Inflammation along with oxidative stress has an important role in the pathophysiology of unstable angina which leads to acute myocardial infarction, arrhythmias and eventually heart failure. Curcumin has anti-inflammatory and anti-oxidant effects and thereby, it may reduce cardiovascular complications. This randomized controlled trial aimed to investigate the effects of curcumin on the prevention of atrial and ventricular arrhythmias and heart failure in patients with unstable angina.Forty patients with unstable angina who met the trial inclusion and exclusion criteria, participated in this double-blind randomized clinical trial. The patients were randomized into two groups: curcumin (80 mg/day for 5days) and placebo (80 mg/day for 5days). Cardiac function was evaluated by two-dimensional echocardiography devices at baseline  and 5 days after the onset of the trial. Atrial and ventricular arrhythmias were recorded by Holter monitors in cardiology ward, Ghaem academic hospital, Mashhad, Iran. Progression to heart failure, myocardial infarction, and pulmonary and cardiopulmonary resuscitation events as well as mortality were recorded daily throughout the study.There were no significant differences between the two groups in atrial and ventricular arrhythmias (p=0.2), and other echocardiographic parameters  at baseline and five days after the start of the trial. Nanocurcumin administered at the dose of 80 mg/day for five days had no effect in the incidence of cardiovascular complications in patients with unstable angina. Acute coronary syndrome (ACS) refers to a condition in which myocardial blood supply is disrupted. ACS includes ST elevation myocardial infarction , non-ST elevation MI , and unstable angina  is associated with ischemic, cardiovascular and cerebrovascular diseases. Among hospitalized patients with ACS, almost 26% have unstable angina  , the yellow substance found in the root of Turmeric Two other studies were also conducted in this field. These studies reported the therapeutic effect of curcumin on cardiac hypertrophy  reported decreased levels of high-sensitivity C-reactive protein (hsCPR) after seven days of using low doses of curcumin , low density lipoprotein (LDL), cholesterol and serum triglyceride (TG) in coronary artery disease . Moreover, it conforms to the CONSORT guidelines. PatientsConsidering that no clinical study had been carried out in this context, it was not possible to determine the sample size based on a previous report; therefore, based on inclusion and exclusion criteria, 40 patients were selected and enrolled in the study. As a pilot study, the results of this experiment could be utilized for calculating sample size in further investigations.Patients accepted their enrollment in the study by signing an informed consent form. Patients over 20 years old, diagnosed with unstable angina (based on New York Heart Association (NYHA) 2013 guideline), were included. Patients with renal and hepatic failure, acute or chronic infections, malignancies, chronic inflammatory diseases, history of arrhythmia, heart failure and those who required PCI (percutaneous coronary intervention) emergency, or were allergic to curcumin or immunosuppressive and anti-inflammatory drugs except statins, and pregnant or lactating women were all excluded.The diagnosis of unstable angina was made by an experienced cardiologist. At first, all the patients were examined by an internist and evaluated for inclusion and exclusion criteria. Patients diagnosed with unstable angina were visited daily by a cardiologist and arrhythmia was evaluated during the study. The cardiac arrhythmias were recorded by cardiac monitoring during their hospitalization in the CCU. On the first and fifth days, an echocardiographic evaluation was performed by a second cardiologist who was blinded to the study protocol.InterventionPatients were randomly allocated into two groups by simple randomization based on computer-generated random numbers. Neither patients nor investigators knew that who will be allocated to which group. The assessor and the statistical analyst were also blinded to the treatment allocation. Each group consisted of 20 patients .Curcuma longa L. (turmeric) and comprises curcumin, desmethoxycurcumin, and bisdemethoxycurcumin. These components are all together known as the C3 complex. Each soft gelatin capsule of SinaCurcumin possesses 80 mg curcuminoid as nanomicelles. The encapsulation adequacy of curcuminoid in nanomicelles is almost 100%. The mean diameter of nanomicelles is around 10 nm, as measured by dynamic light scattering. The oral absorption of SinaCurcumin was at least 50 times greater than the conventional powder of curcumin, in mice  and at the end of the study (day 5) by echocardiography,  and atrial and ventricular arrhythmias were recorded by Cardiofax C, Nihon Kohden. Heart failure, myocardial infarction, the rate of cardiopulmonary resuscitation, and eventually the mortality rate were all noted throughout the experiment.Criteria of effectivenessEvaluating the incidence of arrhythmiaPatients’ electrocardiograms were taken and the occurrence of atrial and ventricular arrhythmias was evaluated during five days (day 0-5). Arrhythmias were recorded by the nurses who were checking cardiac monitoring of patients constantly in CCU.Evaluating echo and factorsEchocardiograms were obtained using SIEMENS, Acusons SC2000 with a 2.5-3.5 MHz probe by experienced echocardiologist according to last echocardiographic guideline. The sizes of the left ventricle and left atrium were measured in the parasternal view in M mode. The left ventricular ejection fraction was calculated in the apical two- and four-chamber views in two-dimensional mode using the Simpson’s rule. The left ventricular diastolic function was evaluated using the mitral inflow velocities  pattern, which usually can be defined as various stages of diastolic dysfunction.Myocardial relaxation was also assessed by tissue Doppler imaging. Both of the above methods were employed to grade diastolic dysfunction. The ratio of transmitral Doppler early filling velocity to tissue Doppler early diastolic mitral annular velocity (E/Em) was utilized to estimate the filling pressure. The pulmonary capillary wedge pressure will be ≥20 mmHg if the E/Em is ≥15 and will be normal if the E/Em is <8. When the E/Em is between 8 and 15, pulmonary vein flow velocities and Valsalva maneuver were used to estimate the pulmonary capillary wedge pressure. The pulmonary arterial pressure (PAP) was measured based on echocardiographic parameters..The primary endpoint of this study was progression towards heart failure and ST segment elevation myocardial infarction (STEMI)The secondary endpoint was the effect of curcumin on electrophysiology and mechanical function of the heart, based on Holter monitoring and echocardiography.Statistical analysisKolmogorov-Smirnov (KS) test was used to assess normal distribution of data and Levene test .It was found that pulmonary artery pressure (PAP) was substantially different in the two groups at the onset of the study . After five days, the difference between the two groups was slightly significant . Other factors mentioned in Contrary to our expectations, curcumin failed to reduce cardiovascular complications such as arrhythmias and heart failure in unstable angina. Echocardiographic studies showed no significant difference between placebo and curcumin groups in left ventricular ejection fraction (LVEF) and echocardiographic factors.Several studies have found a strong relationship between the risk of cardiovascular diseases and inflammation In contrast to earlier findings, in another double-blinded clinical trial, researchers randomized 75 ACS patients into three intervention groups (15 patients in each group) taking different doses of curcumin , and the placebo group (30 patients). It was found that lower doses of curcumin could significantly decrease hsCRP level after seven days of use  had no effect on the incidence of cardiovascular complications in patients. This randomized controlled trial has extended our knowledge about curcumin effects on ACS.


