Three‐dimensional echocardiography can elucidate the phasic functions of the left atrium if a simultaneous acquisition of a pyramidal full‐volume dataset, as gathered from the apical window and containing the entire left atrial and left ventricular cardiac sections, is obtained. Hence, conduit can be quantified as the integral of net, diastolic, instantaneous difference between synchronized atrial and ventricular volume curves, beginning at minimum ventricular cavity volume and ending just before atrial contraction. Increased conduit can reflect increased downstream suction, as conduit would track the apex‐to‐base intracavitary pressure gradient existing, in early diastole, within the single chamber formed by the atrium and the ventricle, when the mitral valve is open. Such a gradient increases in response to adrenergic stimulation or during exercise and mediates an increment in passive flow during early diastole, with the ventricle being filled from the atrial reservoir and, simultaneously, from blood drawn from the pulmonary veins. In this context conduit, and even more conduit flow rate, expressed in ml/sec, can be viewed as an indirect marker of left ventricular relaxation.It is well known, however, that a large amount of conduit (in relative terms) is also supposed to contribute to LV stroke volume in conditions of increased resistance to LV filling, when diastolic function significantly worsens. Stiffening of the atrio‐ventricular complex implies increments in LA pressure more pronounced in late systole, causing markedly elevated “v” waves, independently of the presence of mitral insufficiency. The combination of increased atrio‐ventricular stiffness and conduit flow is associated with an elevation of the right ventricular pulsatile relative to resistive load that negatively impacts on exercise capacity and survival in these patients.Atrial conduit is an “intriguing” parameter that conveys a noninvasive picture of the complex atrioventricular coupling condition in diastole and its backward effects on the right side of the heart and the pulmonary circulation. Given the easiness associated with its correctly performed quantification in the imaging laboratory, I am sure that conduit will survive the competitive access to the list of valuable parameters capable of deciphering, although not necessarily simplifying, the complex diastolic scenario in health and disease. Atrial conduit is an “intriguing” parameter that conveys a noninvasive picture of the complex atrioventricular coupling condition in diastole and its backward effects on the right side of the heart and the pulmonary circulation. Given the easiness associated with its correctly performed quantification in the imaging laboratory, I am sure that conduit will survive the competitive access to the list of valuable parameters capable of deciphering, although not necessarily simplifying, the complex diastolic scenario in health and disease. During late diastole, the atrium also actively contributes to ventricular filling. Such pump function can be defined as the blood volume pushed into LV during atrial systole, plus the volume of the backward flow into the pulmonary veins. Finally, during early and mid‐diastole, the atrium passively contributes to LV filling (conduit function). During this phase, the cavity is directly exposed to the LV pressure through the open mitral valve and conduit flow is obviously and strongly influenced by the left heart diastolic properties and the gradient relative to the pulmonary venous compartment  cavity, which connects the pulmonary circulation with the corresponding ventricle, is characterized by phasic activity which makes the description of the atrium as of a passive player in the complex scenario of the cardiac cycle unrealistic  during mitral valve E‐wave acceleration  patients prognosis is strongly associated with the performance of the right ventricular (RV) cavity and its loading conditions  may be abnormally elevated like in HF patients. Tedford et al. , in factIt is well known that a large amount of conduit is supposed to contribute to LV stroke volume in conditions of increased resistance to LV filling (and this would explain why conduit contribution to LV stroke volume would increase with worsening diastolic dysfunction; Marino et al., According to the above reasoning increments in conduit flow may reflect increased suction, acting on the LV side, or exaggerated filling and pulsatile pressure, acting on the LA side Figure , left, aIt is challenging to quantitatively separate the rapid filling volume of blood entering the LV in early diastole into the conduit versus reservoir components. More than 2 decades ago, in order to quantify conduit, we proposed an approach that integrated the information derived from the Doppler mitral flow velocity profile with that of one single pulmonary vein (taken as a representative of all the four veins; Prioli et al., More recently, we adopted 3D echocardiography, gathering simultaneous acquisitions of a pyramidal full‐volume dataset from the apical window and containing the entire LA and LV cardiac sections (Nappo et al., cannot be faithfully reflected by the atrial volume curve alone. In the phase of passive atrial emptying and atrial diastasis pulmonary veins drain blood from the lungs into the ventricle. Further, not to forget is that, during atrial contraction, some blood does flow back into the pulmonary veins, although it is known that sleeve contraction should normally limit this retrograde flow to a small amount (Thiagalingam et al., Whatever the way conduit is nominally expressed, it must be emphasized that the amount of blood entering LV from the atrium during diastole It has been anticipated that simultaneous volumetric measurements of LV and LA cavity is not possible with 2D images because the LV major axis differs from LA major axis (Lang et al., Conduit is an “intriguing” parameter that conveys a noninvasive picture of the complex atrioventricular coupling condition in diastole and its backward effects on the right side of the heart and the pulmonary circulation. Given the easiness associated with its correctly performed quantification in the imaging laboratory, I am sure that conduit will survive the competitive access to the list of valuable parameters capable of deciphering, although not necessarily simplifying, the complex diastolic scenario in health and disease (Nishimura & Tajik, The author confirms that he has no conflict of interest to declare in relation to the submitted paper.Paolo N. Marino conceived, drafted, and finalized the manuscript to be published.


Inflammation is a key feature of heart failure including HFpEF. The leukocyte count is a marker of inflammation that is widely used in clinical practice. However, there is little available evidence for the relationship between leukocyte count and the outcomes of HFpEF.We analyzed data from the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) trial. The primary outcome was all-cause mortality, the secondary outcome was composite cardiovascular events and hospitalization for heart failure. Multivariable Cox proportional hazard models were used to compare the risk profiles of patients with leukocyte quartiles, subgroup study divided by sex was also analyzed.The present study included 2898 patients with HFpEF.429 deaths, 671 composite cardiovascular events and 386 hospitalization for heart failure occurred during a mean 3.4 years follow-up. The association between leukocyte count and adverse outcomes followed a U-shaped curve. After multivariable adjustment, the patients with the lowest leukocyte count (Q1) and the highest leukocyte count (Q4) faced higher risk of all-cause death. The subgroup analysis showed a consistent result in female but not male patients.The association between leukocyte count and risk of adverse outcomes followed a U-shaped curve. Both higher and lower leukocyte count are associated with worse outcomes in patients with HFpEF, which may be attributed to the two sides of inflammation in cardiac remodeling.The online version contains supplementary material available at 10.1186/s12872-021-02142-y. Heart failure with preserved ejection fraction (HFpEF) has emerged as anpivotal problem with increasing prevalence and poor prognosis in recent years . HoweverLeukocyte, as an inflammation driver, plays an important role in cardiovascular disease. In further, it even serves as an important predictor for various cardiovascular events –6. HeartAlthough limit evidences indicateinflammation biomarkers are associated with adverse outcomes in patients with HFpEF , 15, theTOPCAT was a randomized, placebo-control, double blind, multi-centerclinical study.The study aimed to investigate the treatment efficacy of spironolactone in patientswith HFpEF. The study information including background, design, inclusion and exclusion criteria, and baseline characteristicshave been published previously , 17. BriAccording to the current guideline , this anBasic informationandmedical histories were obtained in patients by a detailed baseline visit in TOPCAT study . For exa2 test.Baseline plasma BNP levels were expressed as log-transformed data.Glomerular filtrationrates were estimated by incorporating creatinine into the ChronicKidney Disease Epidemiology Collaboration (CKD-EPI) formula [www.empowerstats.com, X&Y solutions, IncBoston, MA) andSPSS version 25.0 .Baseline characteristics were compared by quartiles of leukocyte counts. Data are presented asmean ± SD,nonnormal variables were reported as median  implanted,angina pectoris, systolic blood pressure, left ventricular ejection fraction (LVEF), heart rate, the use ofb-blockers, calcium channel blockers, angiotensin-converting enzyme inhibitor/Angiotensin Receptor Blocker (ACEI/ARB)and spironolactone.However, male sex, smoker, dyslipidemia, previous myocardial infarction, percutaneous coronary intervention (PCI), Coronary artery bypass graft (CABG), diabetes mellitus, atrial fibrillation, chronic obstructive pulmonary disease (COPD), asthma, thyroid disease, peripheral arterial disease, use of statins and loop diuretics were more prevalent in participants the higherleukocyte quartiles.At the same time, higher leukocytecount was associated with higher heart rate, body mass index, BUN, hemoglobin and platelet.The higher leukocyte count was also associated with lower diastolic blood pressure, eGFR and prevalence of New York Heart Association class III-IV.A total of 2898 patients  were included in this analysis. Table Over a median follow-up of 3.4 years (25th-75thpercentiles = 2.0–4.9 years), 429 deaths, 671 composite cardiovascular events and 386 hospitalization for heart failure occurred. Kaplan–Meier estimates of the cumulative incidence ofall-cause death, the compositecardiovascular eventsand hospitalization for heart failure are depicted in Fig. 9/l(Q2) .Actually, the associationbetween leukocyte count and risk of adverse outcomes followed a U-shaped curve, with increased risk above and below the reference range of 5.5 to 6.7 × 10Q2) Fig. .The resuInterestingly, subgroup analyses of female participants confirmed the U-shaped relationship between leukocyte count and all-cause death . Supplemental Table 2. Subgroup analysis of Cox proportional-hazards model divided by gender for Composite cardiovascular events (n = 2898). Supplemental Table 3. Univariate and multivariable Cox regression analysis of hospitalization for heart failure (n = 2898). Supplemental Table 4. Subgroup analysis of Cox proportional-hazards model divided by gender for Hospitalization for heart failure (n = 2898).


