluid-filled container equipped with 61 surface electrodes was placed around the heart, allowing the recording of pseudo-body surface potential ECGs simultaneously with needle electrograms . The apex of the heart was magnetically fixed to the bottom of the container to avoid swinging of the heart but allowing rotational and vertical movement . A minimAfter the experiment, the geometry of the container with the heart and the needles inside the heart was detected using CT images from a Philips Brilliance 64, Best, The Netherlands .From the CT images, the geometry of the heart  and the container were reconstructed with GeomPeacs software  . Needle To determine the region that was separately perfused by the LAD, the following three aspects were investigated: (1) CT with contrast in LAD, (2) changing QT time and T-wave polarity on needle electrodes, and (3) photos from the heart where LAD was shortly blocked, giving a slightly blue color to its perfusion region. An estimate for the LAD perfusion area was delineated in the heart geometry by manually combining this information. The delineation of LAD was performed before the inversely reconstructed RT maps were available.The inverse computation was performed using the EDL method, as previously described in the study by van der Waal et al. . A briefThe EDL method estimates AT and RT based on the body surface potentials, between which there is a nonlinear relation. Therefore, a nonlinear parameter estimation procedure is needed, which requires an initial estimate. The initial estimate for activation is provided by the fastest route algorithm; each node on the heart surface is iteratively considered as an initial focus, and the corresponding ATs on the heart surface is computed, assuming different propagation velocities along the myocardial surface  and relative difference (RD) values between the measured and calculated pseudo-ECGs were determined. The RD was defined as the Frobenius norm of the difference between the simulated and reconstructed signals relative to the simulated data. The difference between repolarization timing for the measured and reconstructed patterns on electrode locations is presented as the mean ± SD of the absolute difference. The differences between groups were tested using Mann–Whitney n = 8), LV (n = 4), or RV (n = 3) paced beats, atrially paced beats with cold infusion (n = 4), and an atrially paced beat with pinacidil infusion. The number of needle electrodes included was 82.2 ± 16.3 (range = 59–115). A single beat was analyzed for each condition. In In the 4 explanted pig hearts, the following 16 beats were analyzed: atrially (n = 8). Although some deviations occurred, especially in the minimum value of RT, the range of the reconstructed RT pattern was similar to that of the measured RT pattern ( pattern . This isWe then studied the repolarization differences induced by ventricular pacing associated with secondary T-wave changes.In p = 0.6), with an overall mean difference of 18.6 ± 13.7 ms (n = 7) between the calculated and measured RTs. Also, the range of the calculated RTs was accurately represented.Overall, as shown in The dispersion of repolarization has been shown to be arrhythmogenic . This may be explained by the fact that the regularization of the inverse method smoothens the steep gradient in RT at the margin of the cold region.After the temperature had reached the normal level, a local infusion of drugs was performed in the LAD region. In heart 2, pinacidil was infused, leading to the shortening of repolarization by about 40 ms. p < 0.01). This is also related to a larger difference between minimum and maximum for the reconstructed and measured RTs. For normal atrially and ventricularly paced beats, the difference between the minimum reconstructed and measured RTs is 20.1 ± 13.1 ms and that between the maximum reconstructed and measured RTs is 9.7 ± 5.8 ms. For the beats with increased RT gradients, it is 42.6 ± 34.3 ms for the minimum and 21.2 ± 28.7 ms for the maximum difference between the reconstructed and measured RTs .For these four hearts, the localization of the regions with shortened (pinacidil) or prolonged (cold) RT had an error of a maximum of 2.5 cm. The absolute difference between the measured and calculated RTs is higher for the beats during increased and decreased RTs than for the baseline atrially or ventricularly paced beats  than for epicardial validation points , p < 0.01. This may be related to the endocardium being more susceptible to errors in geometry determination due to the postmortem contracture of the heart (refer to the “Discussion” section).Overall, 1,643 measured RTs were compared with the reconstructed RTs in different hearts and conditions. This resulted in an absolute error of 25.7 ± 22.3 with a COR of 0.63 . The errex vivo setting with an accuracy of about 25 ms. We showed that this inverse method detects the regions of prolonged and shortened repolarization, with a correct localization of the region of prolonged repolarization in 3 out of 4 hearts .In this study, we demonstrated that the EDL-based inverse methods allow the adequate reconstruction of RTs and repolarization patterns on the endocardium and epicardium of a heart in an in silico validation study. In that study, we found validation errors ranging from 12 to 19 ms. However, in that study, the whole repolarization pattern  was taken into account in addition to the selected electrode sites , given that the repolarization process occurs gradually and that the duration of the T-wave was 1.5–3.5 times longer than the QRS duration. These activation errors are comparable to the previous in vivo validation results , while the inclusion of the beats with increased RT gradient results in a correlation of 0.63 .No other validation studies regarding RTs with the EDL model have been performed. However, it is possible to compare our results to the validation results achieved at the epicardium with other inverse modeling approaches. The EP method was applied in a study by Zhang et al. on patients undergoing open-heart surgery . Since the relationship between activation and repolarization is not so straightforward  changes on a millimeter-scale resolution, as some of the maps may suggest. This is especially relevant for the detection (using the EP method) of steep repolarization gradients that may be artifactual , showing a correlation between the measured and reconstructed ARI patterns of 0.75 with an average difference of 2 ms . The EDL method additionally helps to determine a primary endocardial or epicardial approach for invasive diagnostic studies.Regional infusion of cold fluid in the LAD region resulted in RT differences between the normal and late repolarizing regions of up to 144 ms, with a relatively large region of prolonged repolarization. In clinical cases, RT gradients are likely to be more subtle. However, the exact relationship between the amount of repolarization dispersion and susceptibility to arrhythmias is not fully understood  . This may also have played a role in heart 1 in which a localization error of 2.5 cm was observed. In the clinical situation, the expected localization error, therefore, is less.In the current measurement setup, the heart is placed in an electrode-equipped container filled with conducting fluid. This does not reflect the placement of the heart in the torso. In the container, the distance between the heart and the electrodes is less, and other tissues  in between that influence the measured signal on the body surface, are absent. The presence of lung and other tissues may reduce the accuracy of the inverse method in an We compared reconstructed RT with RT that was determined from needle electrodes in the myocardium. As a result, we compared RT calculated on the myocardial surface with RT that was not exactly on the surface. We tried reducing this influence by excluding the measurement sites of >5 mm distance of the reconstructed myocardium. This led to a reduced amount and uneven distribution of measurement sites and denied us the possibility of extrapolating a full repolarization pattern from the measured RTs.We have validated the reconstruction of the endocardial and epicardial repolarization patterns by using the EDL method in isolated perfusion pig hearts under normal conditions , secondary T-wave changes , and regional infusion of action potential prolonging or shortening drugs. A repolarization error of about 20–25 ms was observed for both endocardial and epicardial recoding sites, corresponding to other inverse techniques and also in line with the inaccuracy of AT detection. The technique potentially allows the early detection of patients with large repolarization gradients and opens new strategies for primary and secondary prevention. The noninvasive mapping of repolarization, therefore, can help to select patients who are in need of anti-arrhythmic drug therapy or triaging patients who require further (invasive) assessment.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The animal study was reviewed and approved by Animal Research Institute AMC/Animal experiment committee AMC Academic Medical Center Amsterdam.JW, VM, TO, and RC conceived the design of the study, with the development of the EDL technique by TO. VM, CB, GS, and RC prepared and performed the experiments, with GS focusing on the imaging part. JW performed the analysis, analyzed the results, and wrote the manuscript, with VM, TO, and RC involved in supervision and contributed to the final manuscript. All authors contributed to the revision of the manuscript, read, and approved the submitted version.This study was supported by the Technology Foundation STW (Grant No. 10959), the Leducq Foundation , and ZonMw .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.


Systemic Sclerosis (SSc) is a chronic connective tissue disorder with an inflammatory and autoimmune nature. The disease presents with microvascular changes, endothelial cell dysfunction, and fibrosis in visceral organs and tissues including lung, skin and heart. Cardiac involvement is a predictor of poor prognosis in this disease; therefore, early and pre-clinical diagnosis of cardiac involvement can be helpful in management of SSc. Two-dimensional Speckle Tracking Echocardiography (2D-STE) is a new method for the evaluation of myocardial strain in longitudinal, circumferential and radial planes. This study aimed at evaluating the mechanical performance of all cardiac chambers by using 2D-STE in patients with scleroderma, and its comparison with normal individuals. This study demonstrated that using 2D-STE can result in the diagnosis of impaired chamber mechanics and function in subclinical stages. Based on our findings, the simultaneous evaluation of all cardiac chambers by 2D-STE provides valuable information regarding myocardial involvement in patients with SSc.Objective: Cardiac involvement is a predictor of poor prognosis in patients with systemic sclerosis (SSc); therefore, preclinical diagnosis of heart involvement is crucial. Two-dimensional speckle tracking echocardiography (2D-STE), a method for evaluating the myocardial strain, could be helpful for the early diagnosis of cardiac mechanical function abnormalities. In this study, the simultaneous evaluation of all cardiac chambers was studied in patients with SSc, compared