Obstructive sleep apnea syndrome (OSAS) can lead to alterations in right ventricular (RV) performance and pulmonary vascular haemodynamics. Additionally, altitude-related hypoxia is associated with pulmonary vasoconstriction, and the effect of high-altitude on the pulmonary circulation in OSAS patients can be further altered. We sought to assess alterations in RV morphology and function in OSAS patients living at high altitude by way of 2-dimensional speckle tracking echocardiography (2D-STE), real-time 3- dimensional echocardiography (RT-3DE) and cardiac biomarkers. We also evaluate the impact of continuous positive airway pressure (CPAP) treatment on RV performance. Seventy-one patients with newly diagnosed OSAS and thirty-one controls were included in this study. All individuals were assessed for cardiac biomarkers as well as underwent 2D-STE and RT-3DE. Forty-five OSAS patients underwent CPAP therapy for at least 24 weeks and were studied before and after CPAP treatment. RT-3DE was used to measure RV volume, and calculate RV 3D ejection fraction (3D RVEF). Peak systolic strain was determined. Cardiac biomarkers, including C-reactive protein (CRP), N-terminal pro-B-type natriuretic peptide, and cardiac troponin T were also measured. Right atrium volume index, RV volume, RV volume index, systolic pulmonary artery pressure (sPAP), pulmonary vascular resistance (PVR) and level of serum CRP were significantly higher in OSAS group, while OSAS patients showed lower 3D RVEF and RV longitudinal strains. Compared to the patients with sPAP < 40 mmHg, RV longitudinal strains in patients with sPAP ≥ 40 mmHg were lower. Both RV global longitudinal strain and sPAP were associated with apnea–hypopnea index. Patients treated with 6 months of CPAP therapy had significant improvement in RV geometry and performance. RV structural abnormalities and RV function impairments were observed in OSAS patients living at moderate high altitude compared to control highlanders. The reversibility of these changes after application of CPAP were further confirmed. It is associated with an increased risk of cardiovascular morbidity and mortality2. OSAS is also independently associated with the occurence of cardiovascular disease such as atrial fibrillation3, coronary artery disease4, heart failure5 and stroke6.Obstructive sleep apnea syndrome (OSAS), which is characterized by periodic upper airway obstruction during sleep, waking up repeatedly from sleep and excessive daytime sleepiness, is a common clinical form of sleep disordered breathing8. However, there are few reports indicating the effect of OSAS on the right ventricular morphology and function. The exact pathophysiological mechanism of right ventricle (RV) remodeling in OSAS patients is unclear, but studies have shown that elevated sPAP and hypoxic-oxidative stress caused by apnea/hypopnea may be related to it9.Several observations have confirmed the adverse effects of OSAS on the left ventricle. For example, LV systolic function and diastolic function were both adversely affected, that was, global longitudinal strain (GLS) and LV ejection fraction decreased10. Compared to healthy highlanders, even OSAS patients who lived at moderate high altitude had shown higher systolic pulmonary pressure and more significant RV remodeling11. Previous studies have assessed the impact of OSAS treatment with continuous positive airway pressure (CPAP) on the functional changes of the left ventricle13 and right ventricle15, confirming the improved LV and RV function. However, the degree of RV alterations in OSAS patients who lived at mid-high altitudes with CPAP treatment remains to be studied.Hypoxia is a strong stimulus to pulmonary artery vasoconstriction, which causes increased pulmonary artery pressure and pulmonary vascular resistance, and further leads to adaptive changes of RV16 and real-time 3-dimensional echocardiography (RT-3DE)17 are independent on the assumption of cardiac geometry and have no angular dependence. Therefore, in theory, both 2D-STE and RT-3DE are suitable for evaluating the structure and function of right ventricle.The right ventricle (RV) has a complex anatomical structure with a "crescent shape" in the cross-section, which contains a large number of muscle trabeculae and thick control cords. In addition, the ventricle is located behind the sternum. It is difficult to assess RV geometry and function with conventional echocardiography. Two-dimensional speckle tracking echocardiography (2D-STE)18. In addition, serum C-reactive protein (CRP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and cardiac troponin T (cTnT) levels were previously evaluated in OSAS patients22. Although cardiac biomarkers are useful in the diagnosis of many cardiovascular disease, their roles in evaluating OSAS-associated cardiac dysfunction remain controversial26, not to mention in high altitude settings.The right ventricular volume and ejection fraction measured by RT-3DE have a good correlation with the "gold standard" results measured by cardiac magnetic resonance (cMRI)We hypothesized that the use of new echocardiographic techniques and cardiac biomarkers could assess changes in RV geometry and function in patients with OSAS living at moderate high altitude, and that RV structural abnormalities and dysfunction could also be reversed by CPAP treatment.The present study was conducted in accordance with the principles of Declaration of Helsinki. Gansu provincial people’s hospital ethics committee approved the protocol, and written informed consent was obtained from all enrolled subjects.11.A cohort of newly diagnosed patients confirmed by polysomnography were recruited and referred to Sleep Center of Gansu provincial people's hospital, China. Healthy subjects were from physical examination Center of Gansu provincial people’s hospital. Exclusion criteria were: chronic lung disorders, congestive heart failure, cardiomyopathies, previous myocardial infarction, more than mild valvular heart disease and atrial fibrillation. All OSAS patients meet the following criteria: (i) all selected candidates were born in Lanzhou , and (ii) all selected candidates should not live at a lower or higher altitude for a long time (6 months or more)28. If the patient's AHI is greater than or equal to 5, it can be diagnosed as OSAS. Patients with AHI values between 5 and 15 are considered mild, patients with AHI values between 15 and 30 are considered moderate, and patients with AHI values greater than or equal to 30 are considered severe OSAS29. Forty-five compliant patients with OSAS who had performed CPAP (Philips DS500) therapy and completed RT-3DE and 2D-STE analyses were studied before and after treatment. Patients who received CPAP treatment were instructed to use the CPAP device nightly for at least 6 months, and echocardiograms were repeated on the second day after the last nocturnal CPAP treatment while patients were awake.All enrolled subjects  underwent polysomnographic recording using ALICE5  for a full-night within 24 h of admission. Obstructive apnea was defined as: compared with the baseline, after at least 10 s of breathing effort, the peak deviation of the oral and nasal heat sensor decreased b  ≥ 90%, at least 50% of the airflow decreased, and at least 3% of the oxyhemoglobin saturation decreased. The number of apnea/hypoventilations per hour was defined as apnea–hypopnea index (AHI).OSAS was defined as ≥ 5 AHI events per hour in the presence of clinical symptoms suggesting OSASEchocardiographic data were obtained using the EPIQ 7C  within 24 h of admission. The mean values of all echocardiography data were measured for three consecutive cycles. The examination was carried out by two experienced cardiologists who were unware of the existence of the disease or the severity of the individual.2 × 4) and the average pressure of the right atrium yields sPAP. Estimate the right atrial pressure by the quantitative assessment of inferior vena cava 30. Place the pulse wave Doppler at the proximal end of the RV outflow tract on the short axis side of sternum to obtain the RV outflow tract time–velocity integral (RVOT-VTI). The pulmonary vascular resistance was determined using the equation: pulmonary vascular resistance = peak tricuspid regurgitant velocity/RVOT-VTI × 10 + 0.1631.RV diameters  were measured in apical 4-chamber view. RV thickness was measured in sub-costal view when the tricuspid leaflet was parallel to the free wall of RV. Right atrium volume (RAV) was calculated by the area-length method in apical 4-chamber view and the right atrial volume indices (RAVI) were derived by dividing the RAV by the body surface area (BSA). RV global systolic function was assessed by measuring M-mode derived tricuspid annular systolic excursion (TAPSE). In apical 4-chamber view, early diastolic (E) and atrial (A) peak velocities (m/s) and E/A ratio at the tips of the tricuspid leaflets were recorded by pulsed Doppler. Pulsed Tissue Doppler of the lateral tricuspid annular was to measure systolic (S’), early diastolic (e’) and atrial (a’) velocities . The E/e’ ratio was obtained by dividing E by e’. The sum of the Bernoulli equation  equipped with STE analysis. The software analyzes motion by tracking the motion of natural acoustic markers between frames in a two-dimensional space. At the end of the systole, manually track the right ventricle rim and adjust the automatically generated region of interest according to the thickness of the myocardium. RV global longitudinal strain (RV GLS) was the average of 6 segments of the RV lateral wall and interventricular septum. Free lateral longitudinal strain (RV LLS) was the average of 3 segments of lateral wall and septal longitudinal strain (RV SLS) was the average of 3 segments of interventricular septum39.Peak systolic longitudinal strain of the RV free wall Fig.  was meas33. The RV end-diastolic volumes (RVEDV) and end-systolic volumes (RVESV) were determined by visual inspection throughout the cardiac cycle. The RV end-diastolic volumes indexs (RVEDVI) and RV end-systolic volumes indexs (RVESVI) were derived by dividing the RVEDV by the BSA and by dividing the RVESV by the BSA, respectively.RV 3D images Fig.  were obtPlasma and serum samples were stored for a maximum of 2 weeks at − 20 °C before being moved to a − 80 °C freezer. Serum levels of CRP were measured with latex agglutination immunoassay . NT-proBNP levels were measured with an electrochemiluminescence sandwich immunoassay . Quantitative determination of cTnT levels was performed using a third-generation Roche Elecsys assay.t test is used for comparison, and for the parameters of the non-normal distribution, the Mann–Whitney U test is used for comparison. For comparisons involving categorical variables, use the chi-square test or Fisher's exact test based on the expected cell count. Linear regression analysis was used to evaluate the correlation between AHI and clinical variables, and the Pearson (r) coefficient values were obtained. Independent links between variables were determined by multiple linear regression analysis.. The coefficient of variation was used to assess the intra- and interobserver variabilities for RV GLS, RV LLS, RVEDV, RVESV and RVEF assessed by 2D-STE and RT-3DE in a sample of 20 patients.All statistical analysis was performed with SPSS 19.0 for Windows software in a compatible computer. Data for continuous