Background and objectives: Endothelial dysfunction is associated with exercise intolerance and adverse cardiovascular events. Transcatheter aortic valve implantation (TAVI) is applied to treat elderly patients with severe aortic stenosis, but less is known about the impact of TAVI on endothelial dysfunction, which can be assessed by measuring flow-mediated vasodilation (FMD). In this parameter, a low value indicates impaired endothelial function. Materials and Methods: Vascular endothelial function was evaluated by FMD of the brachial artery just before and one week after TAVI. Factors associated with the normalization of FMD and their prognostic impact were investigated. Results: Fifty-one patients who underwent TAVI procedure  were included. FMD improved significantly from baseline to one week following TAVI . Among 33 patients with baseline low FMD (≤6.0%), FMD normalized up to >6.0% following TAVI in 15 patients. Baseline higher cardiac index was independently associated with normalization of FMD following TAVI . Conclusions: Endothelial dysfunction improved following TAVI in many patients with severe aortic stenosis. The implication of this finding is the next concern. Severe aortic stenosis (AS) is associated with limited cardiac output, impaired functional capacity, and poor outcomes . TranscaVascular endothelial dysfunction develops early in the pre-stage of arteriosclerosis and its assessment is practical for the early detection of arteriosclerosis. One of the major indices of vascular endothelial function is flow-mediated vasodilatation (FMD). FMD consists of (1) increased blood flow after the release of ischemia due to cuff release, (2) endothelium-derived nitric oxide (NO) release triggered by incremental shear stress, and 3) vasodilation caused by the NO-related relaxation of the vascular smooth muscle  vasodila. It has The progression of AS not only has negative impacts on the left ventricle but also on vascular function, including systemic vascular compliance . AlthougPatients who were admitted to our institute to receive TAVI between June 2015 and January 2019 were included in this prospective study. TAVI candidates were assigned to one of three teams randomly during the index hospitalization. Patients assigned to a certain team were finally included in this study and received FMD measurement just before and one week after TAVI.Patients with symptomatic severe AS who had a high risk of surgical procedure were indicated to receive TAVI determined by the heart valve team. All procedures were performed with a balloon-expandable valve  or self-expandable valve  via a trans-femoral approach or trans-apical approach under general or local anesthesia. Informed consent was obtained beforehand, and this study was approved by the local institutional review board on 13 August 2018 (IRB 30-415).Preoperative baseline characteristics including demographics, transthoracic echocardiographic findings, and hemodynamic data were collected. Postoperative data including laboratory and echocardiography data were collected one week following TAVI. All-cause death during the two-year observational period following the index discharger was counted. Vascular endothelial function was evaluated by FMD of the brachial artery just before and one week after TAVI. Patients rested at least for 10 min in the supine position beforehand in a quiet, light- and temperature-controlled room. Vasodilatation responses were determined by the ultrasound technique using a semi-automatic device  by experts who were blinded to the clinical data. Briefly, the diameter of the brachial artery was measured from B-mode ultrasound images using a 10-MHz linear array transducer. Then, a blood pressure cuff on the forearm was inflated to 50 mmHg above the systolic blood pressure for 5 min. The diastolic diameter of the brachial artery was semi-automatically followed using an instrument equipped with software for two minutes. The changes in the diastolic diameter were continuously recorded and the maximum diastolic diameter of the brachial artery was determined. FMD was determined as the maximum change in diameter after cuff release.® Pro 15 . Two-sided p-values < 0.05 were considered statistically significant. The primary outcome was the change in FMD following TAVI. The secondary outcome was the impact of FMD normalization on two-year survival. Statistical analyses were performed with JMPp < 0.20 in the univariate analyses.Continuous variables were expressed as median and interquartile and compared between the two groups using the Mann–Whitney U test. Categorical variables were expressed as numbers and percentages and compared between the two groups using Fischer’s exact test. Wilcoxon signed-rank test was performed to compare the coupled data such as FMD before and after TAVI. Logistic regression analyses were performed to investigate baseline characteristics associating with the normalization of FMD, defined as FMD >6.0%, among those with baseline abnormal FMD. Multivariate analysis was performed using parameters with 2. Left ventricular ejection fraction and cardiac index were preserved as 65%  and 2.64  L/min/m2 in most of the patients.Among 181 patients, 51 received FMD measurements and were included in this study. The baseline characteristics of all 51 patients are summarized in p < 0.05 for both; Thirty-three patients (65%) had FMD < 6.0% at baseline and were assigned to the low FMD group. The low FMD group had more men and less advanced AS . Echocardiographic parameters remained unchanged except for aortic valve data. Systolic blood pressure increased, diastolic blood pressure remained unchanged, and pulse pressure increased. Plasma BNP levels decreased significantly  (The effective orifice area was significantly improved 1 week after TAVI (from 0.57 cm< 0.001) .p < 0.001; In total, FMD was significantly improved at 1 week following the TAVI procedure , 15 patients achieved a normalization of the FMD value , whereas FMD remained at low values in the remaining 18 patients  (Among those with low FMD at baseline ( = 0.87) .p < 0.20 in the univariate analysis including cardiac index, plasma BNP level, peak velocity at aortic valve, and the use of angiotensin converting enzyme inhibitor, were enrolled in the multivariate analysis. Finally, a higher cardiac index at baseline was an independent predictor of FMD normalization  tended to have a higher two-year survival rate compared with those with persistently low FMD (n = 18) . Two of these deaths were in the baseline low FMD group, one of which was cardiac death. There were no heart failure readmissions. Patients with normalized FMD  among 33 patients with baseline low FMD (<6.0%). A higher cardiac index at baseline was associated with the achievement of normalization in FMD following TAVI. Normalized FMD tended to be associated with higher survival compared with persistently low FMD. AS is one of the expressions of systemic atherosclerosis. Atherosclerosis accompanies vascular endothelial cell damage, which is facilitated by the existences of hypertension, hyperglycemia, hyperlipidemia, and physical irritation. In the progression of atherosclerosis, physiologically active substances such as PDGF are released to form initial lesions . SimilarFurthermore, the progression of AS increases wall shear stress due to fast systemic blood flow . IncreasThe improvement of AS reduces wall shear stress at rest. Following TAVI, the changes in wall shear stress following the cuff release become significant. This was the dominant mechanism of improvement in FMD following the intervention in the overall cohort. Both TAVI and SAVR seem to improve vascular endothelial function at least in the chronic phase ,9. The impact of intervention to AS on FMD levels in the early phase remains controversial. FMD seems to decrease soon after SAVR , probablOther groups reported the opposite finding to ours, in that wall share stress was impaired soon after TAVI . We founp = 0.10). We cannot completely deny any factors other than cardiac output that might have a considerable impact on the improvement in FMD. Fifth, most patients in the baseline normal FMD were female (17/18). The progression process of endothelial dysfunction might be different between men and women, and further sub-analysis between men and women might bring us further insights.First, this is a single-center analysis among a small-sized cohort. Second, there might be intra- and inter-rater variability in the measurements of FMD. In this study, a single experienced expert operator performed all procedures. Third, we investigated the impact of normalization in FMD on survival, but its impact on other clinical outcomes remains the next concern. Fourth, those with improvement in FMD tended to be non-smokers (87% vs. 61%), although this did not reach statistical difference (Endothelial function, assessed by using FMD, improved immediately after TAVI. Preserved cardiac output might be a key to improve FMD. The clinical implication of improvement in FMD following TAVI remains the next concern.