with normal individuals. Methods: The results of transthoracic echocardiography (TTE) and 2D-STE of 37 patients with SSc and 37 healthy individuals and the longitudinal strain (LS) of all chambers was precisely evaluated. The collected data were analyzed using SPSS version 16, and independent-sample t test and Chi-square test were used for comparison between the groups. Results: The mean ± SD of the participants’ age was 45.7 ± 11.54 (range of 17 to 68) years; most of them were women (75.7%). TTE showed higher left atrial (LA) volume (p < 0.001), right atrial (RA) area (p = 0.007), the severity of ventricular dysfunction (p < 0.05) and inferior vena cava diameter (p = 0.005), compared with the control group. Spectral and tissue Doppler echocardiography showed higher systolic pulmonary arterial pressure (sPAP) and mitral A wave velocity, and lower E/A ratio, E’ velocity of left ventricular (LV) septal and lateral wall in the case group (p < 0.05). Color Doppler echocardiography showed a higher frequency of valvular regurgitation in the case group (p < 0.05). The results of 2D-STE showed lower LA roof LS (p < 0.001), LA average LS (p = 0.015), LA global LS (p = 0.028), and LA ejection fraction (LAEF) (p = 0.001), lower mean RA left wall (p = 0.048) and EF (p < 0.001), and higher RV global LS in the case group (p = 0.025). Conclusions: Simultaneous evaluation of all cardiac chambers by 2D-STE provides valuable information about the myocardial involvement in patients with SSc. Therefore, it is suggested to use this method for the early diagnosis of cardiac involvement in such patients. Systemic Sclerosis (SSc) is a complex chronic connective tissue disorder, presenting with microvascular changes, endothelial cell dysfunction, and fibrosis in visceral organs and tissues, as well as complex autoimmune responses . The preTwo-dimensional speckle tracking echocardiography (2D-STE), which generates frame-by-frame patterns in different directions and amplitudes of motion and demonstrates myocardial deformation throughout the cardiac cycle , is suggDespite the systemic nature of SSc that can involve any cardiac chamber, the previous studies were limited to the evaluation of one chamber (atrium or ventricle) or one side (left or right). Therefore, in the present study, we aimed to perform a detailed four-chamber 2D-STE for the accurate evaluation of four-chamber function in patients with SSc, compared with the normal population. The study was confirmed by the ethics committee of Shiraz University of Medical Science.In the present study, patients who were diagnosed with Scleroderma by a rheumatologist (according to 2013 ACR/EULAR SSc Classification Criteria ) and refThe participants’ demographic characteristics, including sex, age, weight, height and length of disease were recorded, and their body mass index (BMI) and body surface area (BSA) were calculated using standard formulas. Their history of chronic diseases, such as hypertension (with maximum mild left ventricular hypertrophy [LVH] in TTE), hyperlipidemia, hypothyroidism, ischemic heart disease (with no history of previous PCI or coronary artery bypass graft [CABG]), and diabetes mellitus were recorded. It should be noted that we tried to choose our control group with the same medical histories as the case group.All individuals underwent TTE and 2D-STE using a Siemens Acuson sc2000 PRIME ultrasound machine at Shahid Faghihi Hospital Echocardiography Center by one cardiologist. We utilized the eSie Velocity Vector Imaging (VVI) application, designed for quantitative and visual assessment of cardiac dynamics on Acuson sc2000 PRIME for STE. All participants were examined in the left lateral decubitus position using the grey-scale 2D imaging technique with adjustment of image contrast, frequency, depth, and sector size for adequate frame rate and optimal images. All images and measurements were obtained from the standard views with stable ECG. Offline analysis of 2D images was performed precisely in an echocardiography workstation for measuring the following parameters in proper time: interventricular septum (IVS) thickness, ventricular and atrial diameters, aorta diameter at sinuses, left ventricular (LV) ejection fraction (EF), and RV fractional area change (FAC).Tricuspid annular plane systolic excursion (TAPSE) was measured through M–mode images. Left atrial (LA) volume and right atrial (RA) area were measured with the apical monoplane method in four-chamber view at end-systole . The function of each valve was evaluated by the color Doppler method in different views and was reported according to the 2020 ACC/AHA guideline for the management of patients with valvular heart disease. The mitral, aortic, and tricuspid valve regurgitation were assessed and categorized as “at risk”, “progressive”, “asymptomatic severe” and “symptomatic severe” . InferioThe spectral Doppler parameters were evaluated including mitral valve (MV) E and A points velocity and E/A ratio. The LV diastolic function was determined from the mitral flow velocity pattern by pulsed Doppler echocardiography, in addition to the tissue, Doppler parameters measured included LV lateral e’ and LV septal e’. To assess the myocardial function of atria and ventricles, the endocardial border was manually traced using a point and click technique. The eSie VVI application automatically generated a wide range of interest and was re-adjusted manually, which included dividing the atria into three segments: (1) left free wall, (2) right free wall, and (3) roof; generating the average and global longitudinal strains, summarizing all the data in a table per atrium. To evaluate the ventricular