variables are presented as the mean ± SD or median and interquartile range, and categorical variables are presented as frequencies and percentages. One-way Kolmogorov–Smirnov test is conducted to test normal distribution within the groups. For the parameters of the normal distribution, the independent-samples p value < 0.05 was considered statistically significant.All statistical tests were two-sided, and a A total of 80 patients with first OSAS were initially evaluated. Nine patients were excluded: 5 (8%) patients did not have sufficient image quality for tracking of RV walls. Another 4 (7%) patients refused to enroll in the study. Thus, 71 patients were enrolled in the present study. Mean age was 48.0 ± 7.8 years, and 52 patients were males. Thirty-one patients matched to age and sex were control group.aO2) and time SaO2 < 90% significantly decreased in the OSAS group.Detailed demographic, clinical information and polysomnographic data from both OSAS patients and controls are displayed in Table a velocity, E/e’ value and RVOT-VTI. OSAS patients had lower RV GLS and RV LLS but not RV SLS than controls. These differences in RVEF, RVEDV, RVESV, RVEDVI and RVESVI were also observed in OSAS patients  increase in minimal SaO2. However, we did not observe any significant changes in clinical data before and after CPAP treatment, including BMI, body surface area (BSA), heart rate, cholesterol, LDL cholesterol, HDL cholesterol and triglyceride.The effects of > 6 months CPAP therapy on the echocardiographic and polysomnographic variables were listed in Table r = −0.66, p = 0.03), RV GLS , RV LLS , sPAP  and RVOT-VTI . In forward stepwise multivariate linear regression analysis, RV GLS , RV LLS  and sPAP  were independently related to AHI with a regression model r = 0.56.On correlation analysis, the following echocardiographic variables correlated with AHI: RVEF  A significant reduction in RV function  and increase in RV volume (both RVEDVI and RVESVI) were observed in OSAS patients compared with healthy controls; (2) RV GLS and RV LLS were significantly lower in patients with sPAP ≥ 40 mmHg compared to those with sPAP < 40 mmHg; (3) In the absence of significant changes in NT-proBNP and cTnT, serum CRP was significantly higher in the OSAS group than in the control group; (4) both RV GLS and sPAP were independently associated with AHI; (5) CPAP treatment could improve RV structure and function in OSAS patients living at high altitude.36. It is well known that pulmonary artery pressure could increase during apneas, but the mechanism of daytime PAH in patients with OSAS is still under discussion39. In the present study, we demonstrated that sPAP (42.7 ± 8.4 mmHg) and pulmonary vascular resistance  are significantly higher in the OSAS patients than in the control highlanders. The most likely primary cause of the OSAS-related increase in PVR and sPAP is hypoxemia. We recognize that pulmonary vasoconstriction is a response of the body to acute hypoxia, and it can also regulate capillary perfusion to adapt to alveolar ventilation40. Meanwhile, Experimental studies of simulated repeated nocturnal apnea in mice have shown that intermittent hypoxia may induce pulmonary vasoconstriction, which in turn leads to pulmonary hypertension and increases right ventricular afterload42. Previous studies had confirmed the effect of obese or OSAS patients living in high altitude areas on pulmonary artery pressure37. This study found that an sPAP ≥ 40 mmHg was present in 30% of the healthy group and in 48% of the OSAS patients, which were lower than the data for OSAS patients living at high altitudes11 and were markedly higher than the data for the healthy population37. In summary, the degree of pulmonary vasoconstriction is closely related to hypoxemia, thereby increasing the pulmonary artery pressure. Recently, Guvenc et al. demonstrated that compared to healthy highlanders, the significant increase in pulmonary artery pressure (38.35 ± 8.60 mmHg) was observed in OSAS patients, whose pulmonary artery pressure seemed to be slightly lower than our results (42.7 ± 8.4 mmHg)11. In the present study, we displayed that sPAP  and pulmonary vascular resistance  are significantly higher in the OSAS patients than in the healthy group. Therefore, our results not only support the view of adverse effects of hypoxemia, but also show the fact that sPAP is markedly higher in OSAS patients than in healthy group.SomeOSAS patients (17–52%) exhibit pulmonary artery hypertension (PAH) during daytime45. Previous study pointed out that 3D-RVEF and apical strain were the more sensitive predictors of unfavorable outcome after atrial septal defect closure compared to 2D-Doppler indexes43. Recently, Buonauro and colleagues demonstrated reductions of RV GLS and RV LLS in 59 OSAS patients compared to healthy controls, and found that RV GLS was independently related to the level of sPAP and the severity of AHI. However, there was no difference in 3D-RVEF between the two groups45. In our present study, we not only confirm the reduction of RV GLS and RV LLS between the two groups, but also display that 3D-RVEF in OSAS patients have a significant reduction. It is well known that 3D-RVEF has a stronger correlation with MRI compared with traditional echocardiographic indicators, such as right ventricular fractional area change (RVFAC), the TAPSE and myocardial performance index (MPI)43. Interestedly, 34 patients with sPAP ≥ 40 mmHg do not show significant changes of 3D RVEF whereas RV GLS and RV LLS were were markedly lower than 37 patients with sPAP < 40 mmHg, which is agreement with previous study45.Both STE and RT-3DE have been used to evaluate RV function in many cardiovascular diseases, including OSAS and atrial septal defect (ASD)47. Oliviera et al. had revealed that 56 patients with OSAS had significantly increased RV end-diastolic and end-systolic volumes and volumes indexes by using 3-DE47. More recently, Guvenc et al. had found that RV end-diastolic and end-systolic volumes indexes were significantly higher in OSAS patients than healthy highlanders11. In addition, Li et al. used velocity vector imaging (VVI) technology to evaluate the changes in the RA volume and function of OSAS patients46. Our study also finds that the RA and RV volumes and volumes indexes have significantly increased in OSAS patients. In our opinion, the most reasonable explanation for RA and RV dilatation is the increase in sPAP during the daytime in OSAS patients. However, previous studies on OSAS patients with normal daytime PAP had also revealed RV remodeling and dysfunction49, which provided evidence that other factors could have adverse effects.Previous studies had demonstrated changes in right ventricular structure and function in patients with OSAS50. In addition, during sleep, patients with OSAS experience periodic upper airway obstructions that cause a sudden decrease in intrathoracic pressure, which increases venous blood return and RV volume51. At last, the recurrent PAH can also induce a decrease in coronary artery blood flow in the RV, and then affect myocardial contractility of the RV52.Furthermore, in multiple linear regression analysis, we found that RV GLS and sPAP are independently associated with AHI. Overall, the results of our study suggested that nocturnal apneas have a potentially harmful effect on the RV. The cause can be partly explained by that RV afterload is increased due to the elevation of sPAP, and then leading to geometrical and functional changes of RV53 and Jane et al.50. It is believed that repeated hypoxic stress and sleep deprivation may be a pathophysiological mechanism leading to elevated CRP levels in patients with OSAS. Repeated hypoxic stress can not only lead to increased sympathetic nerve activity and endothelial dysfunction, but also induce the release of cytokines and the activation of inflammatory cells26. This may be the cause of increased morbidity and mortality in of atherosclerosis and cardiovascular diseases in OSAS patients26. Akashiba et al. found that CPAP treatment did not reduce CRP levels in OSAS patients54. Becker et al. showed that the levels of CRP and interleukin (IL)-6 in patients with OSAS could be decreased by CPAP treatment in agreement with our results but (IL)-6 not be measured in our study55. Effective CPAP treatment can improve the sleep quality of OSAS patients and reduce the decrease of nocturnal oxygen saturation, thereby reducing the body's hypoxic stress, reducing sympathetic nerve excitement, and further reducing the release of CRP.In the present study, we find that CRP levels are significantly higher in OSAS patients than in control group, whereas NT-proBNP and cTnT levels did not differ significantly between the two groups, which is agreement with the findings by Roche et al.56. Magalang et al. reported that the end-diastolic volume of RV decreased significantly in OSAS patients who received CPAP treatment for 3 months57. In our study, after > 6 months treatment with CPAP, RV morphology and function had significantly improved, including decreased RA and RV volumes, increased RV ejection fraction and improved RV strains, which indicated a physiopathologic association between RV performance and OSAS. The CPAP may reduce excessive negative intrathoracic pressure, leading to a reduction in apnea-hypoxic events associated with hypoxemia, subsequently reducing pulmonary vascular resistance58. The lower RV afterload would allow a smaller RV volume and lager RV ejection fraction. In addition, Romero-Corralm and colleagues report that the treatment effect of CPAP on patients with OSAS is similar to that of chronic beta-bolckers on heart failure patients14. In the present study, we found a significant change in RV structure and performance after CPAP treatment. However, we did not compare the treated CPAP patients with those without CPAP after 24 weeks to verify the effects of CPAP. Although all of our subjects were OSAS patients living at high altitude, there was also no comparison between CPAP at high altitudes and CPAP at sea level to verify the effects of high altitude on pulmonary vessels and RV.Researches that CPAP can improve LV and RV function indicate the most direct evidence that OSAS causes cardiovascular abnormalitiesSome limitations should be discussed. First, this is a single-center experience, with a small number of individuals enrolled. Second, the potential limitation is that there are some clinical factors in the population, such as hypertension, BMI and aging.. Therefore, selection bias and potential selection bias should be taken into account when interpreting our findings. Additionally, one limitation was the difficult to obtain quality images from the selected population.We demonstrate that OSAS patients living at high altitude have increased sPAP, PVR and 3D RV volume, as well as RV dysfunction, which suggests that they respond to overload by OSAS disease. Furthermore, sPAP increase and RV GLS impairment are both associated with the severity of OSAS (as expressed by AHI and its grading). The detection of CRP levels may enable us to determine whether OSAS is associated with cardiovascular diseases, and CPAP treatment significantly reduces CRP levels, possibly further reducing the incidence of cardiovascular disease. Long-term CPAP treatment can reverse RV structural and functional abnormalities, and may improve clinical outcomes.


