Background: In chronic kidney disease (CKD), endothelin-1 (ET-1) always increases and there are changes in cardiac ultrasonography. In the present study, we aimed at investigating the role of serum ET-1 in predicting cardiac complications in patients with CKD.Methods: The level of serum ET-1 was measured by enzyme-linked immunosorbent assay (ELISA) and cardiac ultrasonography was performed in enrolled patients. Indexes of heart failure, such as left ventricular mass index, interventricular septum thickness and left ventricular end diastolic diameter, were measured in patients with CKD.Results: In the present study, we found that the level of serum ET-1 was significantly correlated with left ventricular mass index, interventricular septum thickness and left ventricular end diastolic diameter (p < .001) in non-dialysis patients with CKD.Conclusions: The results of the present study indicated that the level of serum ET-1 is closely related to the cardiac complications of CKD and is a useful predictor of cardiac complication. Chronic kidney disease (CKD) is one of the major causes of death in patients with kidney disease. Early detection and active treatment of its complications, especially cardiovascular complications, can significantly improve the prognosis of patients. In the present study, we observed changes in serum endothelin-1 (ET-1) levels and ultrasonographic parameters reflecting structural and functional changes in non-dialysis patients with CKD. The aim of the present study was to investigate the role of serum ET-1 in the prediction of cardiac complications in patients with CKD.One hundred seventeen patients with CKD without dialysis were enrolled in the present study at the Department of Nephrology, Qilu Hospital of Shandong University from July 2014 to April 2016. All met the diagnostic criteria for CKD. All enrolled patients were divided into five stages according to the US NKF-K/DOQI working group recommendations in 2003 [2), 19 cases, 11 males and 8 females, average age (43.26 ± 11.56) years;Stage I, glomerular filtration rate (GFR) ≥ 90 mL/(min·1.73 m2), 25 cases, 11 males and 14 females, average age (46.48 ± 12.23) years;Stage II, GFR 60–89 mL/(min·1.73 m2), 23 cases, 12 males and 11 females, average age (48.95 ± 14.91) years;Stage III, GFR 30–59 mL/(min·1.73 m2), 27 cases, 16 males and 11 females, average age (47.56 ± 12.58) years;Stage IV, GFR 15–29 mL/(min·1.73 m2), 23 cases, 11 males and 12 females, average age (49.68 ± 12.63) years.Stage V, GFR <15 mL/, HP Sonos 5500 color Doppler echocardiography , LD24-0.8 Automatic balance microcentrifuge , 772 grating spectrophotometer , and Bayer l650 automatic biochemical analyzer . The ET-1 kit was provided by Nanjing Jiancheng Bioengineering Research Institute, with intra-assay variation CV <10% and inter-assay variation CV <15%.Six milliliters of venous blood was collected from the left elbow median artery from all patients with a fasting status in the morning (at least 8 h without eating). Serum was separated from 2 mL of venous blood and was stored by cryopreservation, and the level of ET-1 in the serum was measured from these samples. The remaining 4 mL of venous blood was evenly injected into glass anticoagulant test tubes, 2 mL each. Serum urea nitrogen, creatinine and hemoglobin were measured by enzymatic methods the picric acid method and the high iron oxide method. Medication with an angiotensin-converting enzyme inhibitor (ACEI), an Angiotensin II receptor antagonist (ARB), calcium channel blockers (CCB), diuretics, nitrates, digitalis drugs and vasodilators was excluded from all enrolled patients at least 36–48 h before blood samples were collected.H + 0.0128 × W − 0.1529) to calculate the body surface of enrolled patients. Glomerular filtration rate (GFR) was calculated using the modification of diet in renal disease (MDRD) [Left ventricular end-diastolic diameter (LVDd), interventricular septal thickness (IVST) and left ventricular posterior wall thickness (LVPWT) were measured from the standard sternal left ventricular long axis, according to the American Society of Echocardiography (American Society of Echocardiography) standard by HP Sonos 5500 color Doppler echocardiography. The left ventricular ejection fraction (EF) was calculated according to Simpson7S. The left ventricular mass index (LVMI) and relative wall thickness (RWT) were calculated according to Devereux’s calibration formula. All enrolled patients were measured for height , weight , systolic blood pressure (SBP), diastolic blood pressure (DBP), hemoglobin (Hgb), and age on admission to the present study. We used the following formula (body surface area (BSA) = 0.0061 × e (MDRD) .LVM(g)=2 and in females it is LVMI ≥111 g/m2. RWT > 0.45 was the standard for cardiac enlargement [We used echocardiography normal references from Ruijin Hospital, Shanghai Second Medical University, Institute of Hypertension. Normal standards of LVDd, IVST, and LVPWT were 40–60, 6–11, and 6–11 mm, respectively. EF < 50% and E/A < 1 are diagnosed as