Background: Accurate diagnosis and classification of ovarian hyperstimulation syndrome (OHSS) is important for its management. We employed a new high-sensitivity chemiluminescence immunoassay to detect the thrombin-antithrombin complex (TAT), plasmin alpha2-plasmin inhibitor complex (PIC), soluble thrombomodulin (sTM), and tissue plasminogen activator-inhibitor complex (TPAI-C), and evaluated their diagnostic and classification performance for OHSS.Methods: A total of 106 women were enrolled, including 51 patients with OHSS , and 55 without OHSS (control group). TAT, PIC, sTM, and TPAI-C levels were measured using the Sysmex HISCL5000 automated analyzer.Results: Compared to the control group, TAT, PIC, and TPAI-C levels were significantly higher , whereas the sTM level was significantly lower (P < 0.001) in the patients with OHSS. The receiver operating characteristic was used to evaluate the diagnostic efficiency. For the diagnosis of OHSS, the area under the curves (AUCs) for TAT, PIC, sTM, and TPAI-C were 0.991, 0.973, 0.809, and 0.722, respectively. In particular, the sensitivity, specificity, positive predictive value, and negative predictive value for TAT and PIC were all above 90%. For the differential diagnosis of mild–moderate and severe OHSS, the AUCs for TAT, PIC, and TPAI-C were 0.736, 0.735, and 0.818, respectively. The cutoff values of TAT, PIC, and TPAI-C for the differential diagnosis of mild–moderate and severe OHSS were 11.5 ng/mL, 2.4 μg/mL, and 5.8 ng/mL, respectively. Based on these cutoff values, eight cases of mild–moderate OHSS exceeded the cutoff values, two of which developed to severe OHSS in the following days. However, of the remaining 17 cases of mild–moderate OHSS patients with negative biomarkers, none subsequently developed severe OHSS.Conclusions: TAT, PIC, sTM, and TPAI-C can be used as sensitive biomarkers in the diagnosis of OHSS. Meanwhile, TAT, PIC, and TPAI-C also displayed remarkable potential in the classification of OHSS. In addition, the levels of TAT, PIC, and TPAI-C above the cutoff values in patients with mild–moderate OHSS might predict a high risk of developing severe OHSS. The reported incidence of OHSS varies markedly, and is estimated to be 0.5–5%, and even up to 10% in high-risk women (Ovarian hyperstimulation syndrome (OHSS) is a major iatrogenic complication associated with controlled ovarian stimulation during sk women . Howeversk women .Hypercoagulability is a common syndrome in patients with OHSS. Moreover, if hypercoagulability develops further, thrombosis may occur, which is the most serious and life-threatening complication of IVF. Thromboembolic disease has been reported in many sites of patients with OHSS, including in the internal jugular, subclavian, axillary, ulnar, popliteal, cortical, mesenteric, coronary, and cerebral vessels –9. To prHowever, according to the existing diagnostic and classification criteria of OHSS, such as the Golan criteria, the guidelines published by the Practice Committee of the American Society for Reproductive Medicine and the Royal College of Obstetricians & Gynecologists, no hemostasis indicators are available –12. CurrThe thrombin-antithrombin complex (TAT), plasmin alpha2-plasmin inhibitor complex (PIC), soluble thrombomodulin (sTM), and tissue plasminogen activator (t-PA)-inhibitor complex (TPAI-C) are four sensitive coagulation and fibrinolysis biomarkers in the hemostatic system. Elevated levels of these have been found in many underlying diseases. TAT, PIC, sTM, and TPAI-C levels are significantly higher in patients with disseminated intravascular coagulation (DIC) than in those with non-overt DIC, and TAT, sTM, and TPAI-C levels are significantly higher in patients with pre-DIC than in those with non-overt DIC . Yuying In this study, we aimed to evaluate the diagnostic and classification value of TAT, PIC, sTM, and TPAI-C for OHSS, and preliminarily evaluate the potential use of these biomarkers in clinical practice in a Chinese population.This study was performed at the Women's Hospital, School of Medicine, Zhejiang University (China) from July 2020 to February 2021. The study protocol was approved by the ethics committee of the hospital . Eligible participants were those who underwent IVF using either the gonadotropin-releasing hormone agonist (GnRHa) long protocol or the GnRH antagonist protocol and suffered from OHSS. The exclusion criteria were data missing from the database; age over 45 years; receiving GnRH agonist trigger or withholding hCG; any known hereditary or acquired thrombotic or bleeding disorder; having already received anticoagulant therapy; and chronic diseases, such as cardiovascular disease or diabetes mellitus.During this period, 83 patients were diagnosed with OHSS, 32 of which were excluded based on the exclusion criteria, and 51 were enrolled in the final study, including 25 patients with mild or moderate OHSS and 26 with severe OHSS, according to Golan and Wasserman's 2009 criteria . All patThe standard treatment protocol for controlled ovarian hyperstimulation (COH) using the GnRHa long protocol or GnRH antagonist protocol was applied to all participants. In the GnRHa long protocol, GnRHa was administered in the midluteal phase preceding the cycle to downregulate estrogen production. Thereafter, COH was performed by the administration of both recombinant FSH (rFSH) and human menopausal gonadotropin (HMG), depending on age, BMI, antral follicle count, size and number of follicles, and estradiol levels. The initial doses of rFSH ranged from 150–225 IU/day, and those of HMG ranged from 75–150 IU/day. The dose was subsequently adjusted depending on the ovarian response, as evaluated by the E2 levels and combined with ultrasound. When at least three follicles reached a mean diameter of 17 mm, 6,500 IU of hCG was injected. The transvaginal ultrasound-guided oocyte retrieval was performed ~36 h after hCG injection.In the GnRH antagonist protocol, rFSH or HMG was injected from the third day of the last menstrual period. The initial doses of rFSH and HMG were the same as those for the GnRHa long protocol, and the dose was subsequently adjusted, depending on the ovarian response. When the dominant follicle diameter was ~12–14 mm, the GnRH antagonist was administered until the day of hCG administration. When at least three follicles reached a mean diameter of 17 mm, 6,500 IU of hCG was injected, and oocyte retrieval was scheduled ~36 h after hCG injection.Blood samples were obtained immediately after OHSS was diagnosed and before any heparin treatment. For the control group, blood samples were obtained ~2 weeks after embryo transfer when the patient visited the hospital for the hCG test. If the hCG level was above 5.3 IU/L , the participant would be followed up throughout the first trimester to ensure that OHSS did not occur, as previously described.g for 10 min, and then PT, APTT, thrombin time (TT), and fibrinogen concentration were measured by the clotting method on the STA-R MAX Coagulation Analyzer (Diagnostica Stago). The rest of the plasma samples were stored at −80°C for the assay of TAT, PIC, sTM, and TPAI-C. The four biomarkers were measured using the HISCL 5000 Automatic Chemiluminescence Immunoanalyzer (Sysmex Corporation) within 6 months. In addition, blood samples were collected in a vacuum tube containing EDTA-K2 (BD Vacutainer Systems) for the measurement of WBCs and Hct. WBC counts and Hct were determined on the Sysmex XN9000 Automatic Hematology Analyzer (Sysmex Corporation). All tests were performed with the original reagents and undertaken according to the manufacturer's instructions.Blood samples were collected in a vacuum tube containing 0.109 M of dehydrated sodium citrate (BD Vacutainer Systems), centrifuged at 2,500 × P-value < 0.05 was considered significant for all comparisons. The Shapiro-Wilk test was used to verify normality. Descriptive statistics are presented as mean ± SD for normally distributed variables and median (25th−75th percentile) for non-normally distributed variables. Parametric (t-test) and non-parametric (Mann-Whitney U test) analyses were performed for normally and non-normally distributed variables, respectively. Spearman's rank correlation analysis was used to analyze the association between the levels of these biomarkers and those of WBCs and Hct. Receiver operating characteristic (ROC) curves analysis was used to evaluate the diagnostic efficiency, and the maximum value of the Youden index served as the cutoff value. Sensitivities, specificities, positive predictive values (PPVs), and negative predictive values (NPVs) were calculated using standard formulas and were expressed as percentages [95% confidence interval (CI)].Statistical analyses were performed using the SPSS 20.0 software. A P = 0.486, P = 0.286, P = 0.805, respectively). The levels of fibrinogen, WBCs, and Hct were significantly higher in the OHSS group than the control group . The levels of TAT, PIC, sTM, and TPAI-C did not demonstrate any significant differences between the two therapeutic protocols .Overall, 51 female patients with OHSS were enrolled in this study, including 25 with mild or moderate OHSS and 26 with severe OHSS. The control group consisted of 55 participants undergoing IVF who did not develop OHSS during the same time period. The baseline clinical characteristics of these participants are shown in P < 0.001, P < 0.001, and P < 0.001, respectively) and the sTM level was significantly lower (P < 0.001) in the OHSS group. The median plasma levels of TAT, PIC, sTM, and TPAI-C (OHSS vs. control group) were 7.4 (2.7–11.6) vs. 0.5 (0.4–0.6) ng/mL, 1.8 (1.2–2.8) vs. 0.4 (0.3–0.5) μg/mL, 5.6 (4.9–6.6) vs. 7.0 (6.4–7.5) TU/mL, and 5.1 (2.9–7.6) vs. 3.5 (2.3–4.6) ng/mL, respectively.As shown in r = 0.531, P < 0.001; r = 0.646, P < 0.001; r = 0.471, P < 0.001, respectively). However, the sTM level was negatively correlated with the WBC level . TAT, PIC, and TPAI-C levels were also positively correlated with the Hct level . There was no significant correlation between sTM and Hct . Based on a comparison, the correlations between the biomarker and WBC levels were higher than those between the biomarker and Hct levels. The correlations between sTM and WBC/Hct levels were lower than those between TAT/PIC/TPAI-C and WBC/Hct levels.As WBC and Hct levels are two routine laboratory indicators in the diagnosis and classification of OHSS, we investigated the correlations between TAT, PIC, sTM, and TPAI-C levels and WBC and Hct levels. As shown in Given the marked changes in TAT, PIC, sTM, and TPAI-C levels in patients with OHSS, we further evaluated them as potential biomarkers for the diagnosis of OHSS using ROC curve analysis. Among the four biomarkers, the highest area under the curve (AUC) was observed for TAT and the lowest was observed for TPAI-C . The optP = 0.004, P = 0.004, P < 0.001, respectively), whereas the sTM level was not significantly different between the two groups (P = 0.940). We further investigated the differential diagnostic value of these biomarkers for mild–moderate and severe OHSS using ROC curve analysis , and 17 had a negative result for all biomarkers . The management measures for these patients in clinical practice involved increasing fluid intake, supportive care, and intensive monitoring . Subsequently, we followed up these patients and found that two of the eight patients with positive biomarkers developed severe OHSS in the following days, and none of the 17 patients with negative biomarkers developed severe OHSS .Accurate diagnosis and classification of OHSS is important for the identification of suitable treatments. However, although a number of diagnostic and classification systems of OHSS have been developed, there are currently no universally agreed upon criteria , 11. FurIn this study, we first investigated the levels of the conventional coagulation tests in patients with OHSS. No significant differences were found in the levels of PT, APTT, and TT between patients with OHSS and control patients. This might be because these tests are designed primarily to screen for coagulation factor deficiencies, rather than hypercoagulability, which is usually related to excessive coagulation factors , 19. AltOur results indicated that TAT, PIC, sTM, and TPAI-C had good diagnostic performance for OHSS; meanwhile, we showed that TAT, PIC, and TPAI-C can also be used to classify the severity of OHSS. TAT is a molecular complex composed of thrombin and antithrombin and is considered to be a sensitive marker of thrombin formation and coagulation activation. PIC is a molecular complex composed of plasmin and alpha2-plasmin inhibitor, and is a marker of plasmin formation and fibrinolysis activation. sTM is not only an indicator of endothelial injury, but can also be combined with