Alström syndrome (ALMS) is a rare ciliopathy characterised by early onset insulin resistance, obesity, and dyslipidaemia and is a model for diseases that have huge social, health and economic impact. Cardiomyopathy develops in the majority, with high rates of morbidity and mortality, the definitive features of which are coarse replacement fibrosis and diffuse myocardial fibrosis (DIF). The pathogenesis of heart failure is thought to involve fibroblast accumulation and expansion of the extracellular matrix with excess protein deposition, leading to distorted organ architecture and impaired contractile function. Consecutive adults with genetically proven ALMS attending the National Centre for Rare Disease in Birmingham, England were studied. All patients underwent serial CMR, echocardiography and venous blood sampling, with computed tomography coronary angiography (CTCA) performed to assess severity of CAD. The aims of this study were: 1) to evaluate changes over time in DIF by cardiovascular magnetic resonance tissue characterization in ALMS; 2) to examine whether changes in DIF are associated with alteration in systolic or diastolic function; and 3) to evaluate the frequency and severity of coronary artery disease as a confounder for progression of ischaemic versus non-ischaemic fibrosis.p < 0.001), 1.1 percentage points , and 2.8 g/m2  per year, respectively. These changes were not associated with significant deterioration in myocardial structure or function.In total, 30/32 adults  participated. The median age at first scan was 21.3 years (interquartile range: 19.0–32.6) and participants were followed for a maximum of 67 months. Only 4 patients had significant coronary artery stenosis on post-mortem, invasive coronary angiography or CTCA. Mid short axis myocardial T1 times, myocardial extracellular volume, and left ventricular mass increased significantly over time, by an average of 21.8 ms (95% CI 17.4–26.1; This is the first comprehensive prospective study demonstrating progression of DIF in ALMS over time, although no structural or functional consequences were noted within a median three and a half years’ follow up. Further study is warranted to define whether DIF is a by-stander or the driver to impaired contractile function, heart failure and death. Alström syndrome (ALMS) is a rare autosomal recessive cardiomyopathy OMIM 203800) characterised by multiorgan disease. Infantile cardiomyopathy and retinal cone rod dystrophy are the earliest and most frequent manifestations of the syndrome. The most severe and often lethal complication of ALMS is heart failure due to cardiomyopathy . Cardiom03800 chaGiven the frequency of obesity, insulin resistance and metabolic syndrome in ALMS, ischaemic heart disease may well represent a potential confounder to increased T1 relaxation times and ECV . DespiteBetween March 2012 and January 2018, 32 consecutive adults with genetically proven ALMS attending the National Centre for Alstrom syndrome at the Queen Elizabeth Hospital Birmingham, United Kingdom (UK) were evaluated as part of standard clinical care. The clinic is unusual in that it is patient-centred, run in association with the charity Alström Syndrome UK and involves physicians from different specialties, nurses and relevant professions allied to medicine, forming a truly multidisciplinary team (MDT). Patients attend for 2 days and in this time, undergo all their relevant investigations, and are seen by all members of the MDT. At the first and subsequent visit, patients underwent annual disease monitoring following a standardized clinical protocol, including: biochemistry, echocardiography, and CMR. This was an observational, retrospective audit, utilizing existing data collected as part of clinical service. It was approved by local clinical governance committees (CARMS-15674) and conformed to the principles of Good Clinical Practice guidelines. Patients were eligible for inclusion in this audit if they were ≥ 16 years of age; had a genetically confirmed diagnosis of ALMS; and had been followed up in the service for a minimum of 1 year. Patients were excluded if they had an absolute contra-indication to CMR (1 patient with implantable cardio defibrillator) or a relative contra-indication for the study . Otherwise, all adult patients in the service were included. Serial CMR and single computed tomography coronary angiography (CTCA) were included as standard for ALMS patients. Annual CMR was instituted from the start of the clinical service, while CTCA was introduced soon after the incidental finding of an occluded right coronary artery in an asymptomatic 38 year old male.Venous blood samples were collected for haematology, biochemistry, and lipid profiles. Serum N-terminal pro B natriuretic peptide  was measured by sandwich immunoassay with magnetic particle separation and chemiluminescent detection on an E170 analyser  with a lower limit of detection of 0.6 pmol/L. Dyslipidaemia was defined as fasting cholesterol > 5 mmol/L and/or triglycerides > 1.7 mmol/L.Resting transthoracic echocardiography  was performed by an accredited sonographer according to the British Society of Echocardiography minimum dataset . Diastol was performed in-line with standard protocols to obtain LV and right ventricular (RV) dimensions, volumes, and mass on a bi-annual basis , total breath hold 17 R-R intervals [Contrast enhanced CMR al basis . A steadal basis . Averagentervals . Tissue ntervals . Analysintervals . T1 valuntervals . Stabilintervals . AnalysiT1 times stability over time was assessed using a phantom made of high density plastic beads of agar/nickle chloride in plastic tubes. High-density polyethylene macrobeads encased these plastic tubes arranged in a 3 × 3 array, with resin layer at the base. Each tube represented a range of T1 times. These were scanned regularly for 12 months on a fortnightly basis using the T1 protocol described above. A tight shim was set with all images acquired at iso-center. The analysis was done using ROI as described above.Participants without renal dysfunction had a single CT coronary artery calcium (CAC) score and CTCA performed on dual energy source 64 multi-slice scanner  using retrospective electrocardiogram (ECG) gated acquisition. A 20 mL test bolus of contrast was used to set delay and 80 mL of contrast given for final image acquisitions. Significant CAD was defined as a lesion > 70% on post-mortem, invasive or CT coronary angiography.The baseline demographics of the cohort were summarised, with continuous variables reported as means ± standard deviations (SDs) where normally distributed, and as medians and interquartile ranges (IQRs) otherwise. Changes over time in a range of markers were then assessed. Initially, Spearman’s correlation coefficients (rho) were produced to measure the correlation between each marker and the timing of the measurement, relative to each patient’s first scan. However, this approach did not account for the non-independence of the repeated scans on each patient. As a result, the analysis was repeated using a generalized estimating equation (GEE) approach. A separate model was produced for each marker, with the timing of the measurement, relative to each patient’s first scan as a continuous covariate, and the patient identification number (ID) as a nominal factor. The patient ID was set as the subject effect, with the within-subject effect being the timing of the scan, relative to the initial scan, rounded to the nearest 6 months. An autoregressive (AR) (1) correlation structure was assumed throughout. Analyses were then performed to assess whether changes over time in T1 corresponded to changes in other markers. For each marker, separate linear regression models were produced for each patient that had data with at least two scans, with the timing of the measurement relative to baseline, as a covariate. The gradients from the resulting models were then used to represent the rate of change in the markers and were compared using Spearman’s rho correlation coefficients. In addition, comparisons of gradients across dichotomous variables (e.g. gender) were performed using independent samples t-tests. All analyses were performed using IBM SPSS 22 , with p < 0.05 deemed to be indicative of statistical significance throughout. For markers that were measured as percentages, gradients are reported as percentage point increases.There are 38 known adult ALMS patients within the United Kingdom, of whom 32 regularly attend the specialized service in Birmingham. Of these, two were excluded due to contra-indications to CMR , hence the analysis was based on the remaining 30. Baseline demographics and imaging data are presented in Table p = 0.081 and p = 0.064), and LV mass (p = 0.008) all increased over time. Analysis of serial measurements using a GEE approach found significant increases over time in T1, as measured on the basal and mid ventricular (short-axis) levels, with similar gradients of 25.8 ms per year  and 21.8 ms per year , respectively  and 1.1 percentage points per year  for basal and mid ventricular levels, respectively . Analyses using a correlation approach returned consistent findings , ECV basal and mid ventricular level , LV end-systolic volume indexed to BSA , LV ejection fraction , left atrial volume indexed , or LV GLS . In addition, no significant changes over time were noted in diastolic function on echocardiography, including mitral early filling (E)/atrial filling (A) ratio (p = 0.313), and average E/early myocardial relaxation velocity  . No significant changes over time were detected in LV end-diastolic volume indexed to BSA . There was no evidence of a significant relationship between change in ECV or T1 with age, hypertension, diabetes, history of infantile cardiomyopathy, or presence/absence of coronary artery disease (CAD)  Table .Table 4Presence or absence of CAD could not be established in 3 of the 30 patients. One patient was not assessed, as they refused to undergo CAC/CTCA due to a combination of claustrophobia and needle phobia, while 2 patients had not undergone CAD assessment at time of data collection. Of the remaining 27 patients, 3 patients presented with symptoms and were diagnosed with CAD. Of these, one died before a CTCA could be performed, but post-mortem showed a right coronary artery occluded with thrombus. The second patient had invasive coronary angiography following onset of symptoms and was found to have severe CAD. The third patient has CAD (> 70% stenosis in the mid left anterior descending artery) identified on CTCA and was treated by percutaneous coronary intervention with stent implantation. The remaining 24 asymptomatic patients all had a CTCA done, and 22 had CAC scoring. Of these, 4 were found to have elevated CAC Agatston scores of 48, 69, 156, and 209. These 4 patients were found to have mild atheroma with no flow-limiting stenosis, with CTCA being normal in the remainder. In summary, a total of 3/27 (11%) had significant CAD defined by > 70% stenosis, whilst a further 4/27 (15%) had non flow-limiting atheroma. Further details about these 7 patients are reported in Table p < 0.001), whilst inter-observer mean bias for basal T1 was 6.4 ms , with an ICC of . Normal T1 measurements and ECV values using the same protocol in normal volunteers on the same scanner were as follows: (n = 26) mid short axis (SAX) pre contrast T1 970 ± 11 ms; post contrast T1 522 ± 58 ms; ECV 25 ± 1%. Over 12 months, 25 MOLLI datasets were collected. The scanner room temperature was stable at 20.96 + 0.98 C. Coefficients of variation across the 9 tubes were stable and ranged from 0.436 to 0.872% when unadjusted for temperature and improved to and 0.436 to 0.868% with correction for room temperature.Ten CMR studies were randomly selected for assessment of intra- and inter-observer variation. There was no consistent pattern of inter-observer bias on Bland-Altman analyses. Intra-observer mean bias for basal T1 was 5.8 ms , with an ICC (random model) of 0.9 . Although increasing native T1 over time was associated with impaired (less negative) GLS, this was an isolated relationship that was not mirrored in relation to ECV and was not associated with other changes in functional parameters, The increased T1 and ECV were not significantly associated with the presence or absence of CAD. These data are consistent with mild, progressive myocardial fibrosis over time in ALMS, although no structural or consistent functional consequences were noted within a median three and a half years’ follow up. Why is this finding of importance? ALMS is characterized by obesity, insulin resistance and dyslipidaemia, diseases that are common but are projected to increase beyond that expected by evolving population demographics . FurtherPrevious studies have demonstrated that T1 values and ECV are increased in ALMS compared to control subjects , 4. ThesInfantile cardiomyopathy is a common finding in infants with ALMS, presenting within the first 3 months of life . The majN = 3 vs. N = 20). Although numbers were small, participants had a genetically confirmed rare disease, recruited from a national centre with one of the largest adult cohorts available. Where significant trends over time were detected, the rates of change were generally small, and may not have been sufficient to have clinical impact in the short-term. However, the fact that the trajectories were similar across the whole cohort, and that testing of the scanner using a phantom within the magnet used demonstrated marked stability of the signal over time, would suggest that these trends are reflective of genuine progression of fibrosis. Further research is needed in a larger cohort, which is likely to require organisation of an international registry.Limitations. The primary limitation of this study, inevitably, is the relatively small sample size. As a result of this, the statistical power of analyses is low, meaning that only relatively large effects would have been detecteable, increasing the risk of false negatives. This was especially applicable to the analyses comparing the T1 and ECV gradients across baseline factors, particularly for comparisons across groups with unequal numbers of patients, such as the presence of CAD (Baseline T1 values were heterogeneous in our cohort, consistent with our previous and other research in ALMS , althougThis is the first comprehensive longitudinal study to suggest that myocardial fibrosis in ALMS progresses over time. There were no associated functional changes in systolic or diastolic function over follow-up, suggesting that these occur later in the natural history of ALMS cardiomyopathy. Longer term studies should be performed to confirm whether the development of DIF over time may be the primary driver rather than a consequence of ventricular dysfunction and heart failure.