left ventricular systolic dysfunction and left ventricular diastolic dysfunction. For males and females, the diagnostic standard for left ventricular hypertrophy is different: in males it is LMVI ≥135 g/margement ,8. Left argement .q-test to assess the significance of the differences among the various groups. Correlation analyzes were assessed by a linear regression analysis. Significance was considered p < .05.Data were expressed as the mean ± SD , including left ventricular concentric hypertrophy in 22 patients (18.75%) and left ventricular eccentric hypertrophy in 37 patients (31.88%). Twenty-seven patients had left ventricular concentric, accounting for 23.13%, and 31 cases that had a normal structure, accounting for 26.25%.R2 = 0.408, F = 12.819, and p = .000 , and promote proliferation and hypertrophy of cardiomyocytes. ET-1 can also promote platelet-derived growth factor (PDGF), TGF release, and indirectly promote myocardial cell proliferation, which leads to cardiac hypertrophy. Another study  found thp < .01). It was confirmed that with renal function deterioration in chronic renal failure, the appearance of hypertension, accumulation of uremic toxins, and imbalance in endothelial function became increasingly serious. The patient’s cardiac structure and function deteriorated, and of all the indicators of cardiac ultrasound, in particular, LVMI and IVST were closely related to ET-1 activity. So, perhaps we can partially predict developing complications of CKD, especially cardiovascular complications, thereby reducing mortality and improving survival and quality of life in patients with CKD.The results of the present study showed that with the deterioration of renal function, LVMI increased gradually in the different groups, and there was a significant correlation between LVMI and ET-1 (In summary, cardiovascular complications are a common complication of CKD, and with the deterioration of renal function in patients with CKD, serum ET-1 levels gradually increased. The level of serum ET-1 is closely related to cardiac complications of CKD.


The aim of our work was to compare the myocardial perfusion imaging by single-photon emission tomography (MPI-SPECT) as a non-invasive, relatively non-expensive test versus the instantaneous wave-free ratio (IFR) for the evaluation of functional significance of the borderline coronary artery lesions in the view of results of fractional flow reserve (FFR) which is considered the gold standard reference test.P value < 0.001) agreement between the MPI results and FFR results and the overall agreement was 88%. The sensitivity of the MPI was 81.8%, the specificity was 92.9%, the positive predictive value was 90%, the negative predictive value was 86.7%, the positive likelihood ratio was 11.45, and the negative likelihood ratio was 0.20. There was a strong (kappa = 0.918) significant  agreement between the IFR results and FFR results and the overall agreement was 96%. The sensitivity of the IFR was 90.9%, the specificity was 100%, the positive predictive value was 100 %, the negative predictive value was 93.3%, and the negative likelihood ratio was 0.09.Our study was conducted in the Cardiology Department. It included 50 patients with borderline coronary artery lesions; they underwent physiological evaluation by stress/rest myocardial perfusion imaging using followed by an invasive physiological assessment by Instantaneous wave-free ratio (IFR) and Fractional flow reserve (FFR). Finally, the results of both SPECT MPI and IFR were compared to FFR as a gold standard reference. There was a strong (kappa = 0.754) significant (The instantaneous wave-free ratio (IFR) may be a valid alternative to fractional flow reserve to assess the functional significance of intermediate coronary lesions. The myocardial perfusion imaging may be an alternative, non-invasive, relatively non-expensive test for the evaluation of the physiological significance of intermediate coronary lesions. Invasive angiography is the reference test for the diagnosis of CAD. However, the relationship between the angiographic stenosis severity and the coronary blood flow is complex. The visual assessment of stenosis severity is subjective and correlates poorly with physiological significance . UnfortuThe aim of this work was to compare the myocardial perfusion imaging by single-photon emission tomography (MPI-SPECT) as a non-invasive, relatively non-expensive test versus the instantaneous wave-free ratio (IFR) for the assessment of functional significance of the intermediate coronary artery lesions in the view of results of fractional flow reserve (FFR) which is considered the gold standard reference test.This study prospectively recruited 50 ischemic heart disease patients presented to the cardiology department with intermediate (40–70%) lesions in coronary arteries to compare the results of single-photon emission tomography myocardial perfusion imaging (MPI-SPECT) versus instantaneous wave-free ratio (IFR) in the view of results of fractional flow reserve (FFR) as a