strain, we divided each ventricular chamber into six regions: (1) lateral base region, (2) lateral mid-region, (3) lateral apex region, (4) septal apex region, (5) septal mid-region, and (6) septal base region. After calculating each region’s strain, the average and global strain were also calculated for each ventricular chamber.The patients with moderate-to-severe left ventricular hypertension, pericardial effusion, or poor quality of echocardiographic images for the evaluation of the endocardial border because of the patient’s poor echo window or tachypnea were excluded from the study. A total of 81 volunteers met the eligibility criteria for the study, 40 patients with SSc and 41 healthy volunteers, and were introduced to the echocardiography laboratory. Seventy-four volunteers were included in this study, as seven cases had poor image qualities and were excluded .t test and Chi-square test for the quantitative and qualitative variables, respectively. For data analysis, SPSS for Windows, Version 16.0.  was used. The p value < 0.05 was considered statistically significant. The descriptive statistics included mean and standard deviation (SD) for the quantitative variables and number (percentage) for the qualitative variables. The normality of the distributions was evaluated using frequency histograms and the Shapiro–Wilks test. The comparison between the groups was performed using the independent samples p > 0.05; p = 0.02; n = 22). Among the 37 Scleroderma patients who enrolled in our study, 23 (62%) were on calcium channel blockers (CCB), 33 (89%) were on Immunosuppressive therapy, nine (24%) were using endothelin receptor antagonists and four (10%) used Angiotensin II Receptor Blockers.A total of 74 participants completed the study, 37 in each group. The mean ± SD of the participants’ age was 45.7 ± 11.54 (range of 17 to 68) years; most of our participants were women (75.7%). As shown in p < 0.001), RA area (p = 0.007) and IVC diameter (p = 0.005) compared with the control group.According to the results of TTE, as shown in p < 0.05; p < 0.05; p = 0.001).According to the results of spectral and tissue Doppler echocardiography, the case group had a statistically higher estimated sPAP and mitral A wave velocity (p < 0.001). The frequency of stage A and B mitral valve regurgitation was also higher in the case group compared with the control group , and there were no cases of severe mitral valve regurgitation in our study population. The aortic regurgitation was only observed in two patients (5.4%) of the case group, and there were no cases of progressive or severe aortic valve regurgitation in our study population .According to color Doppler echocardiography results, 16.2% of the case group had progressive (stage B) and 8.1% had severe  tricuspid regurgitation, respectively, while only stage A (at risk) of tricuspid regurgitation was observed in the control group , LA average longitudinal strain (p = 0.015), LA global longitudinal strain (p = 0.028), and LAEF (p = 0.001) in the case group (p = 0.048) and RAEF (p < 0.001) between the two groups  and PAH in patients with SSc. However, other TTE parameters were not different between the groups. The results of STE also showed that the mechanical function of LA (LA EF) and longitudinal strain in LA roof, global, and average longitudinal strain were markedly reduced, even in patients with preserved LV systolic function. Furthermore, the STE parameter indicates the involvement of LA with SSc, independent of the LV systolic function. They can also develop these mentioned right atrial changes secondary to elevated sPAP , notablyPrevious studies have also confirmed impaired LA function in patients with SSc when evaluated by 2D-STE, which emphasizes the role of this imaging modality in the diagnosis of LA dysfunction in such patients ,15. In tTissue and spectral Doppler results in the current study revealed higher mitral A wave velocity and lower E/A ratio, e’ velocity of LV septal and lateral wall in patients with SSc, which indicated a higher prevalence of LVDD in patients with SSc, compared with the control group. Studying 153 consecutive patients with SSc showed LVDD in 23% of patients, while LV systolic dysfunction was only present in 5.2% of patients with SSc , which iThe biventricular analysis in the current study has yielded that RV global longitudinal strain has declined, whereas the LV global longitudinal strain has been preserved. Previously, RV impairments were thought to occur as a result of PAH and pressure overload ,31, and The present study was limited in terms of sample size, sex disproportion of the study population, non-randomized inclusion of patients in the study and the two groups, the exclusion of patients with overt heart failure (which could have affected our strain measurements), and the evaluation of PAH and diastolic function using non-invasive methods (Doppler Echocardiography) rather than the gold standard methods of evaluation, that is, catheterization. The lack of long-term follow-up was another limitation in the present study, and we could not identify whether the atrial impairments were associated with future ventricular dysfunction or not.The results of the present study showed that the simultaneous evaluation of the four chambers using 2D-STE resulted in the diagnosis of impaired either mechanics or function of the chambers in subclinical stages and even more apparently, the changes in the left atrium before any involvement of the left ventricle in TTE or STE. Further studies are required to confirm these results and evaluate the association of these impairments with patients’ morbidity and mortality rates.