Little is known about the causality and pathological mechanism underlying the association of seasonal variation with myocardial injury in patients with ST-segment elevation myocardial infarction (STEMI).We evaluated the association of seasonal effect with myocardial injury using cardiovascular magnetic resonance (CMR) imaging in STEMI patients undergoing primary percutaneous coronary intervention (PCI).In 279 patients undergoing primary PCI for STEMI, CMR was performed for a median of 3.3 days after the index procedure. Of these, STEMI occurred in 56 patients in the winter (Winter group), 80 patients in the spring (Spring group), 76 patients in the summer (Summer group), and 67 patients in the autumn (Autumn group), respectively. We compared myocardial infarct size, extent of area at risk (AAR), myocardial salvage index (MSI) and microvascular obstruction (MVO) area as assessed by CMR according to the season in which STEMI occurred.P = 0.475). The extent of AAR, MSI, and MVO areas were similar among the four groups. In the subgroup analysis, myocardial infarct size, extent of AAR, MSI, and MVO were not significantly different between the Harsh climate (winter + summer) and the Mild climate (spring + autumn) groups.In the CMR analysis, the myocardial infarct size was not significantly different among the Winter group (21.0 ± 10.5%), the Spring group (19.6 ± 11.5%), the Summer group (18.6 ± 10.6%), and the Autumn group (21.1 ± 11.3%) (Seasonal influences may not affect advanced myocardial injury in STEMI patients undergoing primary PCI. Seasonal variations influence the incidence of acute myocardial infarction (MI) . PreviouThis study was approved by the institutional review board of Samsung Medical Center and Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, respectively and all subjects provided written informed consent to participate in this study.Between December 2007 and July 2016, 439 consecutive patients were eligible for enrollment in this study after presenting with STEMI and undergoing CMR at the Samsung Medical Center, Seoul, Republic of Korea and the Samsung Changwon Hospital, Gyeongsangnam-do, Republic of Korea. The inclusion criteria for this study were: 1) patients treated with primary PCI within 12 hours after symptom onset, and 2) patients that underwent CMR after the index procedure. The exclusion criteria were: 1) previous coronary artery bypass grafting, 2) history of previous MI, 3) patients received reperfusion therapy over 12 hours from symptom onset, 4) insufficient information regarding symptom onset time, 5) door to balloon time over 90 minutes, and 6) patients with poor-quality CMR imaging data for analysis. Finally, 279 patients were included in this study .South Korea lies in the temperate zone and has four distinct seasons, with the annual mean temperature ranging from 10 to 16°C and the climate extreme ranging from -32.6 to 40.0°C according to Meteorological Administration climate . The fouThe primary outcome was myocardial infarct size (% of left ventricle or -cular [LV]) as assessed by CMR imaging according to the occurrence season of acute MI. The secondary outcomes included extent of the area at risk , myocardial salvage index (MSI), and microvascular obstruction (MVO) area (% of LV).Baseline characteristics, angiographic findings, and CMR data were prospectively recorded in the dedicated registry. Blood samples for N-terminal pro B-type natriuretic peptides and creatine kinase myocardial bands (CK-MB) were drawn from patients before primary PCI. Serum CK-MB levels were measured every eight hours from the index procedure until peak values were confirmed. The baseline left ventricular ejection fraction  was measured by transthoracic echocardiography using the Simpson’s method immediately after primary PCI . The KilAll measurements were made in the Samsung Medical Center-CMR core laboratory using validated software . Infarct size and extent of MVO were assessed on delayed enhanced images, whereas the AAR was measured on T2-weighted images. Two experienced radiologists blinded to patient information performed measurements based on visual assessment. After acquiring short-axis images at the end-diastole and end-systole, the endocardial borders were traced. The Simpson algorithm was then used to calculate the LV end-diastolic volume (LVEDV), the LV end-systolic volume (LVESV), and the LVEF. Infarct size was calculated from summation of the area with delayed hyperenhancement within each segment of the short-axis images. This value was multiplied by slice thickness to cover the entire left ventricle. Endocardial and epicardial borders were planimetered to calculate the myocardial area. They were then summed to calculate LV myocardial volume using the same method. Infarct size was expressed as the percentage of affected LV myocardial volume. T2-weighted images were used to determine the presence of hemorrhagic infarction . AAR wast-test and One-way ANOVA. Categorical variables were described as numbers (n) with percentages (%), and differences were analyzed by using Pearson χ2 or Fisher’s exact tests. Multivariate logistic regression analysis was performed using a step-wise backward selection process to determine the independent predictors of large myocardial infarcts (percent infarct volume ≥ mean of infarct size in the present study). Clinical variables  were included in regression models. Criteria for the inclusion and exclusion of variables were set at 0.05 and 0.20, respectively. All tests were two-tailed, and P <0.05 was considered to be statistically significant. Statistical analyses were performed using the SAS software .Continuous variables were expressed as mean ± standard deviation or as median (25th percentile to 75th percentile) when variables lacked a normal distribution. An analysis of continuous variables was performed using the Student’s P = 0.018). Other demographic and clinical characteristics were not different among the four groups. Angiographic and procedural findings additionally showed no significant differences among the four groups , the Spring group , the Summer group , and the Autumn group  according to their STEMI occurrence season. Peak CK-MB levels tended to be lower in the Winter group than in other groups, but the difference was not significant . In termr groups . The mosr groups .P = 0.475). The extent of AAR , MVO area  and MSI  were similar among the four groups (CMR was performed for a median of 3.3 days (interquartile range: 2.8–4.2) after the index procedure, and intervals from primary PCI to CMR were not different among the four groups. The myocardial infarct size was not significantly different among the four groups  and LVEF ≤40% . Separately, the use of ACE inhibitor or ARB after primary PCI represented a uniquely negative predictor of large myocardial infarct   included male gender  .The Winter and Summer groups were combined into the Harsh climate group, which was compared with the Mild climate group (consisting of the Spring and Autumn groups) in order to analyze the relationship between excessive temperature and myocardial injury. Of the 279 study patients, 132 suffered from STEMI in the winter and summer , while 147 suffered from STEMI in the spring and autumn . The Harsh climate group had no differences with respect to myocardial infarct size, extent of AAR, and MSI compared to the Mild climate group .We investigated the association between seasonal variation and myocardial injury using CMR imaging in STEMI patients treated with primary PCI. The main finding of our study was that there was no significant difference of myocardial infarct size between winter, spring, summer, and autumn; furthermore, the extent of AAR, MSI, and MVO area were similar among the four seasons. Between harsh climates (winter and summer season) and mild climates (spring and autumn season), the nature of myocardial injury as assessed by CMR was not significantly different either. To the best of our knowledge, this is the first study to evaluate seasonal variations associated with myocardial injury as determined by CMR imaging data in STEMI patients. Our findings corresponded well with those of earlier studies that established an absence of seasonal effect on myocardial infarct size in acute MI patients . TherefoPrevious studies have reported that environmental temperature may play an important role in the pathogenesis of acute MI . AutonomIn addition, we investigated the relationship between excessive ambient temperature and myocardial injury in our subanalysis. Myocardial infarct size, AAR, MSI, and MVO as assessed by CMR imaging were not significantly different between the harsh climates (winter and summer season) and the mild climates (spring and autumn season). Bhaskaran et al.  reportedThis study had several limitations. First, its design was nonrandomized, retrospective, and observational, which may have significantly affected the results attributed to confounding factors. Second, patients undergoing CMR may have been clinically stable with modest myocardial injury. Because only patients available for CMR were included, the sample size of our study was small and it may have limited our results. Third, due to the retrospective nature of our registry, we could not thoroughly identify detailed meteorological data or angiographic and clinical variables relating to the SYNTAX score in all study patients during follow-up. Fourth, South Korea has four distinct seasons, but this may represent a bias because the definition of the four seasons may be different in other geographic regions or countries. Finally, demographic population factors such as socioeconomic status and living area were not considered, and demographic factors could be one of the important factors affecting temperature-associated acute MI and its clinical outcomes, particularly in hot or cold weather.Seasonal effects could influence the incidence of acute MI, especially in the winter or summer; however, these are not associated with a larger extent of myocardial edema, less myocardial salvage, or greater myocardial infarct size as assessed by CMR imaging. Based on our study, seasonal variation may not affect advanced myocardial injury in STEMI patients undergoing primary PCI. Further investigation with potential therapeutic implications of these findings should be considered.S1 FigScatter plot shows peak CK-MB levels according to STEMI occurrence date.CK-MB = creatine kinase myocardial band.(TIF)Click here for additional data file.S1 Table(DOC)Click here for additional data file.