thrombin to play an anticoagulant role. TPAI-C is formed through the combination of t-PA and plasminogen activator inhibitor 1, and is a marker of endothelial injury and fibrinolysis activation. Therefore, these biomarkers are highly sensitive coagulation and fibrinolysis indicators and may highlight even minimal hemostatic activation . The datr = 0.646, P < 0.001). Owing to the significant correlations between the biomarkers and WBC levels, Hct levels further confirmed their diagnostic and classification value. The correlations between the biomarker and Hct levels were relatively weak. As Hct mainly reflects hemoconcentration, the relatively weak correlation implies that other mechanisms contribute to the hypercoagulability in OHSS other than hemoconcentration. This is consistent with the results of a study by Zohav et al. . Meanwhile, TAT, PIC, and TPAI-C levels in the severe OHSS group were significantly higher than those in the mild–moderate OHSS group . This revealed that the hypercoagulability in OHSS was a gradual process. Therefore, these biomarkers might have important roles in its classification. The ROC curve analysis results of the present study also supported this. We investigated the differential diagnostic value of these biomarkers for mild–moderate and severe OHSS. Except for sTM, all biomarkers showed significant potential value for the classification of OHSS. The highest AUC was observed for TPAI-C (0.818), with a sensitivity of 73.1% and a specificity of 88%, which suggested that TPAI-C was the most optimal biomarker. The cutoff value for TPAI-C in the differential diagnosis for mild–moderate and severe OHSS was 5.8 ng/mL.The AUCs for the diagnostic biomarkers TAT, PIC, sTM, and TPAI-C were 0.991, 0.973, 0.809, and 0.722, respectively. These biomarkers showed good diagnostic efficiency for OHSS. In particular, the sensitivity, specificity, PPV, and NPV for TAT and PIC were all above 90%, which showed extremely high diagnostic value. Once a diagnosis of OHSS is made, disease severity should be classified. The treatment approach for the clinical management of OHSS is multifaceted and individualized based on disease severity and progression. Most mild and moderate cases of OHSS are self-limited and require only intensive monitoring in the outpatient department; however, severe OHSS requires hospitalization to relieve symptoms and control the progression of the disease , 24. In In this study, to further validate the value of these biomarkers in clinical practice, we followed up the outcomes of the patients with mild–moderate OHSS. There were eight patients with mild–moderate OHSS who exceeded the cutoff values obtained by ROC analysis, two of which developed severe OHSS in the following days. However, of the remaining 17 patients with mild–moderate OHSS with negative biomarkers , none subsequently developed severe OHSS. These results indicated that the patients with mild–moderate OHSS with positive biomarkers were at a high risk of developing severe OHSS; namely, the presence of positive biomarkers in patients with mild–moderate OHSS might predict a poor prognosis. Considering that the treatment approach for OHSS is multifaceted and individualized based on disease severity and progression, these biomarkers could help identify high risk patients with mild–moderate OHSS who need to be more closely monitored and who may even require early prophylactic anticoagulant therapy.In addition, the clinical application of these biomarkers has been markedly restricted owing to the inconvenient and inefficient detection methodology used in the past. Currently, with the development of the high-sensitivity chemiluminescence immunoassay, these biomarkers can be detected quickly and automatically in a clinical laboratory. For the test used in this study, the minimum volume for a sample was 20 μL, and the results were available within 17 min. The improvement of the methodology will facilitate the spread of these biomarkers to thousands of laboratories in China.There were some limitations in this study. The sample size was not sufficiently large, especially after grouping. Therefore, larger sample studies are needed. Another limitation is that all participants were subjected to a single sampling. If a series of sampling is performed at different time points, such as during COH, on the day of hCG administration, and on the oocyte retrieval day, this will allow the evaluation of the value of these biomarkers more comprehensively, which may be the focus of our future studies.In conclusion, we found that TAT, PIC, sTM, and TPAI-C can be used as sensitive biomarkers in the diagnosis of OHSS. Meanwhile, TAT, PIC, and TPAI-C also displayed remarkable potential in the classification of OHSS. In addition, the levels of TAT, PIC, and TPAI-C above the cutoff values in patients with mild–moderate OHSS might predict a high risk of developing severe OHSS.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 the Women's Hospital, School of Medicine, Zhejiang University (China). Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.SLi, YQ, and SLu conceived the idea and designed the study and drafted the article. SLu revised the article. YP and KW contributed the collection and analysis of the data. All authors have 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.


Proper and regular physical activity (PA) plays an important role in improving people’s health. With the outbreak of the COVID-19 pandemic, which has posed a serious threat to individual health, residents’ PA has aroused deep concern. Based on the theory of planned behavior, this study examines the impact of residents’ PA intention and behavior in response to the COVID-19 pandemic. Data were collected from a sample of 961 residents in Wuhan in China using a questionnaire survey. The results show that residents’ PA intention and behavior have been affected significantly by residents’ PA attitude, subjective norms, and perceived behavioral control. The COVID-19 pandemic has a significant impact on both residents’ PA intention and behavior. In addition, there were gender and region differences in this impact. The findings are of great significance in promoting residents’ PA intention and PA behavior, which are of positive significance to the development of residents’ physical and mental health in the period of global serious health crisis. Previous studies have shown that proper and regular physical activity (PA) could not only maintain physical health but also help people mediate anxiety and depression, release pressure, and improve the immune system to prevent the serious complications of pandemic . PA is dSo far, the COVID-19 pandemic has posed a serious threat to individual health, which has led to more than 200 million confirmed cases and 5 million deaths . It has Studies have found that PA behavior is significantly affected by the social environment, individual intention, and other personal characteristics . In addiBased on TPB, this study focuses on residents’ PA intention and PA behavior and their influencing factors before and after the outbreak of the COVID-19 pandemic to understand the impact of the COVID-19 pandemic on residents’ PA intention and behavior. In this study, Wuhan in China, which is one of the earliest outbreak cities of the COVID-19 pandemic and the earliest city to implement “lockdown” with suspending all the traffics, shops, factories, and schools on January 23, 2020, has been chosen to be the research region. The city has been unsealed since April 8, 2020, with the COVID-19 pandemic under control. In addition, the residents in Wuhan, which refer to those who have resided in Wuhan for at least 1 year from 2019, had gone through the most impressive experience of influences of the COVID-19 pandemic, especially self-isolation at home. This study puts forward the research hypotheses H1–H5 as follows.H1: Residents’ PA intention has a significantly positive impact on residents’ PA behavior.H2: Residents’ PA attitude, SN, and PBC have significantly positive impacts on residents’ PA intention.H3: Residents’ PA intention has been significantly influenced by the COVID-19 pandemic.H4: Residents’ PA behavior has been significantly influenced by the COVID-19 pandemic.H5: There are gender and urban—rural differences in residents’ PA intention and behavior under the influence of the COVID-19 pandemic.I plan/intend/hope to do physical activity for at least 20 min at least three times a week in the next 2 weeks.” The attitude of PA is measured by five items, including “It is satisfying/pleasant/enjoyable/useful/important to me at least 20 min of physical activity at least three times a week for the next 2 weeks.” SNs are measured by three items, including “Most people who are important to me will happy when I do physical activity in the next 2 weeks, for more than three times a week, each time for at least 20 min,” “Most people who are important to me approve of me doing the above physical activity,,” and “Most people who are important to me hope me to do physical activity.” PBC of PA is measured by four items, namely, “It is easy for me to do the above physical activity,” “I can accept myself to do the above physical activity,” “It is beyond my ability to do physical activity”, and “I can control myself to do physical activity.”Residents’ PA intention, attitude, SN, and PBC are measured based on the TPB-related structure scale developed by strongly disagree” 1 to “strongly agree” 5. The original questionnaire was translated into Chinese by 4 bilingual scholars with more than 5 years of experience in translation and cross-cultural identification to ensure consistency between the two translated versions. The validity was evaluated by 10 experts, and a preliminary study was conducted on 30 volunteer participants. Based on the preliminary test, the questionnaire was modified to clarify the ambiguity.The internal consistency of the original measurement was 0.85 . All itelight physical activity intensity”, “light physical activity with not too intense intensity”, “moderate and mild physical activity with more intense and persistent intensity”, “heavy but not persistent physical activity with shortness of breath and sweating a lot”, and “heavy and persistent physical activity with shortness of breath and sweating a lot”. Duration level is divided as ≤10, 11–20, 21–30, 31–59, and ≥60 min, respectively. Frequency includes “once a day”, “3–5 times a week”, “1–2 times a week”, “2–3 times a month”, and “once a month or less”. The three dimensions of PARS-3 just meet The WHO Guidelines on physical activity and sedentary behavior, which provide recommendations for people on the amount of PA  (The PARS-3 proposed by uration) .PA level = Intensity × (Duration-1) × Frequency  and the second time after the outbreak and lockdown of the COVID-19 pandemic  in the same community. Our sample included only residents aged 5 or older who claimed to reside in Wuhan during the period from June 2019 to June 2020. A total of 1,053 responses were collected with an effective rate of 91.3%, in which 92 responses were invalid and 961 responses were valid. Questionnaires were issued anonymously, and the content of the questionnaires was strictly confidential and can be used only for academic research. In the survey, 53.3% of residents were men and 46.7% were women, with ages 5–17, 18–34, 35–59, and 60 and above as 11.3, 26.5, 39.4, and 22.7%, respectively. The proportion of urban and rural residents was 50.2 and 49.8%, respectively refer to .p ≤ 0.05, the result was considered statistically significant  and composite reliability (CR) were adopted to examine reliability , and theThe test of validity included convergence validity and discriminant validity . Standart-test analysis, only gender and urban-rural demographic variables were significant. Therefore, this study compared the differences in PA in gender and urban-rural before and after the pandemic. Gender was divided into two groups, namely, male and female, to study the difference in PA. The homogeneity of variance test showed that data of the two groups before and after the lockdown had homogeneity of variance . The t-test results showed t(df)before = 3.424(959), p = 0.001 < 0.05, t(df)after = 2.473(959), p = 0.014 < 0.05. Both before and after the pandemic, the scores of male residents’ PA was higher than that of female residents. However, after the pandemic, the difference in the score between male and female residents was smaller. The scores of male residents’ PA declined, while the scores of female residents’ PA increased. The region was divided into two groups to study the difference in PA between urban and rural. The homogeneity of variance test showed that data of the two groups before and after the pandemic had homogeneity of variance . The t-test