A 49-year-old prior healthy male without any cardiovascular risk factors living in the western part of Switzerland, noted in mid of March 2020 anosmia and dysgeusia, similar to his wife and four people from his close family, with whom he had frequent contact and who were positive for SARS-CoV-2. Six weeks later, he presented to the hospital with new-onset of dyspnea NYHA 3, general weakness, intermittent epigastrical pain and nocturia without orthopnea nor fever. The retro-nasal SARS-CoV-2 PCR, 6 weeks after initial anosmia and dysgeusia was negative but the antibody IgG blood test for SARS-CoV-2 was positive. Computed tomography of the lungs showed no pulmonary embolism, no infiltrates but left heart congestion, suspected by previous thoracic X-ray (A) and pleural effusion (B). Echocardiography revealed diffuse hypokinesia with severely depressed left- and right-ventricular function. The patient showed elevated C-reactive protein, troponin and NT-proBNP. ECG showed dynamic T-wave changes (C) and after ruling out coronary artery disease, he was diagnosed with isolated peri-myocarditis using multiparametric cardiac magnetic resonance imaging (CMR). CMR showed diffuse thickening of the myocardium and pericardium due to edema confirmed with T2 weighted imaging and T2 mapping (D). Further, pericardial effusion could be seen and tissue characterization revealed diffuse LGE, elevated T1 mapping values and an elevated extracellular volume fraction of 38% , indicating diffuse fibrosis (E). Global myocardial strain of all heart chambers was diffusely impaired  (F). No other cause was found as an underlying reason for the peri-myocarditis. In the clinical setting of suspected Covid-19 with respiratory symptoms and negative pulmonary imaging, elevated C-reactive protein and troponin should lead to the suspicion of isolated peri-myocarditis. CMR is the primary noninvasive imaging tool to assess peri-myocarditis, also in Covid-19 patients [


Based on the analysis of multimodal cardiac imaging, our results provide mechanistic insights into PV remodeling and its potential role as a link between diastolic dysfunction and developing AF.Pulmonary vein (PV) enlargement is associated with atrial fibrillation (AF). However, the predictive value of PV volume for new-onset AF has not been determined. We retrospectively assessed and enrolled non-AF subjects who underwent echocardiography and cardiac CT angiography (CCTA) around the same time and evaluated the development of AF longitudinally. PV volume was assessed by estimating the three-dimensional CCTA-derived mid-diastolic PV volume from the ostium to tertiary branches. Overall, 1105 subjects were enrolled. Among them, 29 developed AF during a mean follow-up of 4.28 ± 3.08 years after baseline CCTA and echocardiography. The AF group had a higher proportion of older aged subjects, a higher ratio of early mitral flow velocity (E) to early mitral annular tissue velocity (Em), higher Em, and larger left atrial (LAVI) and PV (PVVI) volume indices. PVVI was independently associated with male sex, left ventricular dimension, E/Em and LAVI. AF incidence increased markedly across each baseline PVVI tertile . In the multivariate Cox model, increased PVVI was independently associated with new-onset AF (hazard ratio (HR) = 5.401, 4.931–6.193,  Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in the general population and is associated with an increased risk of morbidity and mortality . The estIn AF arrhythmogenesis, the pulmonary veins (PVs) play an essential role as a trigger or driver of AF ,5,6. PriIn this study, we hypothesized that increased PV volume could be a predictive risk factor for AF. To test our hypothesis, we analyzed imaging data and the clinical course of patients without atrial arrhythmias who underwent both echocardiography and cardiac computed tomography angiography (CCTA). Subsequently, we assessed the following data: (1) the clinical and echocardiographic determinants of the PV volume and (2) the utility of PV volume for the prediction of new-onset AF.We retrospectively recruited 1365 adult subjects who underwent electrocardiography (ECG), CCTA, and transthoracic echocardiography within a 2-week interval between January 2002 and December 2012 at the Korea University Ansan Hospital in Ansan-si, Korea. As CCTA in our hospital was installed in 2002, we defined the study period from January 2002. Also, we set the study period of interest (2002–2012) to ensure a statistically significant volume of study subjects. The exclusion criteria included history or clinical evidence of paroxysmal or permanent AF. In addition, patients with a history of cardiomyopathy, pericardial disease, chronic kidney disease (serum creatinine ≥2 mg/dL), more than moderate valvular heart disease, congenital heart abnormality, chronic obstructive pulmonary diseases, pulmonary vascular disease or previous cardiac surgery were excluded. We defined the follow-up period as from the date of the CCTA scanning to the day of the last follow-up or to December 2017, to ensure the clinically meaningful observation time. Data regarding demographics, medical history, and clinical course after undergoing CCTA were collected. All of the serials of ECG of each subject were reviewed longitudinally by two cardiologists using the MUSE Cardiology Information System . New-onset AF was defined as AF lasting more than 30 s detected on a 12-lead ECG or 24 h Holter monitoring during the clinical follow-up in patients with no history of paroxysmal or persistent AF or atrial flutter. The case was considered censored if (1) new-onset AF was documented or (2) the participant was lost to follow-up. The differences in baseline characteristics between patients who did and those who did not develop AF after baseline CCTA and echocardiography were assessed. Written informed consent for CCTA imaging was obtained from all subjects, and the study protocol was approved by our institutional review board (2019AS0011).All CCTA images were acquired using the QXi LightSpeed scanner . Cardiac cycle-gated CT scanning was performed 20–25 s after radiocontrast administration at suspended full-inspiration from the upper portion of the left diaphragm to the aortic arch with collimation 2.5 mm . Three-dimensional (3D) PV images were provided and analyzed using a dedicated image analysis software . The PV ostium was defined as the point of reflection of the parietal pericardium [2 [Transthoracic echocardiography was performed using commercial systems  and reported by the American Society of Echocardiography-accredited echocardiographers. The LA volume was measured at the end-systolic phase using biplane Simpson’s method and was divided by BSA to calculate the LAVI. The E/Em ratio was calculated by dividing early diastolic transmitral flow velocity (E) by septal mitral annular tissue velocity (Em) . LA enla2 ,11.t-test or Mann-Whitney U test for non-normally distributed data. The categorical variables were reported as count and percentages and compared using the chi-square test or Fisher’s exact test as appropriate. A Kaplan-Meier analysis and log-rank test were used to compare the cumulative incidences of new-onset AF between three groups according to the baseline PVVI tertile. The determinants of PVVI were evaluated using a multiple linear regression analysis incorporating relevant clinical, demographic, and echocardiographic parameters in the model. To evaluate the impact of cardiac hemodynamics on LA and PV structures, we plotted and analyzed the LAVI and PVVI values according to E/Em, as an echocardiographic surrogate of increased left ventricular (LV) filling pressure and LA pressure overload. The best-fit curves were determined based on the R-squared statistic. Correlation coefficient analysis was performed using the Pearson or Spearman rank correlation test, depending on the normality of the distribution. The receiver-operating characteristic (ROC) curve analysis was utilized to determine the predictive performance and optimal cut-off value of the volume indices (the best Youden index = sensitivity + specificity – 1). A multivariate logistic regression analysis was performed to determine the predictors of new-onset AF. All of the potential parameters suggestive of an association with newly developed AF by univariate analysis (p < 0.1) and the conventional AF risk factors were included in a stepwise regression analysis as the variable-selection process; the results were reported as hazard ratios (HRs) and 95% confidence intervals (CIs). All data were analyzed using SPSS  and GraphPad Prism . A two-sided p value of <0.05 indicated statistical significance.The continuous variables were expressed as mean ± standard deviation (SD) and compared using the Student’s Among the 1,365 patients initially screened, a total of 1,105 patients  met all the study criteria and were enrolled in the study . OverallThere were 29 cases of ECG-confirmed new-onset AF during a mean follow-up of 4.28 ± 3.08 years after baseline CCTA and echocardiography. Patients with new-onset AF were older than those without AF. Furthermore, patients with AF were more likely to have higher early mitral annular tissue velocity (Em), higher E/Em ratio, and larger LAVI and PVVI than those without AF .2). The rates per 1000 person-years across tertiles were 2.2%, 5.1%, and 10.8%, respectively , weight , BSA , and BMI . Among clinical and echocardiography-derived variables, PVVI was significantly associated with age, sex, history of hypertension, LV mass index, LV end-diastolic dimension (LVEDD), Em, E/Em, pulmonary arterial pressure, and LAVI. In multiple regression analysis, the independent determinants of increased PVVI were male sex, LVEDD, E/Em, and LAVI  of 0.696, p < 0.0001 vs. 0.651, p = 0.013, respectively; The ROC curve revealed that both baseline PVVI and LAVI, with a cut-off value of >21.8 mL/mp = 0.007) was independently associated with developing AF (p = 0.465), even when a different LAVI criterion  was applied to the multivariate regression model.In univariate analysis, after stratifying the PVVI and LAVI variables by cut-off values determined using ROC analysis, age, LV mass index, the E/Em ratio, and both the stratified LAVI and PVVI were associated with a higher probability of new-onset AF . Howeveroping AF . The prePrior studies that reported the association between PV enlargement and AF were mainly based on a cross-sectional analysis performed on a small population; furthermore, no follow-up data were provided ,8. ThereEnlargement of cardiac chambers and consequent myocardial stretching play a crucial role in the development of arrhythmias in various clinical conditions . This stEnlarged PV could be involved in AF progression, as well as in the initiation of AF. In hypertensive patients with paroxysmal AF, augmented PV backflow leading to cyclic stretching of PV musculature could be a predictor of future AF perpetuation . Also, pTheoretically, in the absence of an effective anatomical barrier between the LA and PV, all hemodynamic conditions leading to elevated LA pressure can affect the structural remodeling of the PV. The LV diastolic dysfunction and its severity have been reported as independent predictors of new-onset AF; however, the pathophysiological link between LV diastolic dysfunction and AF development is not fully understood .Reduced LA compliance and elevated LA pressure may influence the patterns of PV blood flow. In particular, retrograde atrial wave to PV can be a sensitive predictor of elevated LA pressure, and a diastolic wave in PV can be an indicator of LV diastolic dysfunction ,22. AlsoInterestingly, the E/Em-related changing pattern of PVVI differed from the PVVI pattern observed in our study. As E/Em increased, the increase in PVVI was more gradual compared with the increase in LAVI, suggesting that PV is more resistant to structural remodeling than LA. This finding may be attributable to the stretch-resistant physical properties of extra-parenchymal PVs that were previously documented in a human post-mortem study . On the Three-dimensional CCTA is a useful imaging tool for the evaluation of PV anatomy and cardiac volume, and its embedded function of automatic calculation facilitates fast and easy assessment ,25. HoweThe present study provides clinical evidence supporting PV enlargement as a potential consequence of chronically elevated LA and LV filling pressure and could potentially play a causative role in AF development. Further research elucidating the mechanisms behind structural remodeling of PV and its role in AF arrhythmogenesis will help to identify patients at risk, and, consequently, reduce cardiovascular morbidity and mortality.