gold standard reference.The protocol was approved by the committee of the medical ethics of the cardiology department in March 2016 and informed written consent was obtained from all the patients. The pre-procedural assessment was done in the cardiology outpatient clinic.Inclusion criteria:Patients with angiographically borderline coronary artery stenosis (40–70%) in a single coronary artery were assessed by at least two expert operators. The following patients were excluded from our study:I.Patients with certain limitations to FFR:A.Acute coronary syndrome:STEMI.Non-STE ACS.B.Patients with marked left ventricular hypertrophy: as microvascular abnormalities may be present and impair the results of FFR .C.Patients with tandem lesions: FFR pullback has limited value for assessment of tandem successive coronary lesions .II.Contraindications to stress—Tc-99 MPI: Iodine 131 treatment within the last 3 months.Indium 111 or gallium 67 scan within the last month.Tc-99 imaging within 2 days.Pregnant ladies.Congestive heart failure.Severe hypertension (blood pressure > 200/110 mmHg).Uncontrolled cardiac arrhythmias (causing symptoms or hemodynamic compromise).Severe valvular lesions.Acute pulmonary embolism.Other acute cardiac conditions .Previous myocardial infarction and Multi-vessel disease.The patients were subjected to the following:Informed consent: According to the World Medical Association (WMA) Declaration of Helsinki 2013 . For eacMyocardial perfusion image (MPI) protocol: , 10Two-day protocol, stress, and rest Tc99m sestaMIBI myocardial perfusion SPECT was performed.Patients were exercised on a treadmill according to the standard Bruce protocol .Patients with contraindications for exercise test underwent pharmacologic stress test (Dobutamine stress test).Technetium-99m Sestamibi 20 mCi was injected at peak exercise. Then, the patient was instructed to eat a fatty meal to decrease hepatic activity during imaging.After 30–60 min, imaging acquisition started. Imaging was in the supine position.On the second day, patients were re-injected by 20 mCi Tc99m sestaMIBI and re-imaged after 30–60 min with the same protocol. The image processing and reconstruction were performed according to the American Society of Nuclear Cardiology guidelines , 10.Image analysis was performed using a previously validated automated program that determines the extent and severity of LV perfusion defect size and the extent of reversible (ischemia) or fixed (scar) resting hypoperfusion and LVEF.SPECT MPI results were considered positive when the defect size ≥ 10% in the territory of interest.I.Instantaneous wave-free ratio (IFR) and Fractional Flow Reserve (FFR): , 6, 11Philips Volcano system was used for IFR & FFR measurements using prime-prestige pressure wires.Routine preparation:Patients were instructed to stop caffeine intake 24 h before the procedure as caffeine is considered as adenosine receptor antagonist that may interfere with adenosine-induced hyperemia and affects FFR results . No anesAccess: routine trans-femoral or trans-radial approach for cardiac catheterization was applied.Diagnostic coronary angiography was done with localization of the site of stenosis of interest.Calibration of pressure systems: the pressure lines were flushed with saline. Then, the “zero- reference” was recorded.Each patient underwent IFR and FFR measurements, the following technique was applied:Instantaneous wave-free ratio (IFR) was calculated in a computerized manner independent of any induced hyperemia. An IFR value lower than 0.89 was considered positive indicating hemodynamically significant stenosis and IFR value higher than 0.89 was considered negative indicating stenosis that is not hemodynamically significant , 12.To measure fractional flow reserve (FFR); once the transducer was distal to the stenosis, a hyperemic stimulus was administered by injection through the guide catheter, and the FFR is monitored for a significant change.Intracoronary adenosine was used: 100 μg bolus in the right coronary artery or 200 μg bolus in the left coronary artery . IntracoThe mean arterial pressures from the pressure wire transducer and from the guide catheter were then used to calculate FFR , 13.In the case of adenosine-induced hyperemia: an FFR value lower than 0.8 was considered positive indicating significant stenosis and FFR value higher than 0.8 was considered negative indicating stenosis that was not hemodynamically significant , 6.The sensor was then positioned 2 mm distal to the tip of the guiding catheter and we flushed the guiding catheter using saline. At that site, both pressures were identical. If the two pressures were not equal, the measured pressures had to be equalized electronically, using that function of the console. If there was ostial stenosis, this should be performed with the pressure sensor positioned in the aorta. The sensor was then manipulated in the distal part of the artery. In any case, the sensor was placed 3 cm distal to the stenosis to be assessed, a distance where the post-stenotic