This study aimed to translate the English version of the Action Research Arm Test (ARAT) into Chinese and to evaluate the initial validation of the Chinese version (C-ARAT) in patients with a first stroke.α coefficients and item-scale correlations. Concurrent validity was determined using Spearman's rank correlation coefficients. Floor and ceiling effects were considered to be present when more than 20% of patients fell outside the preliminarily set lower or upper boundary, respectively. An expert group translated the original ARAT from English into Chinese using a forward-backward procedure. Forty-four patients (36 men and 8 women) aged 22–80 years with a first stroke were enrolled in this study. The participants were evaluated using 3 stroke-specific outcome measures: C-ARAT, the upper extremity section of the Fugl–Meyer assessment (UE-FMA), and the Wolf Motor Function Test (WMFT). Internal consistency was analysed using Cronbach's α of 0.98 (p < 0.001) and item-total correlations ranging from 0.727 to 0.948 (p < 0.001). The C-ARAT exhibited good-to-excellent correlations with the UE-FMA and WMFT functional ability (WMFT-FA) scores, with respective ρ values of 0.824 and 0.852 (p < 0.001), and an excellent negative correlation with the WMFT performance time (WMFT-time), with a ρ value of -0.940 (p < 0.001). The C-ARAT subscales generally exhibited good-to-excellent correlations with stroke-specific assessments, with ρ values ranging from 0.773 to 0.927 (p < 0.001). However, the gross subscale exhibited moderate-to-good correlations with the UE-FMA and WMFT-FA scores, with respective ρ values of 0.665 and 0.720 (p < 0.001). No significant floor effect was observed, and a significant ceiling effect was observed only on the WMFT-time. The C-ARAT items yielded excellent internal consistency, with a Cronbach's  The C-ARAT demonstrated excellent internal consistency and good-to-excellent concurrent validity. This test could be used to evaluate upper extremity function in stroke patients without cognitive impairment. Stroke, a leading cause of disability in adults worldwide, can result in highly complex clinical situations . ApproxiAlthough numerous upper limb measurement tools have been used in stroke rehabilitation studies, only 15 of them have been applied in more than 5% of studies .Several previous studies have proven the good psychometric properties of the ARAT –14. HsieThe original ARAT protocol and manual were translated into Swedish . To the The original ARAT was translated from English into Chinese using a forward-backward procedure. The forward procedure was performed by 2 native Chinese speakers who accurately translated the scale from English to Chinese according to the original scale. Next, the 2 translators resolved any discrepancies and synthesised the results based on their translations. The backward procedure was then performed by 2 native English speakers who were blind to the original English version. The 2 translators were neither aware nor informed of the concepts explored to avoid information bias and unexpected meanings in the translated questionnaire. The translated questionnaire was then reviewed by an expert committee comprising the principal investigator, the 4 translators, 2 experienced physiotherapists, 2 occupational therapists, and 2 rehabilitation physicians. The expert committee reviewed all versions of the questionnaire and developed what would be considered the final version of the questionnaire for field testing .According to a previous study , a samplPrior to collecting baseline data, an experienced physiotherapist with 9 years of clinical experience in stroke rehabilitation was trained to properly administer the C-ARAT, WMFT, and UE-FMA according to recent guidelines , 21. We The ARAT was developed by Lyle  in 1981 The WMFT is a widely used laboratory-based evaluation designed to assess UE function (test-retest reliability = 0.90–0.95)  in peoplThe UE-FMA, which has been used in 36% of studies, is the most commonly used measure  and has The muscle tone in the elbow, wrist, and finger flexors was assessed using the Modified Ashworth Scale (range: 0–4) . Here, aThe demographic and clinical characteristics of the participants in this study (n = 44) were demonstrated using descriptive statistics.α coefficients and item-total correlations. Cronbach's α values with corresponding confidence intervals (CI) were calculated to determine the internal consistency between the items of the C-ARAT. Here, α values of <0.5, 0.5 to <0.6, 0.6 to <0.7, 0.7 to <0.8, 0.8 to <0.9, and ≥0.9 indicated unacceptable, poor, questionable, acceptable, good, and excellent internal consistency, respectively [In order to evaluate the quality of the translated ARAT, internal consistency was used to test the agreement of each item. The internal consistency of the C-ARAT was assessed using Cronbach's ectively . The iteρ) was used to evaluate these correlations. Here, ρ values between 0 and 0.25, between 0.25 and 0.50, between 0.50 and 0.75, and >0.75 represented weak, fair, moderate-to-good, and good-to-excellent correlations, respectively [The concurrent validity of the C-ARAT was assessed by computing the correlations of the C-ARAT score with the WMFT and UE-FMA scores. As the C-ARAT, WMFT, and UE-FMA are ordinal scales, Spearman's rank correlation coefficient  were enrolled in this study. The median of the participants' age was 57.50 years (range: 22–80 years). The median poststroke duration was 3.00 months (range: 0.5–80.27 months). Thirty-three and 11 patients had ischemic and haemorrhagic stroke, respectively. The right side was affected in 48% of participants. Twenty individuals had hypoesthesia in their affected arms, including 1 case of combined sensory hypoesthesia, 15 cases of superficial sensation hypoesthesia, and 4 cases of combined superficial and deep sensory hypoesthesia. No patient presented with hemineglect. Fifteen individuals had mild speech impediments that did not affect communication. Details of the 44 participants were provided in The C-ARAT, UE-FMA, and WMFT performance scores were summarized in α value of 0.98. (p < 0.001). The Pearson correlation coefficients of the item-total correlations ranged from 0.727 to 0.948. Details were provided in The data of all 44 subjects were pooled to calculate the internal consistency. The C-ARAT items exhibited excellent internal consistency, with a Cronbach's ρ = 0.857; gripping, ρ = 0.844; pinching, ρ = 0.773; p < 0.001). However, the gross movement subscale exhibited a moderate-to-good correlation with the UE-FMA . The data on all 44 subjects were pooled to calculate the concurrent validity. The C-ARAT total score and UE-FMA score yielded a correlation of 0.824 (p < 0.001), indicating a good-to-excellent correlation. Most C-ARAT subscales also exhibited good-to-excellent correlations with the UE-FMA . The gross movement subscale exhibited a moderate-to-good correlation with the UE-FMA . The C-ARAT total score and WMFT-FA score yielded a correlation coefficient of 0.852 (p < 0.001), which indicated a good-to-excellent correlation. Most of the C-ARAT subscales also exhibited good-to-excellent correlations with the WMFT-FA , -0.894 (p < 0.001), -0.927 (p < 0.001), -0.903 (p < 0.001), and -0.782 (p < 0.001). In other words, the total C-ARAT and all subscales exhibited strong negative correlations with the WMFT-time. The C-ARAT scores and WMFT-time score yielded good-to-excellent correlations with Detailed results of the validity analyses were shown in Rapid increases in population aging and medical technique development have led to a growing number of people who suffer from stroke . Furtherα coefficient of 0.98 for the C-ARAT, indicating excellent internal consistency. This result was consistent with previous studies [α decreased by a maximum of only 0.002 if any single item was deleted. Therefore, each item of the C-ARAT was worthy of retention. Nijland et al. [α = 0.98) in people with acute stroke. These findings showed that the C-ARAT showed high internal consistency as well as the original version, which may indicate that the Chinese version ARAT was well translated in each item.In order to estimate how well the items measure the same concept in Chinese version of ARAT, the internal consistency was calculated. Internal consistency is one way to assess the quality of the translation. In this study, internal consistency is defined as agreement among all 19 items measuring the same traits of the construct and the subjects' performance . Our res studies , 52 whic studies , and Crod et al.  also obsρ value than those reported by Wei [ρ values of 0.93 and 0.92 were reported before and after training, respectively [ρ value of 0.93 [ρ values of 0.90, 0.90, 0.82, and 0.92, respectively. However, the poststroke duration and motor performance and intervention in that study differed considerably from those of our participants. Hsieh et al. [ρ = 0.71–0.74) between the UE-FMA and ARAT in chronic stroke survivors who received any 1 of 3 interventions . The discrepant results between the study by Hsieh et al. and our study may be attributable to differences in severity of the motor impairment. The study by Hsieh et al. [Our results demonstrated a good-to-excellent correlation between the total scores of the C-ARAT and UE-FMA , in accod by Wei , See [45d by Wei . In the ectively . Compareectively  included of 0.93 , particih et al.  observedh et al.  includedOur results showed a strong correlation of the C-ARAT total score with the WMFT-FA score , which iρ > 0.75) except for the gross movement subscale, which showed moderate-to-good correlations with the UE-FMA and WMFT-FA (ρ = 0.665–0.720). Nordin et al. [In addition, the C-ARAT subscales correlated strongly with stroke-specific assessments (n et al.  and Van n et al.  reportedIn our study, no significant floor and ceiling effect was observed in C-ARAT, UE-FMA, and WMFT-FA according to the criteria of floor and ceiling effect, which was consistent with the findings reported by Nijland . A signiThe C-ARAT, which is simple and rapid, assesses not only hand dexterity and strength but also the function of the whole UE. In contrast, the WMFT requires participants to change positions to sit on both sides and in front of the table, as well as a close facing position, and even demands that participants stand and lift a basket during the last task. As this test requires the ability to shift position, it is difficult for some stroke survivors, especially those in the early poststroke phase. In comparison, the ARAT does not require changes in body position and only requires the participant to sit in front of the table. Therefore, the ARAT is a satisfactory instrument for the assessment of UE function in stroke patients. Furthermore, the tools required for the ARAT are inexpensive and the assessment is less time-consuming than for other methods. Therefore, it is easily obtained and administered in clinical settings.This study had some limitations. First, the sample size was small. Therefore, we could not conduct analyses according to the severity or type of stroke, type of intervention, or training time. The conclusion may only be applicable to the stroke survivors with the same severity. Second, the enrolled participants had a wide range of stroke onset times; some had been trained in grasping, gripping, or pinching exercises whereas others had no such training. These differences may have led to differences in performance during the C-ARAT. Finally, we only evaluated the concurrent validity, internal consistency, and floor and ceiling effects of the C-ARAT. Further research should explore the comprehensive psychometric characteristics, such as the intra- and interrater reliability, responsiveness, and predictive validity, of the instrument in stroke survivors at different stages.In conclusion, the C-ARAT is an excellent and valid measure of UE function in stroke survivors. Our findings support the generalised clinical or research use of the C-ARAT in Chinese patients with stroke. However, further research is needed to evaluate the comprehensive psychometric characteristics of the C-ARAT.