results showed t(df)before = −3.317(826.473), p = 0.001 < 0.05, t(df)after = −1.472(959), p = 0.141 > 0.05. Both before and after the pandemic, the scores of rural residents’ PA were higher than that of urban residents. However, after the lockdown, the difference between urban and rural scores was smaller. The scores of rural residents’ PA declined, while the scores of urban residents’ PA increased   was used to determine the collinearity of independent variables. refer to .Fbefore = 164.600, p < 0.001, R2 = 0.146, Fafter = 203.806, p < 0.001, R2 = 0.175)  was passed. The regression model was verified to have a good fit . The following regression equation was used: PAbefore = 3.432 * INT-9.875, PAafter = 3.534 * INT-10.928. In other words, when the intention increases by 1 unit, the behavior will increase by 3.432 and 3.534 units, respectively. When the intention increases to a certain extent , the behavior of PA after the pandemic increases significantly compared with that before the pandemic. In terms of the PA level, the moderate level of PA increased slightly from 32.5 to 32.8%, the low level of PA decreased slightly from 30.1 to 29.8%, and the vigorous level of PA did not change significantly (37.5%). In addition, the results showed that the amount of residents’ PA (32.62 ± 25.35) reduced before the pandemic (32.79 ± 26.10), and the average amount of residents’ PA after was 0.17, which was lower than that before the pandemic. Specifically, after the pandemic, residents’ PA intensity decreased (Mbefore = 3.01 > Mafter = 2.99), while the frequency (Mbefore = 3.67 < Mafter = 3.68) and duration (Mbefore = 3.46 > Mafter = 3.50) increased slightly. Hypothesis 1 and 3 were verified.Residents’ behavior intention had a statistically significant impact on the behavior of PA before and after the pandemic  and PBC  had statistically significant effects on intention, and the regression equation was INT = 0.506 * ATT-0.018 * SN + 0.09 * PBC + 0.725. After adjusting the collinearity changes of attitude, PBC, for every unit increase of attitude and PBC, residents’ intention before and after the lockdown increased by 0.506 and 0.09 units, respectively. After the pandemic, attitude , SN , and PBC  had statistical significance on intention. The regression equation was INT = 0.456 * ATT + 0.115 * SN + 0.078 * PBC-0.073. After adjusting the collinearity of attitude, SN, and PBC, residents’ intention before and after the pandemic intention increased by 0.456, 0.115, and 0.078 units, respectively. Hypothesis 2 and 4 were verified.Among the three included independent variables, before the pandemic, residents’ PA attitude  whether before or after the pandemic, residents’ PA intention has a significantly positive impact on PA behavior; (ii) residents’ PA behavior has decreased after the outbreak of the COVID-19 pandemic and there are notable gender and region differences in the aspect of physical activity behavior of residents; and (iii) there are significant changes in residents’ PA intention due to the influence of the COVID-19 pandemic. Before the pandemic, residents’ PA attitude and PBC have a significantly positive impact on residents’ PA intention. However, after the pandemic, besides residents’ PA attitude and SNs, the PBC has a significantly positive impact on residents’ PA intention.Whether before or after the pandemic, residents’ PA intention has a significant impact on PA behavior. Studies have confirmed that the outbreak of pandemics did reduce residents’ PA . AccordiThe outline of the “Healthy China 2030” plan published by the government of China calls for a wide range of public participation in PA with specific requirements such as ensuring that students should participate in PA for more than 1 h at school and participate in PA at moderate intensity at least three times a week (home scientific fitness guide, which suggests children practice physical activities indoors such as standing on one foot or crawling movement; teenagers do 1 h indoor PA every day, such as fitness and aerobics; healthy adults do 150 min of indoor PAs at least 3 days a week, such as walking, jogging, or Qigong; and the elderly do 150 min of indoor PAs, such as tai chi or softball, at least 3 days a week (Residents’ PA intention is affected by attitude, PBC, and SNs. An interesting finding is that before the pandemic, residents’ PA, attitude, and PBC had a significant impact on residents’ PA intention, in which PA attitude has a greater impact on residents’ PA intention, while SNs have no significant impact. This is consistent with the existing studies that residents’ positive or negative evaluation of participating in PA, as well as their perception of their ability, experience, and opportunity to participate in PA, will affect their PA intention and behaviors . After ts a week . The govs a week .From what has been discussed above, residents’ PA intention and behavior have been significantly influenced by the COVID-19 pandemic, and residents’ PA intention has been directly influenced by residents’ PA attitude, PBC, and SNs. Although the residents’ PBC has decreased, the function of SNs comes into play.According to the study results, multiple and effective measures need to be put forward. First, guiding residents to form more positive attitudes, SNs, and stronger PBC. Second, promoting health education and publicity of the importance and usefulness of PA to guide residents to form correct cognition and positive attitude by international organizations and governments. Third, strengthening the role of the Internet through popularizing home PA guidelines, prompting online courses according to the needs of different groups, cultivating residents’ interest and confidence, and eventually guiding residents to form a PA habit. Last but not least, giving full play to the role of family through creating a good family atmosphere to guide family members to participate in PAs and enhancing family immunity.The generalization of these results, which is subject to certain limitations, provides avenues for future research. One of the limitations in this study, which could have affected the measurements, was the tested sample. This study chose 961 residents in Wuhan as the research object group. Although the internal consistency fell above an acceptable level, the relatively small sample size used in the study cannot be a general adaption to the whole situation. Given this, studies could be carried out in a broader population. Moreover, more accurate PA measurement tools should be considered based on more critical appraisal and consideration within the limitations to increase the validity and reliability of studies. Third, more changing factors such as the types of PA practiced by residents could be considered to conduct further research.Notwithstanding these limitations, the study has offered some insight into promoting residents’ PA intention and behavior, which are of positive significance to the development of residents’ physical and mental health in the period of global serious health crisis. This would be a fruitful area for further work.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The questionnaire data were collected anonymously in this study, and the questionnaire filling was voluntary. The subjects were promised that the questionnaire data would only be used for academic research and kept strictly confidential. The participants provided their written informed consent to participate in this study.XC: mainly responsible for data collection, analysis, and manuscript writing. WC: responsible for the revision, proofreading, and supervision of the study. Both 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.


Cardiogenic shock accounts for ~100,000 annual hospital admissions in the United States. Despite improvements in medical management strategies, in-hospital mortality remains unacceptably high. Multiple mechanical circulatory support devices have been developed with the aim to provide hemodynamic support and to improve outcomes in this population. Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is the most advanced temporary life support system that is unique in that it provides immediate and complete hemodynamic support as well as concomitant gas exchange. In this review, we discuss the fundamental concepts and hemodynamic aspects of VA-ECMO support in patients with cardiogenic shock of various etiologies. In addition, we review the common indications, contraindications and complications associated with VA-ECMO use. The primary objective of this paper is to provide a comprehensive review of veno-arterial extracorporeal membrane oxygenation (VA-ECMO) use in the management of adult patients with refractory cardiogenic shock (CS).Cardiogenic shock is commonly defined as a state of low cardiac output that is inadequate to support the systemic perfusion requirements in the context of normal cardiac filling pressures. Organ hypoperfusion is a central feature of CS. The resultant tissue ischemia and reduced nutrient delivery, if persistent, may lead to multi-organ failure including altered mental status, oliguria with <30 cc/h urine output, narrow pulse pressure, and arterial lactic acid level exceeding 2 mmol/L , 2.Historically, clinicians and investigators established the presence of CS by using a combination of select abnormal hemodynamic parameters and evidence of end-organ dysfunction. Consequently, various landmark clinical trials employed different definitions to diagnose CS2 or <2.2 L/min/m2 with hemodynamic support); and (IV) low mixed venous blood oxygen saturation signaling increased peripheral oxygen extraction due to hypoperfusion  and was established based on a combination of distinct hemodynamic parameters detailed above. However, it became increasingly clear that the clinical condition of patients meeting the minimum criteria of CS are extremely heterogenous. It may include outpatients with low cardiac output, those requiring a single inotrope infusion as well as end stage patients needing biventricular mechanical circulatory support (MCS). Recognizing the continuum of hemodynamic instability in this population, the Society for Cardiac Angiography and Intervention (SCAI) recently published an expert consensus statement defining five stages of CS ranging from at risk to extremis , 36. A cAccurately pinpointing the prevalence of CS is challenging and varies based on the era the data was collected and the definition used , 37, 38.Acute coronary syndrome is the most frequent cause of CS, representing 80% of all cases . While mWhile the incidence of post-MI CS has declined over the past decades, there has been a concomitant increase in the incidence of CS caused by other etiologies . The mosMultiple MCS devices have been developed over the past decades with the aim to provide various levels of hemodynamic support to improve the devastating morbidity and mortality associated with CS. The fundamental assumption is that ventricular support and decompression leads to a reduction in myocardial wall stress and oxygen consumption, while concurrently augmenting end organ perfusion.Several types of MCS devices are used in routine clinical practice. The intra-aortic balloon pump (IABP) was first developed in the 1960s and remains the most frequently utilized percutaneous temporary MCS device . While i2) clearance via sweep gas flow. This latter function is a critical distinguishing feature from other MCS strategies, such as IABP and pVADs. VA-ECMO may also be placed surgically, especially in the post-cardiotomy setting, when oxygenated blood is returned directly into the ascending aorta . However, this review focuses primarily on the use of peripherally placed VA-ECMO as this is the most common type of support instituted by cardiologists in the setting of cardiac arrest or refractory CS.VA-ECMO is a temporary mechanical circulatory support system that enables complete and immediate cardiopulmonary support in the setting of cardiogenic shock and cardiac arrest . It consThe preferred approach for percutaneous VA-ECMO is femoral artery and vein cannulation. In an adult, the tip of an 18–28 Fr cannula draining deoxygenated venous blood is positioned in the mid right atrium (RA) or the superior vena cava-RA junction. After passing through the “membrane lung,” oxygenated blood is returned to the systemic circulation via a 15–19 Fr arterial cannula with its tip typically positioned in the iliac artery. Selecting cannulas with appropriate diameters is critical not only to reduce the risk of vascular injury but also to avoid significant negative inflow (preferably <50 mmHg) and high outflow pressure (<300 mmHg). To mitigate the risk of distal limb ischemia, an 8 Fr distal reperfusion cannula is routinely inserted into the superficial femoral artery in our center and is spliced