Septic cardiomyopathy (SCM) is a complication that is sepsis-associated cardiovascular failure. In the last few decades, there is progress in diagnosis and treatment despite the lack of consistent diagnostic criteria. According to current studies, several hypotheses about pathogenic mechanisms have been revealed to elucidate the pathophysiological characteristics of SCM. The objective of this manuscript is to review literature from the past 5 years to provide an overview of current knowledge on pathogenesis, diagnosis and treatment in SCM. Sepsis is defined as a life-threatening organ dysfunction due to a dysregulated immune response to an infection  and has The myocardial depressant factors (MDFs) have been proposed since the 1950s , referriSome progress has been made in understanding the pathogenesis of SCM. In recent years, there are excellent review articles regarding the pathophysiology of cardiomyopathy, present review focuses on the current the evidence on pathogenic mechanism of SCM and the potential of diagnoses and treatments for SCM.Presently, the pathogenesis of SCM is still in its exploration stage. The role of inflammatory cytokines in the pathogenesis of sepsis was identified. But all antibodies based on specific pro-inflammatory cytokines as targets have failed in clinical trials . This inSepsis can lead to the activation of the complement system, resulting in increasing the amount of complement component 5 (C5a). C5a reacts with its receptor, leading to cytokine storm, lymphocyte apoptosis, neutrophilic innate immune function loss, cardiomyopathy, disseminated intravascular coagulation, etc. Meanwhile, C5a also affects intracellular calcium homeostasis . SCM is Cardiomyocytes have a high mitochondrial density, which allows them to produce adenosine triphosphate (ATP) quickly. ATP provides the energy for both energy-consuming endergonic reactions and energy-releasing exergonic reactions. Mitochondrial dysfunction can seriously affect heart function in sepsis. Mitochondrial damage occurs in SCM, mainly manifested as morphological and functional changes, including interrupted oxidative phosphorylation, impaired mitochondrial respiration rate, free radical production of mitochondria, decreased mitochondrial membrane potential, attenuated autophagy, and apoptosis . Takasu In summary, the findings from experimental animal models have shown that changes in mitochondrial morphology and function are involved in the pathogenesis of SCM. Understanding molecular mechanisms of mitochondrial injury may provide evidence for developing new therapeutic targets for SCM.2+ leakage in the sarcoplasmic reticulum (SR) of cardiac myocytes (Toll-like receptors (TLRs), a trans-membrane glycoprotein on the surface of the cell membrane, is an important part of the immune system that can identify different pathogen associated molecular patterns (PAMPs). The stimulation of TLRs by PAMPs causes the nuclear translocation of nuclear factor kappa B (NF-κB), and then leads to the expression of inflammatory mediators, such as TNF-α and interleukins (ILs) . Signalimyocytes . Chen etmyocytes . Based o2+ and also damage to mitochondria, etc. (Nitric oxide is synthesized by the oxidation of L-arginine by nitric oxide synthase (NOS) expressed in cardiac myocytes. NOS can be divided into three subtypes, namely neuronal nitric oxide synthase (nNOS), inducible nitric oxide synthase (iNOS), and endothelial nitric oxide synthase (eNOS) . The onlia, etc. . We haveia, etc. . This evAlpha 7 nicotinic acetylcholine receptor (α7nAchR) is widely expressed in the cytokine-producing immune cells such as macrophages, dendritic cells and T cells . α7nAchRin vitro and inflammatory response in vivo via the inhibition of exosome generation. In addition, the attenuation of cardiac dysfunction and improvement of survival are noted in septic mice  and ventricular dilatation during sepsis . HoweverTo date, there is no gold diagnostic standard for SCM. Most clinical studies use LVEF < 50% as a diagnostic criteria . Based oEchocardiogram: Echocardiography and doppler imaging can detect abnormalities in systolic and diastolic function of the heart in patients with severe sepsis or septic shock. There are three main indicators, namely myocardial performance index (MPI), mitral ring systolic displacement (MAPSE) and global longitudinal strain (GLS). MPI, also known as Tei index, is a parameter measured by echocardiography . The forModified shock index (MSI) refers to heart rate/mean arterial pressure, which can reflect both systolic and diastolic functions. Some biological markers, such as B-type natriuretic peptide (BNP) and troponin I are elevated in patients with SCM, which have no diagnostic value specifically . Chen etFor the diagnosis of SCM, cardiac dysfunction caused by other diseases should be excluded. It is important to distinguish it from acute coronary syndrome. Coronary angiography and coronary computed tomography angiography (CCTA) can determine whether there is myocardial ischemia. But it is a risky examination for the patients with sepsis. Some studies have suggested using ultrasonic myocardial perfusion technology to examine myocardial perfusion abnormalities in the area of impaired myocardial wall in patients with sepsis. SCM and coronary syndromes can be distinguished by this method, but it is still invasive . Also, oDue to the uncertainty of pathogenesis of SCM, no effective disease-modifying treatment is currently available. The strategies to deal with SCM is to control the primary disease to prevent the occurrence of secondary SCM. Specific treatment for SCM is still being developed. Currently some drugs and device-based therapy have been used clinically.Levosimendan is a calcium ion sensitizer, which can directly bind to troponin to increase myocardial contractility, but there is no significant change in heart rate and myocardial oxygen consumption. Studies have shown that levosimendan can effectively reduce the plasma lactic acid in sepsis and increase the myocardial contractility, but its application cannot reduce usage of norepinephrine and has no significant improvement in the mortality of SCM .Natriuretic peptide, a recombinant human brain natriuretic peptide (rhBNP), can bind to human endogenous natriuretic peptide receptor. Natriuretic peptide not only can expand the arteries and veins, urinate and expel sodium to reduce the preload and afterload of the heart, but also can inhibit renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system, which has been widely used clinically for treating heart failure via effectively relieving hemodynamic abnormalities and cardiac dysfunction. Combination of Chinese and western medicine: Clinical studies have shown the application of anti-infection and organ support therapy (MOST) accompanied by traditional Chinese medicine (fu zheng jie du hua yu granules) can further reduce acute physiology and chronic health evaluation (APACHE-II) score and other indicators such as procalcitonin (PCT), BNP and cTnI, in patients with SCM . Animal In septic patients complicated with SCM, extracorporeal membrane oxygenation (ECMO) is a feasible rescue strategy. Some approaches have been reported that application of anti-infection combined with ECMO has been used to treat the patient with SCM and septic shock caused by infection and hemorrhage of ileal diverticulum . Vogel eIntra-aortic balloon counter-pulsation (IABP) supports cardiac function by unloading contractions and enhancing relaxation. The former can lower systolic blood pressure and the latter can raise diastolic blood pressure. A retrospective study was performed among 38 cases with the application of IABP, suggesting that IABP is effective for the patients with cardiac shock by increasing mean arterial pressure and reducing dosage of catecholamine during the acute phase of sepsis. However, no improvement in long-term survival was observed . KenshirBlood purification has long been used to treat sepsis. Recently, Andreja Sinkovic reported that a patient with lymphoma, splenectomy and autologous bone marrow transplant and receiving chemotherapy, and accompanying severe pneumococcal infections, septic shock, SCM and unacceptable drug therapy, was subjected to blood purification. The reductions in the level of IL-6, lactic acid deposition and the dosage of vascular vasopressors, improvement of left ventricular systolic function and clinical features were observed after treatment for 36 h . CytoSorSome studies suggested that the pathogenesis of sepsis is the damage of micro-vessels caused by “Genomic Storm”. BacteriStructural and functional disorders of mitochondria affect the production of energy in cardiac myocytes, resulting in cardiac dysfunction. Maintaining the stability of mitochondrial structure and protecting its function have become the target of treating septic myocardium. Melatonin can restore the physiological functions of mitochondria and endoplasmic reticulum, maintain the stability of cytoskeleton, and thus improve cardiac function in septic mice . The stuIndependent growth factor I (GFI-I) can inhibit the expression of NF-κB and TNF-α, thus inhibiting LPS-induced inflammatory response and apoptosis of HPC2 cells . 3,3′-DiThe treatments discussed in this section are only from animal experiments and have not been applied clinically. Whether or not the genetic response in animal models can mimic human inflammatory disease is controversial.Septic cardiomyopathy, although it is reversible at early stage, has a high mortality rate because its pathogenesis is not well-understood. In terms of diagnosis and treatment, it is an important subject in clinical and basic research. Previous studies in this area have been limited by poor diagnostic strategies that only relied on LVEF reduction. In this review, we have not only discussed pathogenesis of SCM in detail, but also introduced some other approaches that are associated with the diagnosis of SCM. Early detection and intervention of SCM in patients with sepsis can reduce mortality. For example, MSI is considered as a “predictor” of SCM , and MAPHL and WW conceived and wrote the manuscript. ML, QM, and HR revised the manuscript. All authors listed wrote the manuscript and approved for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