Myocardial infarction (MI) leads to complex changes in left ventricular (LV) haemodynamics that are linked to clinical outcomes. We hypothesize that LV blood flow kinetic energy (KE) is altered in MI and is associated with LV function and infarct characteristics. This study aimed to investigate the intra-cavity LV blood flow KE in controls and MI patients, using cardiovascular magnetic resonance (CMR) four-dimensional (4D) flow assessment.EDV. In addition, we investigated the in-plane proportion of LV KE (%) and the time difference (TD) to peak E-wave KE propagation from base to mid-ventricle was computed. Association of LV blood flow KE parameters to LV function and infarct size were investigated in all groups.Forty-eight patients with MI  and 20 age/gender-matched healthy controls underwent CMR which included cines and whole-heart 4D flow. Patients also received late gadolinium enhancement imaging for infarct assessment. LV blood flow KE parameters were indexed to LV end-diastolic volume and include: averaged LV, minimal, systolic, diastolic, peak E-wave and peak A-wave KEiEDV was higher in controls than in MI patients . Additionally, systolic, minimal and diastolic peak E-wave KEiEDV were lower in MI (P < 0.05). In logistic-regression analysis, systolic KEiEDV  demonstrated the strongest association with the presence of MI. In multiple-regression analysis, infarct size was most strongly associated with in-plane KE . In patients with preserved LV ejection fraction (EF), minimal and in-plane KEiEDV were reduced (P < 0.05) and time difference to peak E-wave KE propagation during diastole increased (P < 0.05) when compared to controls with normal EF.LV KEiEDV. Infarct size is independently associated with the proportion of in-plane LV KE. Degree of LV impairment is associated with TD of peak E-wave KE. In patient with preserved EF post MI, LV blood flow KE mapping demonstrated significant changes in the in-plane KE, the minimal KEiEDV and the TD. These three blood flow KE parameters may offer novel methods to identify and describe this patient population.Reduction in LV systolic function results in reduction in systolic flow KEiThe online version of this article (10.1186/s12968-018-0483-6) contains supplementary material, which is available to authorized users. Myocardial infarction (MI) is one of the leading causes of death and disability worldwide. The effects of acute MI on left ventricular (LV) haemodynamics  and the The kinetic energy (KE) of the blood represents a fundamental component of work performed by the heart which results in the movement of the blood . Four-diHence, the aims of this study were as follows: a) quantify dynamic parameters of LV blood flow KE in patients with acute and chronic MI and age and gender matched healthy controls; b) investigate the reproducibility of LV blood flow KE parameters; c) investigate if there are significant changes in LV blood flow KE in different sub-groups of left-ventricular ejection fraction; d) investigate the association of LV KE to infarct size and if LV KE is altered in acute versus chronic MI patients.The study design is detailed in Fig. 2, haemodynamic instability (Killip class III/IV requiring on-going intravenous diuretic therapy For whole heart 4D flow, field of view (FOV) was planned in trans-axial plane making sure whole heart was in FOV. 4D flow was done using fast field echo (FFE) pulse sequence  with retrospective electrocardiogram (ECG)-triggering. The acquisition voxel size was kept as close as possible to 3 × 3 × 3 mm3. FOV and number of slices  was adapted to the subject’s size. Scan parameters: TE 3.5 ms, TR 10 ms, flip angle 10°, FOV 400 mm, number of signal averages 1. VENC 150 cm/sec. Acceleration was achieved by EPI factor 5. Free breathing was allowed, and no respiratory motion compensation was used. Number of slices was 40, temporal resolution used was 40 ms and the number of reconstructed phases was set to 30. EPI sequence is detailed in the Additional file Modified Look-Locker inversion recovery (MOLLI) to determine the T1-inversion time [only done in the patient population]LGE imaging was done at 15-min from gadolinium-based contrast injection in MI patients only. LGE-imaging was done by phase sensitive inversion recovery (PSIR) spoiled gradient echo (GE) sequence as per previous published methods , 23. PSIThe CMR protocol was as follows:4D flow encoding was performed by standard 4-point encoding. Online/offline 4D flow data quality assurance checks were done as per previous published literature .The effects of concomitant gradient terms were compensated using Maxwell correction methods by the CMR scanner. Remaining background errors were corrected by the local phase correction (LPC) filter on the CMR scanner performed in two-dimensional way- slice by slice. The LPC is a magnitude-weighted spatial low pass filter; pixels that are expected to be part of the static background are used with a higher weight than noisy background pixels or pixels that are expected to contain flow to determine the local phase offset. LPC uses surrounding tissue to determine “static” areas , 25.All 3D phase contrast data sets were investigated for phase aliasing artefacts. If present then phase unwrapping was performed as per previously published guidelines on phase-contrast methods . AdditioAll images were analysed by PG , SC  and RVDG . Images were evaluated offline using research software . LV volumes, stroke volume, cardiac index, EF and infarct location on LGE imaging were determined according to standard methods. Acute and chronic infarct size were determined by the full-width at half-maximum semi-automated technique .The degree of LV systolic impairment was categorised as follows: normal EF in controls, normal LVEF. In patients with MI, preserved LVEF was ≥55%, mildly impaired LVEF 45–54%, moderately impaired LVEF 35–44% and severely impaired LVEF < 35%" In patients with MI.For calculation of LV blood flow KE parameters, the LV volumetric mesh was resliced into short-axis sections of 2 mm thickness and pixel spacing equal to the original reconstructed pixel size of the short-axis cine acquisition (1.0–1.2 mm). This high-resolution LV mesh is constructed by representing the mesh in cylinder coordinates. The LV radius for a given angle and LV level is derived by linear interpolation. Correction for translational and rotational misalignment between the short-axis cine and the 4D Flow CMR acquisition was performed using automated image registration as previously described .ρblood being the density of blood (1.06 g/cm3), Vvoxel the voxel volume and v the velocity magnitude. For each phase, the total KE within the LV was obtained by summation of the KE of every voxel. Time-resolved kinetic energy curves were generated to derive physiologically relevant parameters.For each volumetric element (voxel) the KE was computed as LV blood flow KE parameters which were derived for the complete cardiac cycle are described in Table The novel KE parameters studied in this study are detailed below:We define the in-plane KE as the sum of all kinetic energy in the x-y direction, in the short-axis LV from base to apex. In this study, the in-plane KE is represented as a percentage of the total LV KE, this negates the issue with volume normalisation. Most of the blood flow in the LV should be in the through-plane direction – both in systole  and during diastole  and an increase in the proportion of in-plane flow may be associated with pathological flow. Hence, in this study, the in-plane KE parameter was computed mainly to better understand the in-plane flow dynamics within the LV cavity.We also computed the time difference (TD) to peak early mitral inflow velocity (E-wave) from the base of the LV to mid-ventricle. This transit time or TD should be higher if the mitral valve propagation velocity (Vp), as measured by M-Mode echocardiography is lower . Hence, This parameter simply represents the minimal KE of the LV flow at any time point during the complete cardiac cycle. We computed this parameter mainly to understand how KE is preserved in health versus disease. The minimal KE of the LV is likely to be happen when the haemodynamic forces are minimal, and LV is not moving. A rise in the minimal KE may be influenced by heterogenous haemodynamic forces described in the LV fluid dynamics model secondary to dyssynchronous or late systolic contractility seen in infarcted segments .To allow comparison between patients and healthy subjects, all KE parameters were normalized to the LV end-diastolic volume (EDV) and accordingly reported in μJ/ml. In sub-analysis, we also normalised the KE parameters to the stroke volume to develop insight into KE spent per unit of stroke volume.For inter-observer variability, SC and RVDG contoured the short-axis LV cine volumetric stack in 10 random healthy control subjects and 10 random MI patients, blinded to each other’s analysis. Automated KE parameters were again generated using the endocardial contours from second observer. For intra-observer variability, SC re-analysed the LV short-axis cines for the same 10 healthy control subjects and 10 MI patients MI after 3 months. Akin to inter-observer variability, automated KE parameters were generated using the new endocardial contours by the same observer using the time-resolved methods previously described .p < 0.05) were chosen for multi-variate analysis. A p-value < 0.05 was considered statistically significant.Statistical analysis was performed using SPSS® Statistics 21.0 . Continuous measurements are presented as mean ± standard deviation. Quantitative flow imaging parameters expected to be non-parametric were presented as median and inter-quartile ranges (IQR). Demographic comparisons were performed with an independent samples t-test. Comparisons between two groups with non-parametric data were made using Mann–Whitney U test. Intra−/inter-observer reliability tests were done by inter-class correlation coefficient. In different categories of LVEF, post hoc analysis was done by Kruskal-Wallis H test. Association of infarct size to KE parameters was done by Spearman’s rank correlation coefficient test. In multi-variate analysis, a forward-conditional method was used for regression and parameters with statistical significance from one-way analysis (P = 0.1), gender and body surface area . Most baseline volumetric CMR parameters were significantly higher in MI patients than healthy controls (Table P = 0.21). The majority of patients had anterior MI (n = 35) versus inferior/posterior MI (n = 13). The 4D flow CMR acquisition time was 8 ± 2 min.Heart rate was comparable between MI patients and healthy controls  . Time differences to peak E-wave KEiEDV were significantly higher in MI patients compared to healthy controls  .In logistic regression analysis of all the significantly different KEits Table , LV blooEDV (P < 0.05)  Table . For theEDV, the proportion of in-plane KE and TD (P < 0.05) . This association was mainly driven by variation of stroke volume in the MI cohort . However, KE parameters associated with cardiac index included the following: LV, systolic, diastolic, E-wave KEiEDV and in-plane KE (P < 0.05).Kinetic energy parameters that were significantly associated with stroke volume included the following: systolic and E-wave KEi5) Table . In sub-EDV parameters demonstrated significant differences between groups of patients, defined by the degree of LV systolic impairment . These included: minimal, systolic, in-plane KEiEDV parameters and TD to peak E-wave KE propagation. The proportion of in-plane KE and minimal KEiEDV parameters were significantly reduced inpreservedpEF patients when compared to normal EF healthy controls but were increased compared with controls in patients with worsening EF . The systolic KEiEDV decreased significantly with worsening EF .Comparison of LV flow KE parameters  with the degree of LV systolic impairment are detailed in Table EF Figs.  and d. I EF Fig. . TD to pEDV, in-plane KE and the TD for peak E-wave KE  and positively associated with the proportion of in-plane KE  . In multiple regression analysis, in-plane KE was independently associated with infarct size   Fig. . TD of pP < 0.01). Controlling for infarct size, no significant differences were noted for the baseline CMR parameters and the different parameters of KEiEDV between anterior and inferior/posterior MI.Thirty-five patients (73%) had anterior MI and 13 (27%) had inferior/posterior