RV origin of PVCs was more common in the preserved LVEF group but was also significantly correlated with persistently reduced EF post-ablation in the PVC CM group. Scar burden was not correlated with either cardiac function or post-ablation recovery of function. In this cohort, there were no significant CMR findings to predict subsequent recovery of EF after ablation among those with PVC CM. PVC origin in the RV was associated with persistently reduced LVEF after ablation.Frequent premature ventricular contractions (PVCs) can induce cardiomyopathy (PVC CM). We sought to use cardiac magnetic resonance imaging (CMR) to quantify changes in cardiac structure and function of cardiomyopathy patients following catheter ablation for PVCs. Patients undergoing PVC ablation at the Johns Hopkins Hospital with pre-procedural CMR from 2010 to 2018 were included in this study. CMR Images were analyzed to collect information on cardiac structure and function as well as to quantify scar. Of the total 51 included patients, PVC CM (LVEF < 45%) was observed in 51% (n = 29). Of these, 19 had post-ablation ejection fractions quantified, with 78.9% (n = 15) recovering function. Global longitudinal strain was significantly correlated with LVEF (OR 1.831,  PVC CM is often a diagnosis of exclusion, and reversibility with resolution of PVCs, often by radiofrequency ablation, separates it from other underlying cardiomyopathy. Few prior studies used cardiac magnetic resonance imaging (CMR) assess for presence of SHD with relation to improvement of cardiac function after PVC ablation.Premature ventricular contractions (PVCs), while historically thought benign, are now well recognized to carry risk of inducing cardiomyopathy. There have been significant efforts to isolate predictors of which patients will go on to develop PVC-CM, some isolating PVC burdenWe sought to use CMR to quantify left ventricular scar and function in patients undergoing catheter ablation for PVCs, and to identify imaging parameters associated with recovery of ejection fraction after successful ablation.Patients who had undergone PVC ablation at the Johns Hopkins Hospital between 2010 and 2018 were selected. These patients had been shown to have PVC either by Holter monitoring or via inpatient telemetry. Rationale for undergoing PVC ablation included symptomatic palpitations, pre-syncope or syncope, or cardiomyopathy of unknown etiology. Of patients undergoing PVC ablation, those with CMR completed within 6 months pre-procedure were selected.Patients with previously known coronary artery disease (CAD) or valvular structural heart disease (SHD) were excluded. Ischemic evaluation was performed prior to the CMR. When CMR findings suggested alternative diagnosis, such as arrhythmogenic right ventricular cardiomyopathy (ARVC) or cardiac sarcoidosis, these patients were also excluded. However, patients discovered to have scar appearing ischemic in etiology during image analysis were still included.Cardiomyopathy was defined as ejection fraction (EF) < 50%, which was taken from the most recent TTE prior to ablation. Recovery of EF was defined as improvement > 10% after ablation.This was a retrospective cohort study. Retrospective review of patient data was approved by the Johns Hopkins University Institutional Review Board. All procedures were carried out in accordance with the relevant guidelines. Written informed consent was obtained from all participants to have clinical and personal data available for in research purposes.The electronic medical record was used to collect participant demographic data, presenting symptoms, PVC burden (if Holter had been performed prior to procedure), anti-arrhythmic medications prior to procedure, most recent TTE prior to and after ablation, known presence of structural heart disease, and known history of coronary artery disease.Electrophysiology study (EPS) information was extracted from procedural notes in the medical record, including number of PVCs and their morphologies, number of ablated sites and locations, as well as procedural success. Acute procedural success was defined as the post-procedure absence of PVCs after a 30 min observation period.Not all patients had CMR images obtained at the Johns Hopkins Hospital, and many images were acquired at outside facilities. Thus, CMR images were obtained from all major vendors  at both 1.5 and 3 T. A complete sequence included cine sequences in both the short axis, long-axis, 3 chamber views with intervals of roughly 1 cm across the left ventricle, as well as delayed enhancement imaging. CMR images were analyzed using QMass 7.5 . Information on cardiac structure, including left ventricular end diastolic volume (LVEDV), cardiac mass, scar burden, as well as on cardiac function, including cardiac output/index, global longitudinal strain and left ventricular ejection fraction were collected. Delayed enhacement CMR (DE-CMR) was used to identify scar. Scar was identified as myocardium with abnormal enhacement with signal intensity at least 2 standard deviations above identified normal intensity tissue. Scar mass and volume were then indexed as percentage of the LV myocardium.Quantification of LV strain was accomplished using multimodality tissue tracking software . Global longitudinal strain was assessed using cine-CMR in the 4-chamber view. Endocardial and epicardial contours were manually drawn at end-systole and automatically propagated through the cardiac cycle, with manual correction as needed. Strain and strain rate were then calculated within the software by tracking the position of index pixels.Statistics were completed using IBM SPSS Statistics v25 . Group differences were compared with Fisher’s exact test for categorical variables and t-test for continuous variables. Presence of cardiomyopathy was defined as a binary variable, and binomial logistic regression was performed to assess whether age, gender, medication use, PVC burden, number of PVC morphologies, whether ablation was able to be successfully performed, ablation site, presence of scar, scar burden, maximum longitudinal strain, and maximum strain rate (SR) were each associated. Next, ejection fraction was addressed as a continuous variable and ordinary least squares linear regressions were performed to assess the