into the arterial limb of the circuit .Peripheral VA-ECMO is increasingly utilized as a short-term support strategy to manage patients presenting with cardiac arrest, severe biventricular HF and CS stages C-E, independent of etiology . It can VA-ECMO is used in the management of CS due to its capability to reduce myocardial work (pressure-volume area) while providing complete hemodynamic and respiratory support. Myocardial pressure-volume area can be thought of as the sum of myocardial potential energy and myocardial stroke work , 59. BotIn the typical VA-ECMO setup in CS, the venous inflow cannula drains blood directly from the vena cavae or the RA. This significantly decreases right ventricular (RV) preload, trans-pulmonary blood flow and, therefore, left ventricular end-diastolic volume (LVEDV) and pressure (LVEDP) –63. ThusThe use of VA-ECMO also improves systemic perfusion. Typically, mean arterial blood pressure rises after VA-ECMO initiation while the high-volume venous displacement from the RA reduces central venous pressure. The systemic arterio-venous pressure gradient increases as a result, thereby enhancing systemic circulation. This may be particularly relevant to improving blood flow in organs with portal circulation, such as the liver and kidney . Fluid rin vivo.Despite the acknowledged benefits of VA-ECMO, there are still several critical gaps in the literature regarding the hemodynamic implications of prolonged VA-ECMO usage. Most notably, there is an absence of data using invasive ventricular catheterization to define how myocardial work and overall pressure-volume area is affected in the clinical (human) setting. Currently, most published pressure-volume loop data demonstrating the effects of varying levels of VA-ECMO support are based on computer simulations or animal experiments, rather than actual patient data , 66–68. The effect of retrograde arterial flow on LVEDV/LVEDP and LV unloading remains controversial and deserves special mention. Some commentators argue that the retrograde blood flow increases LV afterload by increasing mean arterial BP. This is thought to raise LVEDP, decrease stroke volume, reduce native cardiac output, and render a deleterious effect on LV performance , 68, 69.The populations in which venting devices offer a clear benefit remain largely uncharacterized. The hemodynamics of patients with different HF phenotypes are likely to respond differently to VA-ECMO support, thus creating a differential risk-benefit ratio for the addition of an unloading strategy. Patients with acute CS in the setting of severe, pre-existing HF and elevated left atrial pressure may be best suited for unloading. Moreover, patients with biventricular shock in whom the RV recovers before the LV, may also benefit from unloading. Under these circumstances, the RV may provide increased trans-pulmonary flow prompting a rise in LV preload, despite ongoing VA-ECMO support. The combination of increased preload and afterload may lead to an increase in the LV's myocardial oxygen consumption, thereby supporting the need for an unloading strategy.Despite the widespread use of early revascularization strategies, 6–10% of patients with acute coronary syndrome will progress to develop CS, representing 60–80% of all CS cases , 15, 71.The in-hospital mortality of post-MI patients with CS approaches 70–80% with traditional management, including vasoactive agents and IABP , 16, 17.Ventricular septal rupture (VSR) is a rare but dreaded complication of acute STEMI. It typically develops within 1–5 days after the STEMI and confers ~90% mortality  due to tThe timing of VA-ECMO cannulation is of paramount importance in this population. It should be initiated within 60 min of the recognition of refractory CS, especially if initial attempts at hemodynamic stabilization with fluid resuscitation and pharmacological agents fail . PreferaAcute fulminant myocarditis is a relatively uncommon, but severe condition characterized by the sudden and profound inflammation of the myocardium. Although the exact pathogenesis often remains obscure, myocyte edema and necrosis develop in response to various infectious and non-infectious triggers. The ensuing hypotension may progress to refractory cardiogenic shock within 2 days to 2 weeks of the initial insult. Owing to the profound hemodynamic instability and biventricular failure, escalating doses of vasoactive medications and IABP are often insufficient to maintain sufficient organ perfusion. VA-ECMO is an invaluable asset in the management of these patients. It may limit ongoing myocardial damage by providing prompt and effective circulatory support until the inflammatory storm subsides. Although VA-ECMO may serve as a bridge to durable left ventricular assist device (LVAD) or heart transplantation, full cardiac recovery is common within seven to 10 days in patients with fulminant myocarditis. With the exception of giant cell myocarditis, disease recurrence is uncommon and medical management is effective.The available data also reflect a relatively positive prognosis in this population. In a multicenter, retrospective study of 57 patient with fulminant myocarditis, the mean duration of VA-ECMO support was 9.9 ± 19 days. 71.9% of patients were successfully discharged from the hospital and 5-years survival rate reached 65.2% . Another2 and serotonin released from activated platelets lead to an acute increase in pulmonary vascular resistance  continues to rise and it remains one of the leading causes of cardiovascular death in the US , 102. Mosistance , 107. Assistance . The ass2 elimination, returns it to the arterial system bypassing the pulmonary circulation. Therefore, it reduces RV strain, stabilizes the PA pressure, increases systemic perfusion and normalizes gas exchange.Most patients with massive PE and shock die within the first hour of presentation . TherefoTo date, only a limited number of studies are available on the use of VA-ECMO in the setting of massive PE. These are mostly case reports and case series , 111 andCoronavirus disease 2019 (COVID-19) was declared a pandemic by the World Health Organization on March 11, 2020. The causative virus, SARS-CoV-2 is highly infectious with a case fatality rate approaching 5.94% in the United States , 120. AlGiven the prior use of VA-ECMO in patients with H1N1-associated myocarditis, several centers implemented VA-ECMO support for COVID-19-related CS. Given the extreme number of infections and limited resources, the Extracorporeal Life Support Organization (ELSO) has released guidelines on the contraindications for VA-ECMO use in this population , 130. ThRecent reports suggest that only 5% of ECMO-supported patients for COVID-19 infection required VA configuration, while the need for VAV cannulation was reported in 6% , 133. AsIn the case of respiratory failure and severe right ventricular dysfunction with preserved LV function, a veno-venous cannulation strategy with an oxygenator spliced into the circuit may be considered . A retrospective study by Mustafa and colleagues showed a mortality rate of 15% in 40 patients with most achieving freedom from ventilator care and ECMO support . FurtherVA-ECMO is increasingly utilized as a support strategy in the setting of out-of-hospital and in-hospital cardiac arrest. The provision of early extracorporeal cardiopulmonary resuscitation (ECPR) can maintain vital organ perfusion during and immediately after the arrest. In addition, ECPR provides full hemodynamic and respiratory support while reversible causes of the cardiac arrest are addressed and allows time for patients to recover from multi-organ failure .Data regarding this approach has been available in the literature for over a decade. Survival rates for out-of-hospital cardiac arrest with ECPR use have varied widely from 7 to 45% –149. TheSeveral observational studies from the Minnesota Resuscitation Consortium (MRC) support the use of ECPR strategy for select patients. Early data from the group described the feasibility of community-wide implementation of an ECPR approach . It was p = 0.0063)  of 36 patients with out-of-hospital cardiac arrest due to refractory VT/VF. Patients were randomized to receive ECPR or standard ACLS on presentation. Patients in the VA-ECMO-facilitated resuscitation cohort had significantly higher in-hospital (43 vs. 7%) and post-discharge survival at 6-months  . This wa 0.0063) –155.Sepsis in the setting of underlying cardiomyopathy. Hemodynamic collapse may develop as the left ventricle is unable to augment cardiac output to counteract the severe vasodilation. Limited data has shown a benefit for VA-ECMO use in selected patients  patients , 7, 156 patients ; (II) Pr setting , 158  OAlthough peripheral VA-ECMO is a promising strategy that provides life support to patients with refractory CS, its use may be associated with potentially devastating complications. Some of these are preventable. Here, we review some of the common complications encountered while initiating or managing patients on VA-ECMO.ex vivo thrombus formation, (III) Shear stress-associated platelet activation, (IV) Consumptive coagulopathy, (V) Constant activation of the fibrinolytic system, (VI) Systemic inflammatory response in the setting of CS and cardiac arrest, (VII) Infections and sepsis especially in the setting of prolonged support, and (VIII) Trauma associated with CPR and invasive procedures.Bleeding is the most common complication reported in patients supported with VA-ECMO. In addition to access site bleeding, the risk of systemic hemorrhage is inherently increased in this population. Upper and lower gastrointestinal bleeding, hemopericardium, hemothorax, intra- and retroperitoneal hemorrhage and intracranial bleeding are the most frequent. It may be attributed to a combination of factors: (I) Acquired coagulopathy owing to blood exposure to artificial MCS surfaces, (II) Anticoagulation strategies used to reduce the risk of 3 and replacing coagulation factors as needed also reduces bleeding risk significantly.There is no clear consensus on anticoagulation strategy with VA-ECMO use and practice differs significantly between centers and individual patients. The risk of thrombosis and hemorrhagic complications must be balanced in the clinical context. Similar to our center, the most commonly reported strategy is the use of intravenous heparin for the duration of VA-ECMO support. However, the use of bivalirudin and novel anticoagulants have also been described . Adding Although thromboembolic complications have decreased in recent years with the introduction of biocompatible materials, they are still common and may have devastating clinical consequences, such as stroke , 164. InThe rate of access site complications is reported at around 20% and are mostly related to the urgent need to establish large-bore peripheral vascular accesses , 171. ThAnother serious vascular complication associated with peripheral VA-ECMO use is ipsilateral lower extremity ischemia. The clinical presentation often includes pallor, cool extremity, and gangrene development. Pain and neurological deficits may be difficult to assess owing to the sedation while patient is on VA-ECMO. A pooled analysis of 20 studies including 1,866 patients supported with VA-ECMO for CS or cardiac arrest reported a 16.9% (12.5–22.6%) incidence of lower limb ischemia; the risk of compartment syndrome or need for fasciotomy was 10.3% (7.3–14.5%). Lower extremity amputation was necessary in 4.7% (2.3–9.3%) of patients . SeveralAccess site infections may occur in 7–20% of patients with femoral VA-ECMO support , 174. MeNorth-South Syndrome is a complication unique to peripheral VA-ECMO . It may Acute renal failure is frequent in patients supported with VA-ECMO (55.6%) and is associated with increased mortality . SeveralInfections are one of the most common complications in patients supported with VA-ECMO with a reported prevalence between 9 and 65% –188. AccOne disadvantage of prolonged hemodynamic support via the femoral approach is the need for patient immobility to reduce the risk of cannula kinking and dislodgement. In an alternative VA-ECMO configuration, the venous drainage cannula is inserted through the right internal jugular vein and oxygenated blood is returned into the subclavian or axillary artery using an end-to-side vascular graft. While this strategy allows for extended support while ensuring appropriate cerebral perfusion and, potentially, patient ambulation, ipsilateral arm hypoperfusion is reported in 20% of patients. While early detection of arm hypoperfusion and compartment syndrome may prove challenging in the setting of continuous blood flow and vasoactive medication use, it is essential to avoid limb ischemia.Another complications that is not necessarily related to VA-ECMO include