MI. CMR baseline parameters were similar in both infarct locations Table . InfarctP-value = 0.02). KEiEDV parameters and LV EF were comparable in both groups.Baseline demographics were comparable between patients with either acute or chronic MI Table . From thSV parameters  demonstrated significant rise between different groups of EF (P < 0.05) (Table All KEi5) Table . We note5) Table .Fig. 8CoP-value> 0.9). In addition, the mean bias (%) for all KEiEDV parameters was 2 ± 9% for intra-observer tests and 3 ± 9% for inter-observer tests. TD to peak E-wave flow KE also demonstrated very high intra-class correlation coefficient .Intra-observer and inter-observer variability results for global KE parameters are detailed in the online Additional file EDV parameters are reduced in patients with MI. In addition, decrease in systolic KEiEDV of the LV blood flow is independently associated with the presence of MI and the proportion of in-plane KE of the LV blood flow is independently associated with the infarct size. Another important finding of this study was that worsening degree of LV systolic function is associated TD of peak E-wave KE propagation. MI patients with preserved EF have significantly reduced minimal KEiEDV, the proportion of in-plane KE and increased TD of peak E-wave KE propagation when compared with healthy controls with nEF. Kinetic energy per stroke volume revealed higher systolic KE versus diastolic KE in normal EF, preserved EF and mildly reduced EF groups. However, patients with moderate and severely reduced EF demonstrated reversal and had higher diastolic KE per stroke volume than systolic KE. Finally, global LV blood flow KE parameters demonstrated good intra−/inter-observer variability.In this study, we mapped different parameters of LV blood flow KE in MI patients and matched healthy control subjects. We found that the majority of LV blood flow KEiiEDV, which in essence is the global density of the velocity profile of intra-cavity blood flow, was significantly lower in patients with MI than controls. This is in keeping with results by Kanski et al., who found reduced indexed LV KE in patients with moderate-to-severe heart failure versus controls.  [iEDV of LV blood flow. As a consequence of MI and regional hypo-contractility, there is reduced regional systolic mechanical force imparted on the intra-cavity blood consequently due to lowered pressure gradient between the LV and the aorta, the overall thrust of systolic blood flow is reduced as demonstrated by drop in the systolic blood flow energetics. This is also supported by the finding that LV stroke volume was only associated to systolic KEiEDV in MI cohort and not in the controls.In the present study, the global LV flow KE= 0.025) . Even thDuring diastolic filling of the LV in health, we already know through M-mode Doppler echocardiography that blood flow into the LV cavity from base to apex happens very fast with a mitral valve flow propagation velocity (Vp) of above 50 cm/sec . Even thEDV had a more linear trend to decrease with worsening EF. Decreased LV contractile function leads to impaired emptying and increased preload in subsequent cycles. Even if this causes stroke volumes to return to normal due to the Frank-Starling mechanism, the increased ventricular dimensions will cause the KEiEDV to decrease.The patterns of changes between these LV flow KE parameters to the degree of LV systolic impairment were different. The systolic KEiEDV and the proportion of in-plane KE significantly reduced from normal EF in healthy controls to MI patients with preserved EF and then had a strong trend to increase with decreasing EF – a finding that at first seems paradoxical.The TDs for peak E-wave KE propagation demonstrated a more linear trend to increase with worsening EF. The minimal KEiWe speculate that the in-plane KE of LV flow is made up of several in-plane blood flow movements during the complete cardiac cycle. These include: the physiological systolic in-plane movement of blood towards the outflow track during LV contraction, in-plane flow within the vortex in early and late diastolic filling. The systolic and vortex associated in-plane flow are plausibly decreased in MI patients with preserved EF as they have subtle mechanical dysfunction with preserved LV volumes. This finding would be consistent with other studies demonstrating alterations in diastolic inflow vortex strength in heart failure patients with preserved EF (HFpEF) . HoweverEDV, we speculate that the rise in the proportion of in-plane KE with worsening EF is associated with an increase in minimal KEiEDV. This is possibly explained by the fact that progressive LV impairment leads to LV dilatation and reduced filling of the LV causing an overall increase in the in-plane flow, which results in higher minimal KEiEDV for the LV. This observation is further supported by the analysis of the KE parameters per stroke volume which demonstrate the all blood flow KE parameters rise significantly for each stroke volume with the degree of LV impairment. In addition, once the degree of LV impairment reaches the moderate zone, the systolic KE per stroke volume becomes lesser than the diastolic KE per stroke volume. This perhaps reflect the loss of mechanical push by LV in systole combined with restrictive early filling in diastole associated with high velocities.As the pattern of changes to the degree of LV impairment was similar for in-plane KE and minimal KEiResults from our study show that an increase in infarct size increases the in-plane KE of LV blood flow. Such pathological rise in the in-plane KE may exert heterogenous haemodynamic forces on the LV wall, possibly contributing to more dilatation and increase in endothelial dysfunction in the endocardium –40.EDV was not associated with IS (P = 0.09), however, in regression, the in-plane demonstrated independent association to the IS. This would indicate that some components of LV blood flow energetics are more influenced by infarct size than others and its associated mechanical dysfunction than its location.In our study, anterior infarcts were significantly larger than inferior infarcts. When adjusted for MI size, MI location (anterior versus inferior) was not significantly associated with LV function or blood flow KE parameters. In a previous study done by Kanski et al., in sub-group of patients with MI, multiple stepwise linear regression analysis, averaged LV KE was associated with LV end-diastolic volume and not IS. Similarly, in this study averaged LV KEiWe have demonstrated that using 4D flow that it is possible to detect subtle changes in cardiac function after MI even in patients with preserved EF. Longitudinal prospective studies are needed to establish whether LV flow KE has incremental prognostic impact over established markers such as EF, scar burden and microvascular obstruction. Studies are also needed to establish whether changes in intra-cardiac flow can be altered by medical therapy. After MI, LV remodelling leads to progressive LV cavity dilatation and subsequent heart failure. Using 4D flow it will be possible to investigate these mechanisms and assess the impact of existing and potentially novel pharmacological interventions on these processes.To compute LV blood flow KE parameters, time-resolved LV volumetric endocardial contours are used . Hence, Respiratory navigation was omitted for the 4D flow acquisition which could have influenced KE parameters. However, whole-heart 4D flow head-to-head comparison studies have also demonstrated that non-respiratory navigated acquisition of 4D flow is comparable to respiratory navigated acquisition for intra-cardiac KE quantification . In addiEDV and the TD. Further longitudinal studies are warranted to investigate the long-term clinical significance of mapping LV blood flow KE parameters.Post MI, reduction in LV function results in reduction in LV blood flow KE and is most strongly associated with the systolic LV blood flow KE. Increase in infarct size results in proportionate increase in the in-plane KE of LV blood flow. Degree of LV impairment is associated with TD of peak E-wave KE. Even in patient with preserved EF post MI, LV blood flow KE mapping demonstrated significant changes in the in-plane KE, the minimal KEiAdditional file 1:Supplementary Material. (DOCX 30 kb)


The traditional treatment of myocardial infarction with ventricular septal rupture is surgical treatment. For the elderly patients with cardiac insufficiency, surgical treatment is very risky. The successful treatment of this case by interventional occlusion is a new method. No relevant literature reports have been found.A 77-year-old man with a past medical history of old myocardial infarction presented to the physician with sudden onset of palpitation and shortness of breath. Echocardiography showed thinning of the interventricular septum near the apex and bulging toward the right ventricular side with “paradoxical motion”, on which a rupture of about 8 mm in diameter was seen. CDFI: left ventricular blood shunted to the right ventricle through the rupture.Echocardiographic diagnosis: old left ventricular anteroseptal myocardial infarction with ventricular septal rupture. Due to the older age of the patient and reduced left ventricular function, surgical repair of the ventricular septal rupture site was more difficult. After multidisciplinary discussion, it was agreed that the patient could not afford thoracotomy and was not suitable for thoracotomy, and echocardiography guided interventional occlusion of the ruptured interventricular septum could be performed.Transesophageal echocardiography-guided interventional occlusion of myocardial infarction with ventricular septal rupture in elderly patients with cardiac insufficiency is a new attempt, the successful treatment of this case shows that this method is feasible, for some patients is an appropriate treatment. Interventricular septal rupture is a common complication of myocardial infarction and a serious threat to the lives of patients. The traditional treatment of myocardial infarction with ventricular septal rupture is surgical treatment. For the elderly patients with cardiac insufficiency, surgical treatment is very risky. The successful treatment of this case by interventional occlusion is a new method. No relevant literature reports have been found.A 77-year-old male patient had a history of myocardial infarction for half a year, but without significant discomfort, lived a normal life at home. Two hours before seeing a doctor, he suddenly developed significant palpitations and shortness of breath and was admitted to the Second Hospital of Lanzhou University by ambulance. The patient’s expression was painful and a distinct murmur was heard in the precordium. Electrocardiogram showed old left ventricular anteroseptal myocardial infarction. X-ray showed enlarged heart shadow. Myocardial enzymes and other laboratory test results showed no significant abnormalities. Echocardiography showed that the interventricular septum was thinned near the apex and bulged toward the right ventricular side, exhibiting “paradoxical motion,” and a rupture opening of about 8 mm in diameter was visible on its top Fig. . CDFI: lMyocardial infarction with ventricular septal perforation will cause rapid hemodynamic changes, a serious threat to the patient’s life, often died shortly after the onset . Twenty-Transesophageal echocardiography-guided interventional occlusion of myocardial infarction with ventricular septal rupture in elderly patients with cardiac insufficiency is a valuable attempt, the successful treatment of this case shows that this method is feasible, for some patients is an appropriate treatment.