A correlation was found between HRV induced by postural change and postural control, Δ LF/HF and RMS-AP , Δ LF/HF and ellipse area , Δ LF/HF and AP mean velocity , and Δ LF and AP mean velocity . There is an association between the autonomic and postural systems, such that PD patients with blunted cardiac autonomic function in both the supine and orthostatic positions have worse postural control.Parkinson’s disease (PD) is a neurodegenerative disorder that affects postural and cardiac autonomic control. However, since it is unknown whether these changes are associated, the objective of this study was to determine whether such a relationship exists. Twenty-three patients with PD participated. The RR intervals were recorded in different positions and heart rate variability (HRV) was analyzed. Postural sway was analyzed based on the center of pressure. No significant differences on HRV indices were induced by postural change. A correlation was found between these indices and postural control, high frequency (HF), and anterior-posterior (AP) root mean square (RMS-AP) ( Parkinson’s disease (PD) is a chronic neurodegenerative disorder with a worldwide prevalence of 100–300 cases per 100,000 individuals .Clinical changes in PD include rigidity, bradykinesia, tremor at rest, and postural instability . In addiIn these patients, autonomic changes can be seen through symptoms, such as orthostatic hypotension, constipation, urinary dysfunction , sexual dysfunction, excessive sweating, seborrhea, hypersalivation, and sleep and respiratory disorders ,9. AmongThis can be explained by the fact that gait and balance control mechanisms are already affected by the disease process, and orthostatic hypotension may further predispose patients to accidental falls and trauma, which leads to increased dependency, fear of falls, and reduced quality of life and may even affect disease prognosis ,14,15. FStudies have also shown that there is an association between cardiovascular autonomic control and postural control ,20,21. MGiven that autonomic dysfunction can significantly compromise functional mobility, this represents a cardiovascular risk and can exacerbate motor alterations in this population . The objThe sample consisted of 36 male and female volunteers diagnosed with idiopathic PD by a neurologist, according to UK Brain Bank criteria ,24. All Before the experiment, all participants were familiarized with the experimental protocol and were instructed to abstain from stimulants  and alcoholic beverages at least 24 h prior to the examination. Participants were also asked to refrain from strenuous physical activity at least 2 days before the tests. All experiments were carried out in a climate-controlled room (22 to 24 °C) with relative air humidity between 40% and 60%.To better characterize the participants, the 39-item Parkinson’s Disease Questionnaire (PDQ-39) was used to assess quality of life. The questionnaire comprises the following eight health dimensions considered to be affected by PD: mobility (10 items), activities of daily living (6 items), emotional well-being (6 items), stigma (4 items), emotional support (3 items), cognition (4 items), communication (3 items), and body movement (3 items). Each question can be rated from 0 to 4. The total score was calculated according to the following formula: 100 × (sum of the items PDQ-39/4 × 39). This percentage was calculated for each of the eight dimensions. Higher scores indicate lower quality of life .All volunteers underwent continuous RR interval recording at a sampling frequency of 1000 Hz . Prior to data collection, the volunteers remained at rest for approximately 20 min to stabilize their heart rate and blood pressure at baseline values. Recordings were performed for 10 min under the following conditions: (1) while resting in the supine position and (2) during active standing. The volunteers were instructed to maintain spontaneous breathing throughout data collection, which was observed and recorded by the examiner through visual inspection of thoraco-abdominal movements.2) and normalized units (nu) [Cardiac autonomic control was assessed through HRV analysis in the time and frequency domains. The analysis was performed using Kubios HRV software 3.1.0. Sequences with 256 consecutive RR intervals were selected during the supine and standing periods to perform time and frequency domain analyses. In the time domain, we considered the heart rate and the standard deviation of normal-to-normal intervals (SDNN), which reflects overall HRV . HRV anaits (nu) . Since tits (nu) , even thits (nu) ,29,30.Data on the anterior-posterior and medio-lateral displacement of the center of pressure (COP) were obtained for a period of 60 s using a force platform  with a sampling frequency of 100 Hz.The evaluations were carried out in a quiet room with controlled temperature (22–24 °C) and humidity conditions (40–60%). The participants were instructed to remain in the standing position on a force platform during the recording procedure. To avoid a possible fall hazard, an investigator remained close to the patient throughout the test.The test consisted of maintaining the standing position for 60 s with the feet parallel (3 cm apart at the heels) and the arms relaxed at the sides. The volunteers were instructed to remain as stable as possible and avoid making any voluntary movements while looking at a fixed point 1 m away. RR intervals were simultaneously recorded for subsequent correlation analysis between cardiovascular variables and postural oscillation. Postural oscillation was analyzed by linear methods using the following indices: ellipse area, root mean square (RMS), and total mean velocity (MV) of the COP .The COP data was sampled at 100 Hz for 60 s, from which a series of balance measurements were calculated. The COP RMS distance measures the size of the sway and is believed to be related to the effectiveness or stability achieved by the postural control system ,33. Meant-test for paired samples was applied for variables with normal distribution and the Wilcoxon test was applied for variables with non-normal distribution. Data are presented as a mean and standard deviation. To determine the magnitude of the difference between the postures, effect sizes were calculated using Cohen’s d and interpreted as a small (from 0.2 to 0.5), moderate (from 0.5 to 0.8), or large effect (≥0.8). The association between HRV indices and COP displacement was verified using the Pearson or Spearman correlation test, depending on data normality. In order to account for the possible confounding effect of the disease severity, a partial correlation analysis between HRV and COP indices was performed controlling for the part III of the Unified Parkinson’s Disease Rating Scale (UPDRS-III) scores. The significance level was set at 5% for all tests.The statistical analysis was performed using IBM SPSS Statistics for Windows, vesion 21 . The Shapiro-Wilk test was used to verify normal data distribution. To compare HRV indices between the supine and standing posture, Student’s The demographic and clinical characteristics of the patients with PD are summarized in The scores for the PDQ-39 dimensions are presented in 2 (±287.80).The means and standard deviations for COP stabilometric parameters in the standing position were: RMS-anterior-posterior (AP) 4.52 mm (±2.16), RMS-medio-lateral (ML) = 6.22 mm (±3.20), MV-AP = 7.74 mm/s (±5.34), MV-ML = 12.14 mm/s (±5.0), and ellipse area = 480.58 mmp < 0.05) and RR (p < 0.05) values, indicating that HR was higher when standing than in the supine position. However, no significant differences (p < 0.05) were found for HRV indices between the conditions, which shows that cardiac autonomic modulation had a blunted response to postural change. Linear indices based on time and frequency of supine HRV and HRV in response to orthostatic stress were evaluated. As shown in r = 0.422, p = 0.045, partial correlation: r = 0.435, p = 0.04), which indicates that greater parasympathetic predominance in the supine position is related to greater instability in the standing position. On the other hand, a significant positive correlation was found between LF/HF and MV-AP , which indicates that greater cardiac sympathetic modulation in the supine position is related to greater effort to maintain control in an upright posture.A correlation analysis was performed between linear indices of supine HRV and COP stabilometric variables. As presented in r = 0.448, p = 0.032, partial correlation: r = 0.515, p = 0.01) and between Δ LF/HF and the ellipse area , which suggests that the exacerbated predominance of the sympathetic component in the standing position is related to greater instability in the standing position. In addition, a significant negative correlation was found between Δ LF/HF and VM-AP , which indicates that greater cardiac sympathetic modulation is related to greater effort to maintain control in an upright posture. On the other hand, there was a significant positive correlation between the index Δ LF(nu) and the ellipse area . Finally, there was a significant negative correlation between Δ LF(nu) and VM-AP .A correlation assessment was performed for the delta of linear indices of HRV time and frequency domains in the supine and standing positions  and COP stabilometric variables. Moreover, to avoid a possible confounding effect of the disease severity, a partial correlation controlling for the UPDRS-III was performed. The results are presented in This study aimed to assess the association between cardiac autonomic control and postural control in patients with PD, in addition to cardiac autonomic modulation to posture change. The main results are discussed below.The results of this study showed that PD patients appeared to have a blunted cardiac autonomic response to gravitational stimulation, evidenced by the lack of significant differences in HRV indices  and only a moderate effect size between the cardiac autonomic indices obtained in the supine and standing positions. This suggests abnormalities in autonomic response to postural change in PD patients. Furthermore, the reduced increase in the LF/HF ratio in response to a gravitational stimulus suggests a limited increase in cardiac sympathetic modulation to orthostatic stimuli . These fThere was a significant positive correlation between the LF/HF index in the supine position, which reflects sympathovagal balance, and mean COP AP velocity, which suggests that PD patients with greater cardiac sympathetic modulation in the supine position require greater effort to maintain balance in the standing position. Although there should be less modulation of the sympathetic nervous system at rest and greater parasympathetic predominance , this reIn our study, analysis of the mean COP velocity and HRV indices  showed that PD patients with better autonomic modulation to an orthostatic stimulus (greater standing supine delta) had the lowest mean velocity, i.e., those with limited autonomic modulation to postural change required greater regulatory activity to maintain an upright posture. Various studies have suggested that PD patients have a higher mean velocity in a resting position ,42,43,44Participants with a higher delta in HRV variables (ΔLF/HF) had a higher RMS, i.e., a closer approach to the stability limit corresponds to better autonomic modulation in response to a postural change. Since this is somewhat contradictory to what is proposed by velocity, these data suggest that anomalous autonomic modulation is related to higher velocity values and lower RMS values. These results can be explained by Maki et al. , who draDespite the interesting results, some study limitations should be pointed out. First, since the main objective of the present study was to assess the relationship between cardiac autonomic control and postural control, a healthy control group was not included. Thus, although we have compared our results with some previous published studies, we cannot state categorically that the participants presented a blunted cardiac autonomic adjustment to the orthostatic stimulus. In addition, although no participants presented orthostatic hypotension during the study, future studies should consider using methods such as the Valsalva maneuver, the tilt-table test, or assessing autonomic symptoms through a questionnaire, such as the Composite Autonomic Symptom Score . Such stAnother point to be considered is the lack of simultaneous recordings of COP and electromyographic values. A theoretical model called the cardio-postural closed-loop has been proposed and shown interdependence relationships between cardiovascular and postural balance responses ,52,53. BFinally, although the linear indices are reliable and several studies have shown their clinical relevance, it is well known that cardiac autonomic control and postural control are both modulated by nonlinear dynamics. Therefore, future studies should consider analyzing the association between nonlinear indices of cardiac autonomic control and COP, as well as integrating electroencephalographic activity, since brain-heart interactions are well known  and coulWe have found evidence that suggests an association between the autonomic and postural systems, such that patients with greater cardiac autonomic deterioration, both in the supine and standing positions, also present poorer postural control. This implies that interventions in patients with PD should not be restricted to motor alterations, but should also aim at improving the cardiovascular system.