relation between the same variables and EF.Of the patients with cardiomyopathy, those with follow-up assessment of cardiac function were assessed. Using recovery of ejection fraction as a binary variable, binomial logistic regressions were performed to assess whether the same variables were associated with recovery.p value < 0.05 was considered statistically significant for all statistics.For evaluation of longitudinal strain, Pearson correlation was performed. A Between 2010 and 2018, a total of 56 patients undergoing PVC ablation also had CMR images available prior to ablation. CMR images were obtained on average 1 week prior to the ablation procedure. Of these, 51 patients had complete sets of images for analysis. Cardiomyopathy was observed in 26 patients (51.0%). Of these 26 patients, 19 had follow-up assessment of cardiac function on file. Post ablation follow-up echocardiograms were obtained on average 18 months post-ablation. Fifteen (78.9%) of these patients had recovery of EF after ablation . There as no significant correlation between either the presence of scar or scar burden with EF  had delayed enhancement on CMR. There was an equal number of patients with scar present in both the reduced EF and the preserved EF group (5 in each). The average scar burden was 15.3 ± 7.23% of the reduced EF group and 9.0 ± 7.09% in the preserved EF group  had ablations at the scar site, and 3 (30%) had unsuccessful ablations Table .Table 4Dp < 0.001). Average global longitudinal strain in the cardiomyopathy group was 16.19% ± 4.50%, and 9.0% ± 7.09% in the preserved EF group. Max strain rate was not significantly correlated with any measure.The maximum longitudinal strain was closely correlated with the ejection fraction .Global longitudinal strain was not significantly correlated with scar burden . In investigating the relationship of LVEDV on EF recovery in the cardiomyopathy group, there was no significant correlation.Left ventricular end-diastolic volume (LVEDV) in the cardiomyopathy group was 175.43 ± 77.22 mL and 140.50 ± 36.93 mL in the preserved EF group. There was a significant correlation with ejection fraction . In evaluating post-procedure cardiac function of the cardiomyopathy group, PVC origin in the RV was negatively correlated recovery of EF after ablation .In total, 8 (15.7%) of the patients had PVCs that were either unable to be ablated due to proximity to essential structures or native conduction pathways or that were refractory to ablation. There was not a significant difference between the two groups with regards to whether or not the PVC origin was amenable to ablation. In patients with multiple PVC morphologies, the dominant PVC morphology  was targeted. In total, 21 (41.2%) of patients had ablations in the left ventricle (LV), 23 (45.1%) had ablations in the RV, and 4 (7.8%) had ablations in both ventricles. The preserved EF group had a statistically significant higher incidence of PVC origin in RV .Of the unsuccessful ablations, four were in the LV, two were in the RV, and two had scar localized to the LV with no ablation attempted due to proximity to native conduction system. Five patients who had unsuccessful or partially successful ablations recovered function after ablation. There was no correlation between myocardial scar and unsuccessful ablations  patients with PVC CM had a larger LVEDV, reduced maximum longitudinal strain and were less likely to have a predominant PVC orginating from the RV, (2) there was no significant association of LV scar burden with recovery of LV function, (3) there was no significant baseline CMR functional strain parameter that predicts recovery of LVEF after PVC ablation and (4) PVC origin within the RV was associated with lack of EF recovery after PVC ablation.11. This, combined with our finding of no clinical correlation with T2 LGE suggests that PVC CM is more likely a diffuse process, causing or stemming from diffuse fibrosis, rather than a focal, fibrotic, scar-forming process.PVC CM remains a diagnosis of exclusion. While patients with known scar are more prone to ventricular arrhythmia, the lack of LGE in our patient cohort as well as the lack of correlation between scar and clinical predictors suggests PVC CM is not a scar mediated process. CMR as an investigative tool in patients with purported idiopathic cardiomyopathy remains very important to rule out other reversible etiologies. Previous papers have described extracellular volume (ECV) evaluated in CMR T1 phase as correlating with both PVC-induced cardiomyopathy and with PVC burden12. Amongst patients with PVC CM and ruled out for CAD, this incidence has been shown to be anywhere from 7 to 41%14. We found that in our cohort, 19.6% of patients had LGE present, of which 60% was in a non-ischemic pattern. However, the presence of scar, ischemic or otherwise, was evenly distributed between the cardiomyopathy and preserved EF groups. Furthermore, neither the presence of scar nor the scar burden was significantly associated with recovery of EF after ablation. PVC origin was highly co-localized with the scar site on CMR. Both of these findings are consistent with prior studies13. In a study assessing utility of pre-procedural CMR before PVC ablation, there was some predictive value of mortality in patients with scar and inducible VT on EP study15, but this study did not exclude patients with known ischemic disease, as we did in our cohort.Nearly all patients with ischemic cardiomyopathy form myocardial scar, which is visualized as delayed enhancement on CMR. However, amongst patients with non-ischemic cardiomyopathy (NICM), the frequency has been demonstrated at 12%16. Longitudinal strain and ejection fraction as a continuous variable are unsurprisingly significantly correlated, with our data suggesting an increase in EF of 7.4% per 4.9% increase in longitudinal strain. However, the lack of significant correlation between longitudinal strain and recovery of EF in our study is interesting. Longitudinal strain assessed by speckle tracking on TTE has been well-established to predict recovery of LV function in cases of ischemic cardiomyopathy after revascularization or medical management of ischemia18. In patients with non-ischemic cardiomyopathy hospitalized for new-onset heart failure, the