Hypoxia and low pulmonary arterial (PA) blood flow stimulate the development of systemic-to-pulmonary collateral blood vessels, which can be an adverse factor when performing the Fontan operation. The aim of this study was to use optical coherence tomography (OCT) to elucidate the morphological changes in PA vasculature after creation of a bidirectional cavopulmonary connection (BCPC) in children.This prospective study evaluated PA wall thickness and development of PA vasa vasorum (VV) in the distal PA of eight patients  and 20 age-matched children with normal pulmonary artery hemodynamics and morphology . VV development was defined by the VV area ratio, defined as the VV area divided by the adventitial area in cross-sectional images.There was no significant difference in PA wall thickness between the BCPC and control groups . The VV area ratio was significantly greater in the BCPC group than in the Control group .OCT is a promising new tool for evaluating PA pathology, including the development of VV in patients after BCPC. The vasa vasorum (VV) in the pulmonary circulation are the microcirculatory network of the systemic circulation and, similar to their role in systemic vessels, are thought to contribute to vascular integrity through supply of oxygen and nutrients to the outer part of the vessel wall ,2. Low pHowever, the current understanding of the pathophysiology of the PA is incomplete, since information regarding alterations in pulmonary vasculature is primarily obtained from autopsy or tissue specimens. Only limited data related to intravascular imaging of the PA is available, primarily due to a lack of adequate imaging techniques. The technique of optical coherence tomography (OCT) has led to significant advancements in intravascular imaging, which has enabled precise examination of PA morphology. Recent reports have shown that OCT is useful not only for the diagnosis of pulmonary hypertension, but also for evaluation of the response to treatment ,8.The present study evaluated morphological changes in the PA, including the development of PA VV, to elucidate pathological changes in the PA of children in the interim between creation of BCPCs and the Fontan operation.This was a single-center, prospective, observational study. The study group included 8 consecutive patients after BCPC . The diagnoses in them included: single ventricle (n = 4), pulmonary atresia with intact ventricular septum (n = 3), and double outlet right ventricle (n = 1). The patients underwent cardiac catheterization for evaluation prior to the Fontan procedure. Twenty age-matched children with normal pulmonary artery morphology and pressure were also enrolled . The control group consisted of patients with diagnoses as follows: nine patients after recovery from Kawasaki disease without any coronary artery stenosis or myocardial ischemia, nine patients with patent ductus arteriosus with a pulmonary to systemic blood flow (Qp/Qs) ratio of less than 1.1 who were scheduled to undergo catheter occlusion, and two patients with ventricular septal defect associated with aortic regurgitation whose Qp/Qs was less than 1.1. Participants were included in this study only if they were between 1 and 2 years of age between December 2013 and August 2016. All patients had been scheduled for evaluation of their circulatory status. All protocols were approved by the Institutional Review Board of Tokushima University Hospital and conformed to the ethical guidelines of the Declaration of Helsinki (1975). The parents of all subjects provided their written, informed consent for their children to participate in the study.Catheterization and angiography using an Integris Allura 9 Biplane cardiac catheterization system  were performed using 4 to 6 Fr catheters. All patients were examined under general anesthesia and endotracheal intubation. No patient suffered complications from conventional angiography and OCT imaging. OCT image acquisition was performed using a commercially available ILUMIEN FD-OCT Imaging System . Images were obtained from a segmental PA of the inferior lobe both in the stationary state and during a pull-back rate of 54 mm/sec. The low-molecular-weight dextran flush technique was used to run off blood and obtain high quality images.We evaluated the PA wall thickness and expansion of the PA VV in distal pulmonary vessels with a diameter of 2.0–2.5 mm, because our previous investigation demonstrated that this size of PA was most frequently delineated . DevelopU-test, as appropriate. All statistical data were calculated using Prism version 6.0  and JMP 11  software installed on a desktop computer. A value of p < 0.05 (two-sided) was considered significant.All data are expressed as means (standard deviation) (SD) or as medians with the 5th– 95th percentiles. Statistical significance was determined using Student’s t-test or Mann-Whitney’s This report indicated that OCT is an adequate imaging procedure for demonstration of the development of PA VV in patients after BCPC. Although the precise cellular and molecular mechanisms regulating adventitial neovascularization remain unknown, it has been demonstrated that hypoxia induces the development of PA VV, which form the microcirculatory network of the systemic circulation ,2,4. VasThe results of this study indicate that visualization of the PAs using OCT can be clinically useful to assess pathological remodeling and therapeutic effects in patients after BCPC. This method might also find application in patients with other kinds of cyanotic congenital heart diseases, to predict the future quality of the circulatory condition and pulmonary vascular function.In the present study, development of the VV was evaluated by the VV area ratio, defined as the VV area divided by the adventitial area in cross-sectional images. We defined the outer boundary of the adventitia as 500 μm outside the intima-media layer, because it is morphologically unclear. It would be necessary to determine the more appropriate measuring method in future. This study only demonstrated the enhanced presence of VV in the adventitia of the PA after the BCPC procedure, but did not assess its clinical significance. The correlation between the VV area ratio and SPCA flow volume should be evaluated in future to establish the clinical significance of PA OCT imaging in this patient group. It is also desirable to assess the relationship between the development of VV and oxygen saturation levels. The adventitia and VV may serve as a rich source of various cell types  that contribute to pathophysiological changes in vascular structure. Evaluation of sequential morphological changes in the VV after Fontan operation should also be conducted to assess future prognosis in these cases.Development of VV in children after BCPC can be evaluated using OCT. This technique might also be a promising new tool for evaluating PA remodeling in cyanotic congenital heart disease patients.S1 Table(XLSX)Click here for additional data file.S2 Table(XLSX)Click here for additional data file.


Heart failure is a worldwide leading cause of hospital admissions. There is a critical need for new methods of management in acute heart failure. The current drug panel available in the treatment of hemodinamically unstable patients is not only limited, but it is also associated with deleterious side effects. Discoveries in the heart failure field seemed to lack an adequate answer and a change in paradigm may be necessary. The cardiac myosin activator omecamtiv mecarbil is a new therapeutic approach that improves the myocardial contractility through an innovative mechanism, avoiding the harmful effects of currently used inotropic agents. Several studies provided us with promising results, but further scientific proofs are needed. In the developed world it is estimated that 1-2% of general population have HF5. The pathophysiological mechanisms of this condition are complex and involve various adaptive interconnected neurohormonal pathways which enter a positive feedback loop with deleterious long term effects. HF may have a preserved (HFPEF) or a low ejection fraction (HFLEF), according to the pathophysiological stage. The actual therapeutical approach in chronic HFLEF is focused on neurohormonal antagonism with angiotensin enzyme inhibitors, beta-blockers and mineralocorticoid receptor antagonists, associated with preventive measures, risk factors and comorbidities management. Non surgical and surgical supportive devices play also a role4.A variety of cardiac diseases can converge in time to heart failure (HF), a pathological condition characterized by heart’s inability to provide oxygen in response to tissular metabolic demands, with normal or increased filling pressuresTable 1). These agents stimulate heart contractility through various mechanisms, being particularly administered in order to control hemodynamic status in acute settings and to ameliorate symptoms in chronic patients4,6.A pharmacological class of drugs that is traditionally used to improve systolic function in patients with HF and to break the neurohormonal loop are the inotropes 14. Besides the fact that increased intracytosolic calcium is the main cause to this susceptibility to developing tachyarrhythmias, it also leads to more energy involved into calcium transport back in the sarcoplasmic reticulum through Ca-ATPase (SERCA) pumps, the aftereffect being increased oxygen demand14-16.The downside of using inotropic agents in the treatment of acute heart failure is their possible adverse events. The main inotropic action mechanism is also the reason of potential development of cardiac arrhythmias15-17. Beta adrenergic agonists work by activating G protein, which has as an end-point increased levels of cAMP, through the action of adenylyl cyclase on ATP. In myocytes, this process leads to phosphorylation of L-type calcium channel and the subsequent influx of calcium activates ryanodine receptors, ultimately increasing Ca-mediated myocardial contractility. In the peripheral vasculature, activation of beta-2 adrenergic receptors leads to vasodilation, a process explained by the phosphorylation of the protein phospholamban, which makes possible the reuptake of calcium by the sarcoplasmic reticulum6,18.Another problem that should be taking into account is the possible hypotension, which is the result of increased cAMP in the peripheral vessels, leading to poor coronary perfusion19. On the other hand, PDEI should not be used in patients with reduced glomerular filtration rate, as milrinone is renally excreted6. It is demonstrated in OPTIME-CHF  study that the use of milrinone is not recommended in patients with decompensated heart failure not only because of tachyarrhythmias and hypotension events, but also for the fact that there is no decrease in the rate of mortality between Milrinone and placebo groups20.Patients with decompensated heart failure, under chronic treatment with full-dose beta blockers, might not experience an adequate increase in cardiac output when dobutamine is administered. Instead, they could be treated with phosphodiesterase inhibitors (PDEI)21.Another category of inotropes, calcium sensitizer agents (prototype: Levosimendan), work by improving the binding of Ca to troponin C, independent of adrenergic pathway. For this reason, it seems to have less pro-arrhythmic side effects and does not cause increased oxygen consumption. Moreover, levosimendan appears to cause vasodilation through ATP-sensitive potassium channels, but only at high concentrations, that are not usually used in clinical practice. However, no difference in mortality has been noted between levosimendan and dobutamine. Furthermore, because of its vasodilation effect, calcium sensitizers have not been effectively studied in patients with cardiogenic shock, more clinical trials being required22. Tolvaptan - a selective V2 vasopressin antagonist - is the only HF-related NME approved in the last 10 years but for treatment of hyponatremia, including hyponatremic HF23. According to Pierre Pollesello, some contributing factors to this situation might be the continuously evolving HF definition, the low cost for present medical therapies, the redirection of funds towards other research areas by pharmaceutical companies, the demands for expensive long term mortality trials and study recruiting issues related to the heterogeneity of HF patients24. This might also imply that we are not looking in the right direction yet and new research perspectives are needed.Despite this epidemiological context, there is an important gap in developing efficient new molecular entities (NME) for HF treatment, with no Food and Drug Administration (FDA) approved inotropic agent in the last two decades25. A small molecule that enhances contractile motor protein myosin activity bypassing the second messenger regulation could bring new hope in HF treatment26. Theoretically, an ideal small molecule myosin activator should ameliorate the rate-limiting step in actin-myosin cycle, would recruit more myosin heads during the cardiac circle, would not have vascular effects and would not elicit calcium-related adverse reactions27. So, the overall effect would be to improve cardiac contractility in a “more hands on the rope” manner28. Several compounds have been developed and tested in preclinical studies deepening our understanding about this inotropic mechanism and about the necessary properties29,30.The discovery of a new class of inotropic drugs appeared to be a possibly feasible step form theory to practice31. This new molecule is able to specifically bind at S148 heavy chain activating the cardiac myosin, but it has no effect on the smooth nor the skeletal muscle myosin32. OM appears to speed up the transition of myosin from a weak actin-binding in a strong actin-binding force-generating state, this being the rate-limiting step of actin-myosin-ATP interaction and also of myocyte contraction 32. In vitro, OM increased the duty cycle of acto-myosin interaction in tissue purified ventricular myosin33.A group from Cytokinetics finally succeeded in creating and refining a compound with the needed characteristics for entering the clinical trials step: CK-1827452, AMG 423 or omecamtiv mecarbil (OM)34. Multiple studies in humans were performed, they are listed in Table 2.The results obtained by using two canine models of HF were promising. The HF was induced by rapid pacing in two situations: after myocardial infarction induced by ligation of left anterior descending coronary artery and after myocardial hypertrophy caused by 1 year - long ascending aortic banding. OM was administered in 0.25 mg/kg bolus followed by continuous perfusion of 0.25 mg/kg/h during 24h. The treatment decreased the heart rate (HR), mean left atrial (LA) pressure, left ventricular (LV) end-diastolic pressure and improved LV systolic ejection time (LVSET), systolic wall thickening and stroke volume (SV) at 15 minutes, 4 hours and 24 hours of treatment and increased cardiac output at 24 hours. A reduction in vascular peripheral resistance was noted at 4 and 24 hours. No changes of LV dP/dt max, mean arterial pressure or myocardial oxygen consumption were remarked28. This phase I, single center, double-blind, randomized, dose-escalating, placebo-controlled trial aimed to evaluate the maximum tolerated dose of OM and to investigate its pharmacodynamic and pharmacokinetic properties. 