The trans-catheter closure of atrial septal defect (ASD) usually has a rapid impact on biventricular remodelling and functions. Whether the transcatheter closure of ASD at early childhood or at adulthood age would affect the improvement in biventricular dimensions and functions remains an area of active research.P = 0.038). The baseline mean value of RV free wall LS of G2 was significantly lower than G1 value (P < 0.001). There was no statistically significant difference between the 2 age subgroups regarding biventricular GLS and RV free wall LS changes after device closure. The changes in LV diastolic function immediately and after 1 month of device closure showed a statistically significant change in e′ and its delta change value in group-2 in comparison with its baseline values and to group-1 delta changes .This prospective observational study enrolled 70 subjects (50 ASD cases and 20 control subjects). Tissue Doppler imaging (TDI) and strain (S) were performed for the control group and ASD patients at baseline and at 24 h and 1 month after ASD device closure. The total ASD group was subdivided into two subgroups: group-1—children and adolescent with ASD, who underwent transcatheter closure at age ≤ 19 years; group-2—adult who underwent ASD device closure at age > 19 years old. The right and left ventricular global longitudinal systolic strain (RV/LV-GLS) and RV free wall longitudinal strain  showed a significant decline after 24 h of device closure . However, after a 1-month follow-up, the LVGLS increased in comparison with 24 h changes after device closure (e′ velocity towards abnormality.The ASD transcatheter closure reduced biventricular global and RV free wall longitudinal systolic strain within 1 day of intervention and was associated with a short-term improvement in the LV-GLSS after a 1-month duration. The progressive increase in LV preload results in its strain growth and reduction in diastolic function after transcatheter ASD closure. The older age at the time of ASD device closure was associated with a significant decrease in the RV free wall LS and septal  The typical recorded effect of atrial septal defect (ASD) on ventricular remodelling and function was the RV volume overload and dysfunction under extreme conditions, which in a few cases may lead to LV dysfunction . Device After approval from the institutional ethical committee and written consent of the patient and their parents, 50 ostium secundum ASD patients and 20 age-matched control healthy subjects were recruited.2 and < 2/3 systemic vascular resistance (SVR)   , 18. CW ameter)] , 20. Usipressure .e′) and late diastolic velocity (a′)  [Tissue Doppler imaging (TDI) was estimated at the basal-lateral and septal mitral annulus from the A4C view to calculate the early diastolic velocity (ctively) .The examination of patients and healthy subjects was done in the left lateral position before, at 24 h and 1 month after the ASD closure. Then, the 2D harmonic images of LV and RV for later offline processing were recorded. For offline analysis, 2D strain data were collected and processed in a cine loop format (movie clips) in all apical views. In the apical two-, three- and four-chamber views, the left ventricle’s endocardium was drawn automatically in the end-systole over the entire heart cycle. Afterwards, the RV endocardial borders were tracked manually then divided automatically into seven segments by the same software of LV , where the septum was shared between both ventricles and the average RV free wall longitudinal strain was measured as a mean value of three segments of apical, mid- and basal lateral wall.The Q-lab data analysis (Philips) software showed the global and regional peak longitudinal S for the respective segments of the LV and RV  after approved of the cine loops by the read operator.In the perioperative assessment of ASD patients, TEE was performed for all patients to assess the suitable device size. All patients aged more than 40 years underwent the diagnostic coronary angiography before intervention.2 before ASD closure. According to the exclusion criteria, all patients with elevated left atrial pressure (LAP) and left ventricular end-diastolic pressure (LVEDP) > 12 mmHg at baseline were assumed to have LV diastolic dysfunction and were excluded from the study [Under general anaesthesia, the transcatheter closure of the ASD was carried out with fluoroscopic and TEE assessment. In patients with ASD and pulmonary hypertension, the assessment of pulmonary artery pressure and PVR was done under 100% FiOhe study . In the t test. The paired t test was used to compare the results of the same group before and after the intervention. The statistically significant data was considered when P value < 0.05.The researchers used the Statistical Package for the Social Science (SPSS) 24.0 (IBM) for statistical analysis. The histogram and Q-Q plot were used for testing the normality of data. Continuous variables were presented as mean ± standard error. Comparison between the different groups was done by using independent two-tailed All the ASD and age-matched control subjects’ demographic data were presented in Table Transcatheter closure of ASDs was successfully performed in all patients using the Amplatzer Septal Occluder devices without any significant complications. None of the trivial residual shunts at the end of the procedure was detected at 24 h after closure. There was a significant increase in RVEDD, RV/LV ratio, TAPSE, RVSP and Qp/Qs in ASD cases more than the control subjects’ values; however, they had a lower LAD and LVEDD than the control subjects  after 24 h of ASD device closure  had a significantly larger LA, LVED and RVED diameters indexed to BSA in comparison with subgroup-2 with a mean age of 37.66 ± 3.55 years old  at baseline, whilst subgroup-2 had a significantly higher RVSP and TAPSE . However, there was insignificant difference between the 2 age groups in the rate of acute changes in TAPSE 24 h and 1 month after ASD device closure After the subdivision of the study group into 2 subgroups according to the age at time of intervention, subgroup-1 with a mean age of 6.39 ± 0.84 years old   as septal e′ velocity showed a significant decline in subgroup 2 after 24 h, and this decline was persistent 1 month post-device closure   and was not as prominent as the decline in subgroup 2   Table , Fig. 3,There was a significant difference between the LV/RV GLS in the 2 subgroups at baseline with a non-significant difference between them after ASD device closure as regards the percent change , where ∆1 means the difference change of the RV/LV global strain values at 24 h post-closure and baseline and ∆2 means the difference change between 1 month post-closure and baseline.P < 0.001, Table P = 0.003; G2-Δ1 − 2.50 ± 1.01%, P = 0.026). However, the delta changes in RV free wall LS after 1 month in comparison with 24 h and in comparison with baseline were insignificant in both age groups, with a non-significant difference between the 2 age group delta changes after 24 h and 1 month of ASD device closure .With regard to the mean RV free wall LS at the baseline, the adult group (G2) had a highly significant lower level than the children and adolescent group (G1)  could be associated with a tendency towards decline in diastolic function. The clinical implication of these findings could affect our routine assessment of ASD patients to include thorough assessment of LV diastolic function before device closure especially in adults.The age at the time of ASD closure had a significant impact on LV diastolic function in the form of septal Longer-term follow-up is recommended to validate the results of this study on the impact of ASD device closure in the different age groups and to determine whether the negative effect of device closure on diastolic function in adults is temporarily and will normalise later on or will be persistent.Multi-centre study involving larger number of patients is now considered. This kind of study will enable us to divide the patients into different tiers according to age to accurately identify the ideal age for ASD closure that can achieve the best results concerning both systolic and diastolic function post-closure.