laminar flow is restored. The pressure transducer was located approximately 3 cm proximal to the distal tip of the wire and it could be seen by fluoroscopy.The description of quantitative variables was in the form of mean, standard deviation (SD), median, and range (min-max).The description of qualitative variables was in the form of numbers (no.) and percent (%).The data were explored for normality using Shapiro/Kolomogrov tests of normality.Kappa agreement was done to test the agreement between the MPI and the IFR with the gold standard FFR.Pearson correlation was conducted to test the correlation between the MPI and the IFR with the gold standard FFRr was considered mild till 0.3, moderate till 0.6 and strong for more than 0.6.Kappa and correlation coefficient ROC curve was used to assess the cut-off points of MPI and IFR at which we can find the best prediction of positive cases by FFR.Analysis of the data was performed using SPSS v. 23  for Windows. The description of the variables was presented as follows:P value that was classified into:P value > 0.05Non-significant when P value ≤ 0.05Significant when P value ≤ 0.001Highly significant when The results were assessed in the form of The study was conducted in the Cardiology Department, in the period between January 2017 and June 2019. It included 50 patients with stable coronary artery disease and intermediate coronary artery lesions, they underwent physiological evaluation by stress/rest myocardial perfusion imaging using single-photon emission tomography (SPECT-MPI) followed by an invasive physiological assessment by instantaneous wave-free ratio (IFR) and fractional flow reserve (FFR). Finally, the results of both SPECT MPI and IFR were compared to FFR as a gold standard reference Table P value < 0.001) negative strong correlation (r = − 0.7) between FFR and MPI. There was a highly statistically significant  positive strong correlation (r = 0.947) between FFR and IFR.Table P value < 0.001) agreement between the MPI results and FFR results and the overall agreement was 88%. The sensitivity of the MPI was 81.8%, the specificity was 92.9%, the positive predictive value was 90%, the negative predictive value was 86.7%, the positive likelihood ratio was 11.45, and the negative likelihood ratio was 0.20.Table P value < 0.001) agreement between the IFR results and FFR results and the overall agreement was 96%. The sensitivity of the IFR was 90.9%, the specificity was 100%, the positive predictive value was 100 %, the negative predictive value was 93.3%, and the negative likelihood ratio was 0.09 Table Table Myocardial perfusion imaging by single-photon emission tomography (MPI SPECT) was shown to have high overall sensitivity and specificity estimated at 81.8% and 92.9%, respectively, as well as high positive predictive value (PPV) and negative predictive value (NPV) estimated as 90% and 86.7% respectively. Actually, this concordance between MPI SPECT and FFR results can be already expected and understood from the early validation studies on FFR itself that used MPI SPECT to assess the validity of FFR. In one study; I. Erhard, J. Rieber et al.  SPECT MPTao Zhoua et al.  reviewedIn another meta-analysis, Ibrahim Danad et al.  evaluateOn the other hand, some studies showed poor concordance between MPI SPECT and FFR especially in the patients with multi-vessel disease which was a more challenging situation to MPI SPECT evaluation due to the fact that MPI SPECT actually assesses the relative blood flow differences among vascular territories and so the possibility of balanced ischemia in the presence of more than one vessel disease may be an obstacle for accurate assessment. For example, in Narbeh Melikian et al. study  more thaThe instantaneous wave-free ratio (IFR) was shown to have sensitivity and specificity estimated as 90.9% and 100%, respectively, as well as positive predictive value (PPV) and negative predictive value (NPV) estimated as 100% and 93.3% respectively. Actually, this concordance between IFR and FFR results can be already expected and understood from the validation studies on IFR which compared both IFR and FFR against different other third-party tests and showed a great concordance between the two methods. In one study: the CLARIFY . In nearIn another study; Hwang D, Jeon K-H, et al.  includedThere are also some small studies were similar to our study design and compared IFR results directly to FFR results as a gold standard reference test.rs = 0.81; P < 0.0001). ROC analysis showed an area under the curve (AUC) equals 0.9106, suggesting the high reliability of the IFR as an accurate diagnostic test. The IFR-only technique with a treatment cut-point ≤ 0.89 revealed a diagnostic agreement with the FFR-only technique strategy in more than 120 lesions (nearly 83%) with a sensitivity of nearly 80%, a specificity of 86%. In another study, Alfredo Fede et al. [R = 0.83, P < 0.0001). Deep Chandh Raja et al. [In one study, Tobias Härle et al.  assessede et al.  includeda et al.  found thAlso, there are