utility of longitudinal strain as predictor for recovery of EF has also been demonstrated19.Global longitudinal strain has previously been shown to be a significant predictor of mortality, with estimates as high as 89.1% increase in death per each 1% of worsened strain in patients with cardiomyopathyThe difference in these results compared with our findings may be attributed to the degree of cardiac decompensation. In the study by Swat et al. patients were recruited during hospitalization for heart failure symptoms, while the majority of patients in our cohort were not symptomatic from heart failure, instead citing syncope or palpitations as reason for pursuing ablation. It is notable that the average longitudinal strain in this study was 15.2% in persistently reduced EF patients and 16.5% in recovered EF patients, while the average longitudinal strain of normal EF patients was 20.6%. It may be that the relation of longitudinal strain to EF recovery is more strongly correlated in decompensated heart failure.21, thought likely because these patients do not seek care and have prolonged duration of exposure to PVCs. In the study by Swat et al. the mean time to EF recovery was 135 days. The majority of the patients in our cohort have had PVCs for years, most of whom have also failed medical management. Thus, it may also be that longitudinal strain is less predictive with chronic changes. Finally the use of TTE in that study compared to the use of CMR in our study to assess longitudinal strain should be noted but is unlikely to explain the discrepancy.In addition, the development of PVC-induced cardiomyopathy is thought related to how long a patient has had PVCs. Several studies have shown asymptomatic presentation as a risk for development of PVC CM3. This threshold was later challenged, with a study showing a threshold of PVC burden > 16% 4. In a canine model, PVC CM occurred at a PVC burden as low as 11% in 25% of subjects, but 100% of subjects had impaired LV function at a PVC burden of 50%5. Though thresholds have been defined, there have been outliers and PVC CM has been reported with a burden as low as 4%22.Several studies have attempted to quantify a threshold of PVC burden at which patients were likely to develop PVC CM. Baman et al. introduced a threshold of PVC > 24%, with a sensitivity of 79% and specificity of 78%24. Furthermore, studies have shown correlation of the temporal heterogeneity of PVCs25 or burden of interpolated PVCs to development of cardiomyopathy20 suggesting that there may be more complexity to the issue than pure PVC burden.In our study we did not find PVC burden to be a statistically significant predictor of either reduced EF or subsequent recovery of function. However, in our cohort of patients the overall PVC burden was high, thus limiting comparisons. Both the lack of correlation between PVC burden with the presence of PVC CM as well as with recovery of EF have been previously documented23. However, subsequent studies have demonstrated that there is not a statistically significant difference in whether PVCs arise from the LV or RV27. In the cardiomyopathy group, there was an observed statistically significant correlation of RV origin with persistently reduced EF. RV ablations, specifically RVOT ablations, have been shown to have the highest success rate6. This was supported by our findings as well, with 6 of the 8 unsuccessful ablations localizing PVC origin to the LV. However, these patients were split equally between the cardiomyopathy and preserved EF groups.In our study, we observed a higher incidence of PVC origins in the RV amongst patients with preserved EF. It was previously shown that PVCs arising from the RV, predominantly the RV outflow tract (RVOT) are more likely to cause cardiomyopathy28. Our study corroborates this with a significant correlation between RV site and lack of EF recovery. It may be that with an RV site of origin leads to significant ventricular dyssynchrony, similar to what is observed with left bundle branch bock, and thus patients are at higher risk for developing irreversible cardiomyopathy.With regards to the relationship between PVC origin site and EF recovery, a prior study showed a higher incidence of EF recovery of PVC CM in LV ablations compared to RV ablations, though this was not a statistically significant findingIn this study, we did not exclude unsuccessful or partially successful ablations. Interestingly, of the 8 ablations that were not successful, 3 did not have reduced ejection fractions and 5 recovered function despite the lack of procedural success. As PVC cardiomyopathy is technically defined as cases with improvement of EF after resolution of PVCs, these cases do not qualify for the diagnosis.There were several limitations in this study. First, our medical center is a quaternary care center and receives referrals from all over the world. Thus, there was limitation in access to medical records both pre-ablation, as well as post-ablation follow-up. A major outcome, post-ablation improvement in EF, was not able to be assessed in all cardiomyopathy patients due to lack of records. As previously mentioned, description of ECV correlating with PVC burden and PVC CM has been previously reported. We were unable to include this description in our study as ECV assessment is not part of the clinical protocol at our institution. The sample size of this study was limited due in part to the nature of PVC cardiomyopathy being a diagnosis of exclusion and a minority of patients are referred for catheter ablation. Another limitation was with our CMR image standardization, as patients oftentimes completed CMR imaging at outside facilities. This was addressed as best as possible by excluding incomplete image series.In this cohort of patients undergoing CMR prior to a PVC ablation, and without history of ischemic or structural heart disease, there were no significant CMR findings to predict the presence of PVC CM or to predict subsequent recovery of EF after ablation. The burden of existing scar is was not associated with either endpoint, nor was the magnitude of global longitudinal strain. PVC origin in the RV was associated with lack of EF recovery after ablation and further investigation into the mechanism of this process is warranted.