Despite the progress in the fetal echocardiographic detection of congenital critical heart defects and neonatal physical examination, a significant number of newborn infants are discharged and readmitted to the hospital in severe condition due to cardiac failure or collapse. The aim of this study was to assess the incidence of undetected critical congenital heart disease (CCHD) by a pulse oximetry-screening program in the maternity wards of hospitals with Perinatal Services in a specific geographic area. This is a prospective observational study performed in in the health area corresponding to the city of Valencia. Eligible infants were consecutively admitted newborn infants in the maternities of the participating hospitals with negative fetal echocardiography after normal physical examination in the delivery room. All patients were screened following a specific pulse oximetry protocol before discharge. A total of 8856 newborn infants were screened. A total of three babies presented with severe congenital cardiac malformation and two babies presented with early onset sepsis. Sensitivity was 100% and specificity was 99.97%, with a positive predictive value of 60% and negative predictive value of 100%. Pulse oximetry screening programs in the early neonatal period constitute a valuable tool to avoid inadvertent hospital discharge of severe cardiac malformations and the subsequent life-threatening complications derived. Congenital critical heart defects (CCHD), defined as those needing invasive medical intervention or those that can produce death within the first 30 days after delivery , may in In September 2011, the US Health and Human Services (HHS) Secretary’s Advisory Committee on Heritable Disorders in Newborns and Children recommended that critical congenital heart diseases (CCHD) to be added to the neonatal screening panel based on the evidence of a large number of newborns screened in Sweden and England ,13.In a large meta-analysis in 2012, 13 eligible studies with data for 229,421 newborn babies were analyzed. Pulse oximetry was demonstrated to be highly specific for the detection of critical congenital heart defects with moderate sensitivity . More reWe aimed to assess the relevance of universal screening for critical congenital heart disease (CCHD) in a specific health area  where fetal detection of cardiac malformations by echocardiography had been substantially implemented in recent years.This is a prospective observational pilot study performed in the health area of Valencia (Spain). The study protocol was approved by the Internal Review Board (IRB) of the Hospital Universitario y Politécnico La Fe . Parents/guardians of all recruited patients gave informed consent. A total of 12 hospitals, including level I , level II , and level III hospitals [Included patients were screened between 24–48 h after birth, following the protocol shown in Hence, in the 6-month study period, a total of 66 babies were diagnosed with CCHD; 36 in utero (54.5%), 27 (41.6%) ex utero by clinical examination, and three by pulse oximetry screening at discharge, representing 4.5% of the total instances of CCHD.It has been estimated that 30% of all CCHD patients have a late diagnosis and could benefit from neonatal screening . As mostOur study has obvious limitations. The number of patients and the geographical area are both small, and thus do not represent the entire Valencian community with 55,000 deliveries per year. However, it reveals that despite the excellent prenatal and postnatal detection of CCHD, approximately 5% of these babies would have been discharged home from the hospital. We could speculate that if we translate these numbers to the entire population of our community, at least 15 newborn infants could have been discharged yearly with a life-threatening condition, although the data obtained in our study do not support this conclusion. We did not see any false negative cases, although they have been described in other studies. Unluckily, the number of patients included in our study was relatively small and hindered the possibility of detecting such cases. In addition, our study revealed that it is feasible to systematically perform pulse oximetry screening in the maternity ward without implying a relevant additional workload for the nursing staff. Finally, it is worth mentioning that pulse oximetry screening can also promptly detect other severe conditions, such as early onset sepsis, that went undiagnosed in the routine clinical examination. The Spanish Neonatal Society (SENeo) is very soon going to put forward a protocol for the screening of CCHD that will be adopted by all the maternity wards in our country .


THV) within the pericardium is not constant throughout the cardiac cycle and THV would intuitively be lowest at end systole. We have, however, observed a phase shift between ventricular outflow and atrial inflow which causes the minimum THV to occur before end systole. The aims were to explain the mechanism of the late‐systolic net inflow to the heart and determine whether this net inflow is affected by increased cardiac output or systolic heart failure.Total heart volume (n = 21) and patients with EF<35% (n = 14) underwent magnetic resonance imaging with flow measurements in vessels to and from the heart, and this was repeated in nine controls during 140 μgram kg−1 min−1 adenosine infusion. Minimum THV occurred 78 ± 6 ms before end of systolic ejection (8 ± 1% of the cardiac cycle) in controls. The late‐systolic net inflow was 12·3 ± 1·1 ml or 6·0 ± 0·5% of total stroke volume (TSV). Cardiac output increased 66 ± 8% during adenosine but late‐systolic net inflow to the heart did not change (P = 0·73). In patients with heart failure, late‐systolic net inflow of the heart′s left side was lower (3·4 ± 0·5%) compared to healthy subjects .Healthy controls (Heart size increases before end systole due to a late‐systolic net inflow which is unaffected by increased cardiac output. This may be explained by inertia of blood that flows into the atria generated by ventricular systole. The lower late‐systolic net inflow in patients with systolic heart failure may be a measure of decreased ventricular filling due to decreased systolic function, thus linking systolic to diastolic dysfunction. All subjects underwent cardiac magnetic resonance imaging in the supine position with flow and cine imaging. Eight subjects additionally underwent flow and cine imaging during 140 microgram kgn = 14, five females) with decreased systolic function on echocardiography (EF <35%) investigated for possible treatment of dyssynchrony were included. All patients had left bundle branch block, ventricular dyssynchrony and none had significant valvular disease. Ten patients had ischaemic and four patients non‐ischaemic dilated cardiomyoatphy. All patients had betablocker and either angiotensin converting enzyme inhibitor or angiotensin II receptor type 1 blockade.Patients (http://segment.heiberg.se) . All images were evaluated using freely available software  into the heart  and outflows from the heart (aorta and pulmonary trunk) were added to determine total inflow and outflow over the cardiac cycle. In patients, only flows of the left side of the heart were collected to decrease MR scanning time.Flow images of all vessels leading to  and from (aorta and the pulmonary trunk) the heart were acquired and analysed as previously described . Non‐parametric tests were used to test the significance of the differences between variables as normal variation could not be assumed. The Wilcoxon test was used for comparison of inter‐subject differences and Mann–Whitney test for comparsion between subjects. Results with a The physiological characteristics of the volunteers and patients are listed in Table P = 0·88) or duration of systole (P = 0·13). Also, the late‐systolic net inflow of the left and right side of the heart did not differ .The increase in total heart volume during late systole before the end of systolic ejection (late‐systolic net inflow) for both sides of the heart and for the total heart is illustrated in Fig. P = 0·80)  or the right side .Adenosine increased cardiac output by 63 ± 9% primarily due to an increase in heart rate of 55 ± 8% and to a lesser extent by an increase in stroke volume of 6 ± 3%. THV, THVV and THVV/TSV did not change during adenosine vasodilatation Table . Figure 80) Fig. . Separatr2 = 0·52, P = 0·003, y = −0·03x + 13·5) in patients, but not in controls . There was no correlation in patients between late‐systolic net inflow and ejection fraction (P = 0·78), left ventricular volumes (P = 0·85) or heart rate (P = 0·08).The in‐ and outflows of the left side of the heart from two patients with systolic heart failure are shown in Fig. et al., et al., This study has demonstrated and quantified the presence of a net inflow to the heart during late systole showing that the heart is not smallest at the end of ventricular systole but rather ~80 ms before the end of systolic ejection. This is the result of a phase shift between the rapid systolic ventricular ejection and the resulting atrial filling. We propose that the mechanism for this phase shift is the inertia of the blood in the atria and veins. In patients with systolic heart failure where ejection of blood is slower, the lower inertia does not limit concomitant atrial filling and therefore ventricular ejection and atrial filling is more in phase and the late‐systolic net inflow is lower. This hypothesis was supported by the strong negative correlation between late‐systolic net inflow and systolic duration in patients but the absence of correlation in controls. However, larger studies are needed in patients with heart failure and in particular patients without left bundle branch block. The momentum of blood into the atria towards the atrioventricular valves during end systole might facilitate valve opening and early diastolic filling especially on the right side of the heart where diastolic ventricular suction is less pronounced (Carlsson et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., , et al. , et al. et al., et al., This study has for the first time demonstrated that the heart begins to increase in size before the end of systolic ejection. The volume difference which was generated between the minimum total heart volume and the end of systolic ejection was quantified to ~20% of the total heart volume variation and is due to inflow of blood into the atria. Notably, the late‐systolic net inflow must be located in the atria because the AV valves are closed during this time period of ongoing ventricular ejection. This late‐systolic atrial filling is caused by flow of blood in the pulmonary and caval veins which is accelerated into the atria due to the suction of ventricular systole (Zhang et al., The pumping heart is adapted for high flows during exercise. During exercise with increased flows, the heart functions more like a turbine with continuous flow and at rest it functions more like a displacement pump with acceleration and deceleration of blood into and out of the heart as well as between the atria and ventricles. Therefore, a more matched inflow and outflow during increased flow rates compared to rest, when there is a phase shift between inflow and outflow, could be expected. However, in the present study, there was no difference in phase shift between inflow and outflow using adenosine vasodilatation to pharmacologically achieve increased flow and thus no difference in outer heart volume variations. Interestingly, previous findings during exercise in fact showed increased outer heart volume variations, meaning larger phase shifts between inflows and outflows are present during exercise compared to rest (Steding‐Ehrenborg et al., et al., et al., Ballistocardiography has been used to detect the displacement of the body from the ejection of blood and contraction of the heart and thus detects inertial cardiohemic oscillations (Giovangrandi This is a first description of the late‐systolic net inflow, and further studies are needed to establish if the late‐systolic net inflow is helpful as a measure of diastolic function and dysfunction and if there is a prognostic significance of alterations of this meausure. If the late‐systolic net inflow is decreased, this may indicate a systolic cause of diastolic dysfunction. Studies in patients with valvular heart disease can be performed to show whether the late‐systolic net inflow affects valvular function.Cardiac catheterization was not performed, and therefore, pressure measurement are not available. Flow measurements of the right side of the heart were not collected in patients to minimize MR scan time. Patients with heart failure had left bundle branch block and dyssynchrony. Further studies need to investigate whether the results with a decreased late‐systolic net infow can be extended to patients with heart failure but no branch block.The smallest heart volume is prior to end systole as a result of a late‐systolic net inflow due to a phase shift between ventricular outflow and atrial inflow. This may be explained by the blood inertia as this physical property of blood result in a slower atrial filling by longitudinal shortening of the ventricles than ventricular ejection of blood. The late‐systolic net inflow was unaffected by increased cardiac output but lower in patients with systolic heart failure. This may be caused by inertia of blood that flows into the atria generated by ventricular systole. Patients with systolic heart failure have lower late‐systolic net inflow, and this may be explained by a more sluggish ventricular ejection of blood and a larger role of increased filling pressures for atrial filling compared to healthy subjects. These mechanisms may have relevance for diastolic dysfunction, linking systolic and diastolic function as well as valvular heart disease as the momentum of the late‐systolic net inflow towards the valve may facilitate opening.This study has been funded in parts by grants from the the Swedish Research Council, Swedish Heart Lung Foundation, the Swedish Medical Association, the Faculty of Medicine, Lund University, Sweden and the Region of Skåne, Sweden.Nothing to declare.