34 healthy men divided in 4 cohorts  received 6 hours continuous intravenous infusions of increasing OM doses (0.005 mg/kg/h to 1 mg/kg/h) at one week apart. The maximum tolerated dose was established at 0.5 mg/kg/h which was well supported by 16 subjects during 6 hours, the maximum concentration being 905 ng/ml. Other findings concerning the pharmacologic properties were: mean elimination half time of 17.1-23h, clearance of 132-207 mL/h/kg and mean volume of distribution of 3.7-5.2 L/kg. Serial echographic measurements showed that EF, SV, SET time and fractional shortening increased in a dose-dependent manner.The first one was realized by Teerlink et al. during 2005-2006The diastolic function seemed to be less influenced, with a decrease of ratio between early maximal ventricular filling velocity and late filling velocity (E/A), due to an improvement and prolongation of atrial contraction. The limiting effect was myocardial ischemia (moderate troponin elevation but no infarction) seen at doses higher than 0.75 mg/kg/h. This was most probably generated by a shortening in diastolic coronary filling time due to systolic prolongation. In the tolerated doses range the authors noted some more frequent pain at catheter insertion site, but without other adverse reactions. No effect on HR was observed.35. Only patients with sinus rhythm, glomerular filtration rate  over 35 mL/min, no cardiovascular-related hospital admission during the last 6 weeks and no Canadian Class III or IV angina were included. Divided in 5 cohorts of 8-10 individuals each, the patients received 2h, 24h or 72h escalating infusions doses (loading + maintenance) of OM in order to achieve the previously established tolerated dose range in healthy volunteers. The data analysis confirmed the directly proportional relation between plasma concentration (pC) and systolic ejection time, fractional shortening (at pC >100ng/mL) and stroke volume (at pC>200 ng/mL). The ejection fraction increased at pC>300 ng/mL and both left ventricular systolic and diastolic volumes decreased at pC>500 ng/mL. The results persisted after 24h and 72h of infusion. Atrial contraction was also prolonged, with a decrease of E/A. Interestingly, it was noted a reduction in HR which was not the case in healthy patients, and a slight decrease in QTc. Myocardial ischemia was noticed in 3 patients - one accidentally overdosed, and two others with low drug clearance, obesity and hypertension. For the remaining patients no elevation in NT-proBNP, nor troponin was observed.Cleland et al conducted the first study in stable HFLEF patients  which enrolled 45 patients in a double-blind, randomized, crossover, dose ranging, phase II design36. This double-blind, randomized, placebo-controlled, multicenter, phase II study included 600 patients with decompensated systolic HF (EF<40%) - dyspnea at rest or with minimal effort resistant to diuretics and elevated BNP or NT pro-BNP. Patients were treated in 3 cohorts with 48h OM infusion targeting pC of 115, 230, 310 ng/mL respectively. The primary endpoint of dyspnea amelioration  was not achieved but a favorable trend was observed with higher doses and also a reduction in episodes of worsening of HF. These might be attributed to the lower pC achieved in this study comparative with the other studies. However, the previous findings in healthy volunteers and stable HF were replicated regarding the increase in SET, decrease in HR and safety issues (despite a slightly increase in troponin non related to pC).The data from ATOMIC-AHF (NCT01300013) study were presented at European Society of Cardiology Congress in 2013Other phase I or II studies investigating the pharmacological properties of oral or IV OM in patients with ischemic cardiomyopathy, stable heart failure or with various degrees of renal failure were performed without published results yet . COSMIC-HF (NCT01786512) is an interesting study that may answer some questions about the future of OM but is still recruiting at this moment. Designed as a phase II, double-blind, randomized, placebo-controlled, multicenter, dose escalation study, it aims to evaluate an oral modified release (MR) OM formulation (BID) in HFLEF over 20 weeks of treatment.37. A success for OM in clinical trials might lead to a change in HF management paradigm. Despite that, there are still more questions than answers because the published studies were restricted only to a specific HF population until now. For example, it would be important to clarify the behavior of OM in patients with atrial arrhythmias or atrio-ventricular conduction abnormalities, because it seems that OM might modify atrial contractility and shorten QTc. The patients with valvular pathologies or obstructive hypertrophic cardiomyopathy should also be investigated, prolongation of SET being the marker of OM. COSMIC-HF might bring insights about OM chronic therapy and also about pharmacologic properties of oral administration.Lots of hopes have been generated by OM, supported by the rather positive findings of current studiesAt this moment, omecamtiv mecarbil appears to be a distinctive and unique molecule whose mechanism of action seems promising in the future therapeutic interventions. It is certain that further studies are needed to understand the pharmacodynamics and the therapeutic outcomes of this promising drug.Current inotropes have serious adverse effects trough calcium- or cAMP-mediated mechanismsThere aren’t any inotropic drugs FDA-approved in the last two decadesDirect myosin activator OMECAMTIV MECARBIL emerges as an innovative therapy in heart failure by prolongation of systolic ejection time but further studies are necessary to validate its importance


LVDF), an integrated part of evaluation of left ventricular function is still a delicate task and is performed with substantial inter‐rater variability. Therefore, we aimed to create and evaluate a guidelines‐based automated decision support. An algorithm was created for a hierarchical analysis of LVDF based on variables as recommended by the latest guidelines. Age‐adjusted normal ranges were pooled from previously published studies into an integrated reference table. For proof‐of‐concept, 20 echocardiographic examinations were analyzed offline by four experienced physicians with more than 10 years of echocardiographic experience. The first assessments were to be performed as they would be in the clinical practice. Six months later, the assessments were repeated based on the 2017 ASE/EACVI guidelines. The overall inter‐rater agreement for the first clinical assessments was moderate, while the guidelines‐based assessments had only fair inter‐rater agreement. Both kinds of manual assessment had poor agreement with the standardized automated assessment algorithm of LVDF. In conclusion, the presented automated decision support for evaluation of diastolic LV function by Doppler echocardiography is mainly based on current guidelines involving multiple parameters in combination. Incorporating age dependency aspects in our program (available for use at https://liu.se/en/research/left-ventricular-diastolic-function-decision-support) enhances the accuracy of the evaluation and reduces variability in evaluation of LVDF. The large inter‐rater variation in classification in this study also underscores the usefulness of tools to support a standardized evaluation.Echocardiographic assessment of the left ventricular diastolic function ( Echocardiographic assessment of the left ventricular diastolic function (LVDF) has become an integrated part of clinical routine. The American Society of Echocardiography (ASE) and the European Association of Cardiovascular Imaging (EACVI) have provided clinicians with guidelines and recommendations to facilitate standardized assessment  a guidelines‐based automated decision support algorithm, and (2) to evaluate and compare inter‐rater agreement for manual LVDF assessments and the decision support algorithm.An automated standardized analysis algorithm Fig.  was creaCurrent guidelines , and pulmonary vein systolic/diastolic (PVs/PVd) velocity, both age‐related, and left atrial area indexed for BSA (LAAi) as described in Figure For left atrial (LA) size, recommendations advocate biplane volume determination  from a cohort of 397 patients with severe aortic stenosis who had been referred for operation during a 5‐year period at the Department of Cardiothoracic Surgery, University Hospital, Linköping, and who had been included in a study of preoperative characteristics and outcome. The sample represented a spectrum of diastolic function abnormalities and an age distribution representative of patients where diastolic function is often evaluated.Echocardiographic images  were saved for offline analysis. LVDF was evaluated by four experienced physicians, clinical physiologists with more than 10 years of echocardiographic experience. These physicians were instructed to perform a first assessment, independently from each other, conducting the evaluation as they would do in their clinical practice. The assessments were repeated 6 months later for the same batch by the same clinical physiologists. This time they were instructed to perform the assessments based on the ASE/EACVI guidelines  was computed to evaluate agreement among evaluations. Agreement was considered to be poor for κ < 0.20, fair for κ = 0.21–0.39, moderate for κ = 0.4–0.59, good for κ = 0.60–0.79 and very good for κ > 0.8 .Manual and automated assessments were compared by attribute assessment analysis and Fleiss’ kappa  and every patient signed the informed consent for the study.2 and BMI 24.6 ± 3.3 kg/m2 (mean ± SD). The male‐female ratio was 10:10.The evaluated 20 patients were 72 ± 12 years old with a BSA 1.9 ± 0.2 mThe overall inter‐rater agreement for the first clinical assessments was moderate while the guidelines‐based assessments 6 months later had only fair inter‐rater agreement. Both kinds of manual assessment had poor agreement with the standardized automated assessment algorithm of LVDF Table . The onlEvaluation of the LVDF is complex due not only to the number of variables to be considered but also the factors affecting these variables. For example, filling velocities through the mitral valve can be affected by concomitant aortic regurgitation. Also, because of annular calcification, mitral annulus motion affects the echocardiographic measurements and the variables are age‐dependent. We found poor inter‐rater agreement for assessment of the LVDF, in concordance with previous studies. Unzek et al.  found thIn our inter‐rater study, the instruction to adhere to guidelines did not improve the uniformity of manual classification of diastolic function. Differences in interpretation of the guidelines regarding which algorithm to use and how to handle conflicting data probably influenced this. There was also limited agreement between manual measurements and our decision support tool. Both this and the inter‐rater discrepancy are clinically relevant since the presence or absence of elevated LV filling pressures is related to prognosis in different disease states. Although the tool is based on the same principles as advocated by the guidelines, we have introduced age‐adjusted reference limits to improve the accuracy of the classification. Several studies on normal subjects  facilitates the practical implementation. The large inter‐rater variation in classification in this study also underscores the usefulness of tools to support a standardized evaluation.In conclusion, we present an automated decision support for evaluation of diastolic LV function by Doppler echocardiography. The algorithm is mainly based on current guidelines in that it involves multiple parameters in combination. However, the strong age dependency of several of these parameters implies that an adequate evaluation should involve age‐related normal values and cutoffs. Incorporating age dependency aspects in our program (available for use at The authors have no conflicts of interest to declare.