The patient was discharged uneventfully and at 6- and 12-month follow-up, the NYHA class, and LV volumes were found unchanged. This is a second report describing the use of the 3D print model for the preoperative planning of surgical management of LVA; the first report was described by Jacobs et al. among three patients, one with a malignant tumor and the remaining two patients with LVA. This article focused on the use of the 3D print model to optimize surgical planning and individualize treatment of LVA associated with complete functional revascularization, leading to complete recovery of LV function with a favorable outcome.A 59-year-old woman was admitted to the emergency department for heart failure (HF), New York Heart Association (NYHA) IV, showing an anterior, evolved myocardial infarction (MI) with a wide apical left ventricular aneurysm (LVA), ejection fraction (EF) 24%, and global longitudinal strain (GLS) −5. 5% by echo. Cardiac magnetic resonance imaging (MRI) confirmed an apical LVA without thrombus, EF 20%, and a transmural delayed enhancement in the myocardium wall. Coronarography showed a three-vessel disease with occluded proximal left anterior descending (LAD) and proximal right coronary artery (RCA). Based on the cardiac CT scan, we decided to generate a three-dimensional (3D) print model of the heart, for better prediction of residual LV volumes. After LVA surgery plus complete functional revascularization, an optimal agreement was found between predicted and surgical residual LV end-diastolic (24.7 vs. 31.8 ml/m After myocardial infarction (MI), patients with severe heart failure (HF) carry a poor prognosis, and despite major advances, long-term medical management alone might be insufficient . CardiacOur patient was a 59-year-old woman admitted to the emergency department for HF, New York Heart Association (NYHA) IV, with dyspnea that started 10 days before. She was a former smoker, affected by hypercholesterolemia and hypertension, on angiotensin-converting enzyme (ACE) inhibitor treatment at the time of presentation. We started management of HF using high doses of loop diuretics i.v., beta blockers, ACE inhibitors, mineralocorticoids, statins, and aspirin. Routine blood investigations were notable for NT-proBNP 6,526 ng/dl and troponin-hs 196 ng/l. An anterior, evolved MI infarction was revealed by ECG, and a two-dimensional (2D)-echocardiogram showed a wide apical LVA (6 × 5.5 cm) without thrombus, EF 24% and global longitudinal strain (GLS) 5.5% , and milAfter heart team discussion, the surgical ventricular restoration (SVR) of the LV chamber appeared as an attractive strategy, combined with complete CR. The risk in generating a small residual LV was discussed, as it is not trivial. To optimize surgical planning, we used a 3D print model of the LVA for a better prediction of the residual surgical LV volumes. The patient underwent SVR excluding dyskinetic portions of the anterior wall and septum, reshaping the LV with a stitch that encircled the transitional zone between contractile myocardium and aneurysmal tissue, and using a “Gore-Tex” patch to reestablish ventricular wall continuity. A complete functional CR was also attempted, using the left anterior internal mammary artery for the marginal branch and saphenous graft for RCA. The operation improved the size and geometry of the left ventricle, reduced wall tension and paradox movement, and enhanced overall systolic function, EF 54% , and alspost hoc analysis of that trial showed that a postoperative LVESVI of 70 ml/m2 or lower resulted in improved survival, compared with CR alone   . In addidence B) . Beyond dence B) . Volumetdence B) . Indeed,dence B) . From a dence B) . The ultNowadays, a personalized surgical approach is mandatory to satisfy the different needs of post-infarct LV remodeling. Patient-specific 3D-printed models can be used for a comprehensive assessment of the LVA, pre-procedural planning, and patient education, translating into excellent results. Optimal planning of SVR is of crucial relevance in preventing a restrictive pattern or a distorted ventricular shape, potentially translating into poor outcomes. Based on a 3D-printing model, it is conceivable that, in the near future, a tailored approach to different phenotypes of LVA will make the planning of the most appropriate residual LV volumes possible in the individual patient.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 Careggi Hospital EC. The patients/participants provided their written informed consent to participate in this study.NC: substantial contributions to the conception or design of the work, agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved, and drafting the work or revising it critically for important intellectual content. FB: substantial contributions to the conception or design of the work and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. RF and MC: substantial contributions to the conception or design of the work and provide approval for publication of the content. MV, RV, and AC: substantial contributions to the conception or design of the work, or the acquisition, analysis, or interpretation of data for the work. NM and PS: substantial contributions to the conception or design of the work and provide approval for publication of the content. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.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.