hyperbilirubinemia (12.2%) . MonitorFollowing a few days of full cardiorespiratory support, decannulation may be considered once the initial condition necessitating VA-ECMO improved or resolved and vasoactive medications are reduced to a minimum or off. Regular weaning trials are performed to assess the patient's hemodynamic response to incremental decrease in support. However, to date, the literature on VA-ECMO weaning strategies and timing is limited and is often driven by institutional experience –197. In While VA-ECMO represents a potentially lifesaving intervention for acutely unstable patients, absolute and relative contraindications should be considered. Absolute contraindications are few and, in general, include life expectancy <1-year, acute or preexisting conditions that are incompatible with recovery and VA-ECMO weaning  or if individual patient goals-of-care are not compatible with such level of cardiorespiratory support. Relative contraindications include advanced age (>75 years), unrepaired aortic dissection as the retrograde high velocity flow may further propagate the dissection flap, severe aortic regurgitation as this may lead to progressive left ventricular distension, advanced peripheral vascular disease when peripheral cannulation is considered, and contraindications to systemic anticoagulation . CautionHaving an exit strategy from VA-ECMO support is critically important and should always be considered before cannulation. Lack of such strategy may be considered a contraindication for cannulation. Broadly, the goals of VA-ECMO may be divided into bridge to recovery or bridge to advanced heart failure therapies (such as LVAD placement or heart transplantation). Defining the goals is complex with a multitude of factors contributing, such as clinical reason for hemodynamic collapse, end organ function, age, patient wishes and values. In addition, the chance of meaningful recovery may be unclear at the time of cannulation. When possible, discussion should be held with patient, family and multidisciplinary team using best clinical judgement to define the exit strategy as early as possible.The stagnant in-hospital mortality rates for CS over the past several decades has highlighted the need to develop increasingly granular risk stratification models and to introduce novel MCS strategies to improve outcomes for these patients.In response to these critical needs, multiple steps have been taken. SCAI has published a novel classification schema for CS (Stage A-E) in 2019 . It was Ultimately, the combination of better risk stratification of CS and the emergence of novel MCS strategies may improve outcomes and survival in the most severe cases of CS (SCAI Stages C-E). Accordingly, European and US guidelines on the use of VA-ECMO in patients with CS are evolving and we anticipate updates in the near future as more data becomes available , 207–209Cardiogenic shock leads to ~100,000 hospitalizations each year in the United States alone with a significant proportion of these patients dying during the index admission. While acute coronary syndrome remains the most common underlying cause, the incidence of cardiogenic shock due to other etiologies has been increasing in recent years. Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is the most advanced temporary life support system that can uniquely provide full hemodynamic as well as respiratory support. Our paper provides a comprehensive review on the epidemiology and evolving definition of cardiogenic shock, including the most recent classification system introduced by the Society for Cardiac Angiography and Intervention (SCAI). We discuss the system components, cannulation strategies and hemodynamic aspects of VA-ECMO support in the context of contemporary observational and randomized data. Subsequently, we summarize the most common indications, contraindications and complications related to VA-ECMO usage.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.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.


Background: Elite athlete's heart is characterized by a greater left ventricular mass indexed by body surface area (LVMI) and diastolic function; however previous studies are mainly conducted in non-Asian athletes compared to sedentary controls.Methods: This study included 1,388 male adults, aged 18–34 years, enrolled in the same unified 6-month physical training program in Taiwan. During the midterm exams of 2020, all trainees completed a 3-km run (endurance) test, and 577 were randomly selected to attend a 2-min push-up (muscular strength) test. Elite athletes were defined as the performance of each exercise falling one standard deviation above the mean (16%). Cardiac structure and function were measured by echocardiography and compared between elite and non-elite athletes. Multiple logistic regression analysis was used to determine the independent predictors of elite athlete status at each exercise modality.Results: As compared to non-elite controls, elite endurance athletes had greater LVMI  and lateral mitral E'/A' ratio  with lower late diastolic A' . Elite strength athletes had greater LVMI  and lateral mitral E'/A' ratio  with a greater early diastolic E' . Greater LVMI and lower heart rate were independent predictors of elite endurance athletes . Greater LVMI, lateral mitral E'/A' ratio and right ventricular systolic pressure were independent predictors of elite strength athletes .Conclusions: Cardiac structural and functional characteristics differ between endurance and strength elite athletes. While greater LVMI predicts elite status in both groups of Asian athletes, consistent with findings from Western elite athletes, greater diastolic function, and right ventricular systolic pressure characterize strength elite athletes, while lower heart rate at rest predicts endurance elite athletic status. Aerobic and anaerobic fitness have been associated with cardiovascular (CV) health and mortality in the general population , 2. The Previous reports have revealed racial differences in the physiologically cardiac adaptions to regular exercise and to LV pressure overload –11. For The cardiorespiratory fitness and hospitalization events in armed forces study (CHIEF Heart Study) included 1,388 military males, aged 18–34 years, from the ROC Army Huadong Defense Command Base, in Taiwan in January 2020 –17. All 2). Mean blood pressure (BP) of each participant at rest was defined as (2 × diastolic BP + 1 × systolic BP) divided by 3. Body surface area was calculated as 0.20247 × body height (m)0.725 × body weight (kg)0.425 according to the Dubois formula (Measurements of body height and body weight of each study participant were performed in a standing position. Body mass index was defined as body weight (kg) divided by body height squared  and relative humidity (%) × 0.1 was <40 and the weather was not raining.The muscular strength capacity of each participant was investigated by the 2-min push-up performance . The upw3 – LVIDd3} + 0.6. LV hypertrophy for males was defined as the LV mass indexed by body surface area (LVMI) ≥88 g/m2 based on the Dubois formula  was performed by the same experienced technician under the supervision by the certificated cardiologist at the Hualien-Armed Forces General Hospital. Measurements of cardiac structure such as LV wall thickness and chamber dimensions were based on the recommendations of the American Society of Echocardiography . LV mass formula , 22. Rig formula . LV diasP < 0.05 was considered significant. All analyses were performed using SAS version 9.4 . This study was approved by the Institutional Review Board of the Mennonite Christian Hospital (No. 16-05-008) in Taiwan, and written informed consent was obtained from all participants.Elite athletes were defined as the score of each exercise falling one standard deviation above the mean (16%), and the controls were the other physically active males not getting to the level of elite athletes in each exercise (84%). Demographic, anthropometric, ECG and TTE characteristics of the elite athletes and the non-elite controls were expressed as mean ± standard deviation for continuous variables and numbers (%) for categorical variables, respectively. Continuous variables were compared by analysis of variance (ANOVA) and categorical variables were compared by chi-square or Fisher's exact test. Dimensions of cardiac chambers and wall thickness were compared utilizing analysis of covariance (ANCOVA) with adjustment for body surface area. Multiple logistic regressions were used to determine the odds ratio (OR) of the TTE characteristics with the elite athletes to non-elite controls. In model 1, age, smoking, LVMI, RVSP, and lateral mitral E'/A' ratio were adjusted. In model 2, BMI was additionally adjusted. In model 3, mean BP was additionally adjusted. In model 4, heart rate was further adjusted. A two-tailed value of There were 233 males (16.8%) classified as elite endurance athletes who spent <780 s for a 3-km run and the other 1,155 physically active males (93.2%) were classified as non-elite controls . In addip < 0.001) according to the Soklow-Lyon voltage criterion (p = 0.03) (In riterion . Elite s = 0.03) .2, p < 0.001) and lateral mitral annulus E'/A' ratio  with lower late diastolic A' . In contrast, elite strength athletes had greater LVMI , lateral mitral E'/A' ratio  with greater early diastolic E'  and RVSP .In This study is the largest report to date to demonstrate the cardiac structure and function in Asian male athletes and compare them to physically active controls and to determine the predictors or eliteness based on endurance and muscular strength. The main findings in the present study were that elite endurance male athletes had greater LVMI and LV diastolic function which might be due to reduced heart rate. Greater LVMI, and lower heart rate and BMI were the independent predictors of falling in the elite endurance category. Elite strength male athletes also had greater LVMI and LV diastolic function; greater LVMI, lateral mitral E'/A' and RVSP were the independent predictors of being in the elite strength category.Both elite endurance and strength athletes had greater LVMI, and endurance athletes had greater LV chamber size, which were consistent with the findings in prior studies , 25. MecWith regard to the enhanced LV diastolic function, the present study for elite Asian male athletes showed consistent results that elite endurance athletes had slightly greater E/A ratio due to a decrease in peak A wave velocity, and elite strength athletes had similar E/A ratio compared to their non-elite controls . In addiThe major strength of the present study was that the male participants were enrolled in the same army camp in Taiwan where the training program was standardized. In addition, since the army base is a closed system, the living environment for the participants is very similar and their daily schedule, such as the wake up time, bed time, meal time and the frequency of sentry duty is unified. Third, the detailed information for the baseline confounders to both physical fitness and cardiac structure and function, such as tobacco smoking and alcohol consumption, were considered in this study, which could reduce a potential bias. By contrast, there were merely 36.8% of the overall males randomly selected to attend the push-up test, possibly leading to a selection bias, despite that the baseline characteristics between those with and without attending the push-up test were similar . Second,Our study uncovered that cardiac structural and functional characteristics differ between endurance and strength elite athletes in a physically active Asian male population. While greater LVMI predicts elite status in both groups of Asian athletes, consistent with findings from Western elite athletes, greater diastolic function and RV systolic pressure characterize strength elite athletes, while lower heart rate at rest predicts endurance elite athletic status.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.This study was approved by the Institutional Review Board of the Mennonite Christian Hospital (No. 16-05-008) in Taiwan, and written informed consent was obtained from all participants. The patients/participants provided their written informed consent to participate in this study.P-YL and G-ML wrote the paper. K-ZT made the statistical analyses. JL and CL raised critical comments for the paper and edited the manuscript. G-ML was the principal investigator for the study. All authors contributed to the article and approved the submitted version.This study was supported by the Medical Affairs Bureau Ministry of National Defense and Hualien Armed Forces General Hospital, Taiwan, under the grants MND-MAB-110-148 and HAFGH-D-110008.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.