Long-term cardiovascular magnetic resonance (CMR) data on atrial and ventricular remodeling after ASD-closure is limited and treatment effect on exercise capacity is debated. Sixteen patients undergoing transcatheter ASD closure and 16 age and sexmatched controls were studied. CMR was performed before treatment, the day after and 3 and 12 months later. Exercise test with gas analysis was performed before and 12 months after treatment. QP/QS decreased from 2.1 ± 0.5 to 1.4 ± 0.3 at day 1 and 1.1 ± 0.1 at 3 and 12 months. Left ventricular (LV) volumes increased and normalized on day 1 whereas left atrial volumes were unchanged. RV and right atrial volumes decreased the first 3 months. LV and RV volumes had not equalized at 12 months  and RV ejection fraction remained decreased compared to controls. Improvement of VO2% after ASD closure (P < 0.01) was inversely related to QP/QS at rest  but unrelated to RV end-diastolic volume (P = 0.16). Following transcatheter ASD closure, LV adaptation is rapid and RV adaptation is prolonged, with decreased systolic RV function. Patients with smaller shunts had larger improvement in VO2% suggesting patients with defects of borderline hemodynamic significance might benefit from closure. This may be due to impaired LV diastolic function influencing shunt size and exercise capacity following ASD closure.Investigate ventricular and atrial remodeling following atrial septal defect (ASD) closure and examine if pulmonary-to-systemic flow ratio (QP/QS) and right ventricular (RV) volume predict improvement, determined as percentage of predicted oxygen uptake (VO The indications for surgical or transcatheter closure of secundum atrial septal defects (ASD) are enlargement of the right ventricle (RV) or symptoms including exercise intolerance, fatigue or dyspnea . The lon2%).The aim of the present study was to show the time course of ventricular and atrial remodeling following transcatheter closure of secundum ASD and determine if pulmonary-to-systemic flow ratio (QP/QS) and RV volume could predict improvement after treatment, as determined by predicted peak oxygen uptake  with hemodynamically significant secundum ASD (QP/QS > 1.5) scheduled for transcatheter ASD closure were included and underwent CMR and exercise testing with direct respiratory gas analysis. All patients willing to participate in the study were included, except for patients with atrial fibrillation. CMR was repeated in patients the day after transcatheter closure of the defect and 3 months and 12 months after treatment. Exercise test with respiratory gas analysis was repeated at 12 months follow-up. Sixteen age and sex-matched controls were also examined with CMR and exercise test with 12 months’ time interval.All subjects were planned for CMR at rest in supine position and during end-expiratory breath hold. A 1.5 T CMR scanner was used for all studies . Steady state free precession cine CMR images were acquired in three long-axis planes and in short-axis stacks covering the whole heart. Imaging parameters for cine CMR were typically: retrospective ECG triggering with acquired temporal resolution of 47 ms reconstructed to 30 time phases per cardiac cycle, repetition time 3 ms, echo time 1.4 ms, flip angle 60°, slice thickness of 8 mm with no slice gap. Breath-holds were typically 10 s. Flow velocity mapping was acquired using a retrospectively ECG triggered fast-field echo velocity encoded sequence, acquired as separate acquisitions in the ascending aorta and the pulmonary trunk during free breathing. Imaging parameters were typically: repetition time 10 ms, echo time 5 ms, flip angle 15°, and slice thickness 8 mm, acquired in-plane resolution 2.4 × 2.4 mm reconstructed to 1.3 × 1.3 mm, number of acquisitions 1, no parallel imaging and a velocity encoding gradient (VENC) of 200 cm/s. The flow sequence had an acquired temporal resolution of 20 ms during the cardiac cycle reconstructed to 35 phases per heart cycle and a typical scan time of 2 min.https://segment.heiberg.se) [All image analysis was performed using Segment, v1.9 (berg.se) . Ventricberg.se)  and the 2peak) was defined as the average of three highest VO2 values documented during the last minute of the test. Blood pressure and a 12 lead ECG were monitored during exercise. VO2peak percent of predicted value (VO2%) was calculated according to the Hansen/Wasserman equation [Exercise testing was performed before ASD closure and 12 months later, using Monark 939E cycle ergometer and Oxygen Pro . Peak oxygen uptake . However, RAVi decreased the day after closure with further decrease at 3 months. At 12 months, RAVi did not differ between patients and controls. The QP/QS (r = 0.79) and shunt per heartbeat (r = 0.83) correlated with the RVEDV/LVEDV ratio before ASD closure (P < 0.001 for both) and the change in RVEDV from baseline to 3 and 12 months follow up had a strong correlation with shunt size prior to ASD closure  from cardiopulmonary exercise testing did not differ before ASD closure (25.6 ± 7.2 mL/kg/min) and 12 months later , but the VO2 as percent of predicted value (VO2%) improved from 101 ± 19% before to 108 ± 19% at 12 months , change in RV size from baseline to 12 months follow-up (P = 0.28 for RVEDVi and P = 0.66 for RVESVi), or with RVEDV/LVEDV ratio before ASD closure (P = 0.54). There was no correlation between improved VO2% and the patients’ age (P = 0.77).Absolute peak oxygen uptake VOpeak from2%) at 12 months follow up to be lower in adult ASD patients with larger shunts compared to smaller shunts. This indicates that patients who have had increased pulmonary blood flow for a long time may not have the same positive outcome of treatment as expected in children or younger aged patients [This study is the first to longitudinally investigate secundum ASD patients treated with catheter mediated device closure with serial CMR examinations up to 1 year after closure. Four-chamber volumetric evaluation showed differences in cardiac adaptation between the left and right ventricles. The LV adaptation was rapid, as early as the first day after closure of the ASD, whereas the changes in RV volumes were more gradual and plateaued at 3 months. Right atrial volumes decreased till 3 months, but left atrial volumes did not change after ASD-closure. Patients had similar LV and LA volumes and global systolic LV function after treatment compared to controls, even though the exercise capacity was much lower in the former. The enlarged RV end-systolic and reduced RV systolic function at 12 months after closure may explain this, or alternatively this may be related to impaired LV diastolic function. We observed the improvement of predicted oxygen uptake  did. The lack of increase in absolute VO2peak does not translate to absence of subjectively experienced improvement. Quality of life has been shown to improve after ASD closure [2% = 101%) whereas others have reported considerably lower values [2% = 152%). The pretreatment normal VO2peak in our patient cohort could explain the unchanged absolute VO2peak at follow up, as they may have less potential for improvement compared to patients with impaired pretreatment exercise capacity. Previous studies have shown conflicting results after ASD closure with both improved and impaired exercise capacity reported [VO2peak and LVEF [VO2peak is that patients may have adapted to a certain degree of physical limitation even if NYHA class improved. Indeed, a study by Kröönström et al. found that adults with congenital heart defects have impaired isotonic muscle function compared to healthy subjects [The improvement in oxygen uptake for absolute values from before closure to 12 months follow-up did not reach statistical significance, while VO closure  and inder values , 12, 13.reported , 13, 17.and LVEF . LVEF diand LVEF , 5. The subjects . Low isosubjects . Therefosubjects . It appe2% in patients with larger shunts to be related to LV diastolic function and shunt size because a patient with large ASD and impaired LV diastolic function will have a large shunt and a patient with large ASD and normal LV diastolic function will have a smaller shunt. In addition, patients with diastolic dysfunction may also have increased LV filling pressure during exercise - another cause for reduced pretreatment exercise capacity. This relationship is highlighted in the recent clinical trials of using interatrial shunt device to treat patients with LV diastolic dysfunction and increased LV filling pressure [Diastolic dysfunction that becomes unmasked with ASD closure could be a third factor explaining the modest improvement in exercise capacity in our patients. Increased LV end-diastolic pressure has been reported following ASD closure in the older population, where abnormal LV relaxation, increased LV stiffening and impaired contraction due to chronic underload may coexist –28. In opressure . LA volupressure , but tha2 max is probably negligible as we used age-predicted values. Invasive pressure data after closure of the ASD was not available but would have been helpful to determine if diastolic dysfunction explains the limited improvement in exercise capacity. MRI data on transmitral flow was only obtained from a few patients and thus was not sufficient for assessment of LV diastolic function.The sample size is small which is explained by this being a single center study with a relatively small population. Although we aimed to include age matched controls, there were still a difference in age between healthy controls and patients (mean age 46 vs. 52 years). This could potentially affect cardiac volume comparisons as they are age related, but this effect is probably small. The influence on VOThe time course of ventricular remodeling after ASD closure is faster in the LV compared to the RV. Enlarged RV volume remained in our cohort after one year. The RA volumes showed reverse remodeling until 3 months but LA volumes did not change at all. Exercise capacity was lower in patients even with no difference in LV volumes and function from controls, which may be related to LV diastolic dysfunction or reduced RV global function. The improvement in peak oxygen uptake after ASD closure in adult patients is not straightforward. Patients with smaller shunts in this series had larger improvement in predicted exercise capacity, which suggests that patients with small ASDs also might benefit from closure.