Diastolic dysfunction has been reported as a cardiovascular effect of hyperthyroidism, and is also supposed to be a cause of heart failure manifestations in the patients with preserved ejection fraction (EF).For evaluation of diastolic function in hyperthyroid patients and also diastolic function during performing exercise stress echocardiography, we conducted this study on 25 newly diagnosed hyperthyroid patients compared to 26 healthy subjects as control group. Diastolic function of the patients at rest was assessed using these parameters as follows: left atrium volume index, tricuspid regurgitation (TR) velocity, mitral inflow early diastolic flow (E wave), tissue Doppler of mitral annular velocity (e′), E/e′ ratio, and isovolumic relaxation time (IVRT); and during exercise stress echocardiography, we judged diastolic response by measuring E/e′ ratio and TR velocity at the peak of stress.The mean age of the patients was 39.64 ± 12.23 years old and 52% of them were female. History of exertional dyspnea was found in 64% of patients. All the patients had normal diastolic function at the time of resting and there was no significant difference in diastolic parameters between the two groups except for IVRT, which was lower in hyperthyroid patients. Interestingly, no patients developed diastolic dysfunction during exercise stress echocardiography.Our finding did not show diastolic dysfunction in hyperthyroid patients neither at rest nor during exercise echocardiography and did not support the hypothesis that diastolic dysfunction can be a cause of exertional intolerance and dyspnea in the patients with preserved EF. Hyperthyroidism is defined as a clinical condition that resulted from abnormal high serum thyroid hormone levels . Any incHemodynamic effects of hyperthyroidism increased heart rate (HR), reduced peripheral vascular resistance, and increased preload, stroke volume, and consequently cardiac output . Thus caMore common cardiac manifestations of hyperthyroidism that was documented in various studies are systolic hypertension, left ventricular (LV) hypertrophy, increased LV mass, heart failure, and cardiac arrhythmia including atrial fibrillation ,2,5,6; hThis case-control study was conducted on 25 newly diagnosed and untreated hyperthyroid patients in comparison to 26 healthy. Also, age and sex were matched in subjects as control group in the Rajaie Heart center echo lab. Patients were referred to us for evaluation of cardiovascular status from outpatient clinic of Loghman Hakim Hospital Endocrinology Department. The recruitment phase was done from January 2019 to January 2020, and the study protocol was approved by local research ethics committee and informed consent was obtained from all participants. Patients who were diagnosed hyperthyroid based on clinical and laboratory data, had no history of hypertension, diabetes mellitus, cardiovascular disease, hyperlipidemia, anemia, pulmonary, and neuromuscular disease, and take no medication were entered to the study. Control subjects were chosen among the people with normal stress echocardiography result who came to our echo lab for checkup or non-anginal chest pain and had no past medical history with normal lab test for thyroid function, lipid profile, blood sugar, and hemoglobin.At first, we assessed the patients by electrocardiography (ECG) and conventional echocardiography, and exclude those who had valvular heart disease, any structural heart disease, LV systolic dysfunction by means of LVEF of less than 55% by Simpson method, pulmonary hypertension [systolic pulmonary artery pressure more than 35 mmHg using tricuspid regurgitation (TR) velocity], and nonsinus rhythm. Three of 28 patients who were referred to our center were excluded from the study due to LV dysfunction, pulmonary hypertension, and atrial fibrillation plus LV dysfunction.A complete two-dimensional and Doppler echocardiography was done by an experienced operator at the time of resting in left lateral decubitus position, using the same machine (affinity 70 Philips with 1–5 MHz transducer) in terms of the ASE recommendation. LV end-diastolic volume, end-systolic volume, and EF were calculated from apical two- and four-chamber views based on the modified Simpson method. Diastolic parameters including mitral inflow velocities (E and A waves), mitral annulus tissue Doppler velocities , left atrium volume index (LAVI), and peak TR velocity were measured by averaging in three consecutive cardiac cycles to estimate diastolic function in terms of the 2016 ASE guideline . IsovoluHyperthyroidism was diagnosed when serum-free thyroxine (T4) and triiodothyronine (T3) were more than upper limit of laboratory range, and thyroid-stimulating hormone (TSH) was less than 0.1 mIU/ml .2, and (4) peak TR velocity >2.8 m/s. Diastolic function was normal when more than half of four variables were negative. LV diastolic dysfunction was present when more than 50% of indices were positive, and diastolic function was indeterminate if half of parameters were positive.Based on the ASE guideline, for evaluation of diastolic function in the patients with preserved EF we considered four criteria including: (1) septal e′ velocity <7 cm/s or lateral e′ <10 cm/s, (2) average E/e′ ratio >14, (3) LAVI >34 ml/mStress echocardiography test was considered to be positive for diastolic dysfunction when all of following parameters were present in peak stress: (1) average E/e′ >14 or septal E/e′ >15, (2) peak TR velocity >2.8 m/s, and (3) septal e′ velocity <7 cm/s or lateral velocity <10 cm/s at baseline.IVRT and MPI were calculated by tissue doppler method when myocardial velocities were recorded using spectral pulse doppler from mitral annular level in apical four chamber view. MPI was calculated as sum of IVRT and isovolumic contraction time was divided by ejection time.t-test’ and ‘Mann–Whitney U test’ were used, respectively. Also, chi-square test was used to compare nominal variables. All the tests were performed using IBM SPSS Statistics v. 22 at a 95% confidence level.The results of quantitative variables with normal distribution were expressed as mean ± SD, and numerical variables without normal distribution were expressed as median with interquartile range. Qualitative variables were reported by number and percentage. To compare the numerical variables with and without normal distribution, ‘independent samples n = 13) of them were females. The etiology of hyperthyroidism was Graves (80%), toxic multinodular goiter (12%), toxic adenoma (4%), and subacute thyroiditis (4%). Cardiovascular symptoms and signs include the following palpitation (44%), exertional dyspnea (64%), and atypical chest pain (20%). Baseline characteristics of the hyperthyroid patients are listed in Table Twenty-five newly diagnosed hyperthyroid patients and 26 healthy subjects as control group were enrolled in this study. Mean age of the hyperthyroid patients was 39.64 ± 12.23 years old and 52  showed no notable difference between the two groups; IVRT was the only parameter that was lower in the hyperthyroid patients compared to the control group  reported dyspnea at peak stress that was not restricting for exercise and no one had typical chest pain and dizziness. No significant ST-T change and arrhythmia were induced.For evaluation of diastolic function reserve, according to the mentioned criteria in previous section, no one had developed criteria of diastolic dysfunction in stress echocardiography and mean E/e′ ratio and TR velocity were 7.30 ± 1.37 and 2.6 (2.39–2.88), respectively. There was also no significant difference between the two groups  was frequently reported in many previous studies evaluated the hyperthyroid patients  was freq,4,7,18. By comparing diastolic parameters between the two groups, IVRT was the only index that significantly differed and other indices including E/e′, LAVI, TR velocity, septal, and lateral e′ were comparable. Enhanced diastolic function was also reported in Mintz G’s study , and theIn our study, diastolic function reserve was also assessed by exercise stress echocardiography using ASE guideline criteria. Accordingly, this evaluation was not performed in previous studies, and interestingly, we found that no one in hyperthyroid group had developed diastolic dysfunction criteria despite of reporting dyspnea by 68% of patients during exercise.Our finding did not show diastolic dysfunction in hyperthyroid patients neither at rest nor during exercise echocardiography and did not support the hypothesis that diastolic dysfunction can be a cause of exertional intolerance and dyspnea in the patients with preserved EF and normal PAP.First, by considering that we excluded the patients with any comorbidity and those taken medications, the main limitation of our study was the small sample size. Second, we selected our cases from outpatient clinic and did not include more severe cases who may need hospitalization and probably with more severe cardiac involvement including diastolic dysfunction.Conflicts of interestThere are no conflicts of interest.