some meta-analysis studies that addressed this point and clarified this concordance.P < 0.001). Also, they compared IFR and FFR to a third independent reference standard that was invasive coronary flow reserve, non-invasive coronary flow reserve, hyperemic stenosis resistance, a combined reference standard of myocardial perfusion scintigraphy, and hyperemic stenosis resistance index or positron emission tomography perfusion imaging. There were no significant differences between IFR and FFR, both in terms of diagnostic accuracy, measured as the area under the ROC curve and in terms of the diagnostic agreement to the third comparator used in these studies.In one meta-analysis, Salvatore De Rosa et al.  evaluateIn another meta-analysis Rohit Maini et al.  nearly 6Despite the encouraging results presented in our small study, there were significant limitations including the small sample size and the exclusion of some types of patients that may be candidates for evaluation as patients with previous myocardial infarction and patients with multi-vessel disease.The myocardial perfusion imaging by single-photon emission tomography (MPI SPECT) and instantaneous wave-free ratio (IFR) techniques showed significant concordance with fractional flow reserve (FFR) which is the gold standard reference test for physiological assessment of coronary lesions regardless of the type of diseased coronary artery. In this context, both MPI SPECT and IFR showed high sensitivity, specificity, NPV, and PPV compared with FFR. Therefore, the instantaneous wave-free ratio (IFR) may be a valid alternative to fractional flow reserve to assess the functional significance of intermediate coronary lesions without using agents to induce maximal hyperemia. More importantly, this study may encourage the use of myocardial perfusion imaging by single-photon emission tomography (MPI SPECT) as an alternative, non-invasive, relatively non-expensive test for the evaluation of the physiological significance of intermediate coronary lesions.We hope and recommend that this study will be a nucleus for further larger studies in the future that may present more solid evidence and target special patient populations excluded from this study as patients with previous myocardial infarction and patients with multi-vessel disease.


Septal midwall late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging (CMR) is a characteristic finding in nonischemic dilated cardiomyopathy (DCM) and is associated with adverse cardiac events. QRS-prolongation in DCM is also frequently present and a predictor of arrhythmic events and mortality. Since the His-Purkinje fibres are located in the interventricular septum, QRS-prolongation may directly result from septal fibrosis, visualized by LGE. Our aim was to study the correlation of the presence and extent of septal midwall LGE and QRS-duration.DCM-patients with left ventricular (LV) dysfunction (LVEF < 50%) were included. LV volumes, systolic function and nonischemic septal midwall LGE, defined as patchy or stripe-like LGE in the septal segments, were quantified. QRS-duration on standard 12-lead ECG was measured.165 DCM-patients were included  with a median LVEF of 36% [24–44]. Fifty-one patients (31%) demonstrated septal midwall LGE with a median extent of 8.1 gram [4.3–16.8]. Patients with midwall LGE had increased LV end-diastolic volumes (EDV) 248 mL [193–301] vs. 193 mL [160–239], p < 0.001) and lower LVEF . Median QRS-duration was 110 ms [95–146] without a correlation to the presence nor extent of midwall LGE. QRS-duration was moderately correlated with LV-dilation and mass .In DCM-patients, QRS-prolongation and septal midwall LGE are frequently present and often co-exist. However, they are not correlated. This suggests that the assessment of LGE-CMR has complementary value to ECG evaluation in the clinical assessment and risk stratification of DCM-patients. Dilated cardiomyopathy was classified according to current guidelines DCM patients underwent CMR imaging either for assessment of underlying aetiology in newly developed heart failure or for prognostic evaluation prior to ICD-implantation. Scans were performed on 1.5 Tesla whole body scanners  with dedicated phased array cardiac receiver coils. Cine imaging was performed using retrospective ECG-gated steady-state free precession cine during breath hold in standard 3 long-axis views and a stack of short-axis slices, covering the ventricles from base to apex.42 Circle Cardiovascular Imaging Inc., Calgary, Canada). From that dataset, left ventricular end diastolic volume (LVEDV), end systolic volume (LVESV) and LVEF were calculated. The extent of LGE was quantified using the full width at half maximum (FWHM) method LGE images were acquired 10–15 min after gadolinium contrast administration using a T1-weighted inversion recovery-prepared gradient echo sequence with optimized inversion time. The presence and pattern of gadolinium hyperenhancement were assessed visually by certified CMR-cardiologists and LGE was considered present if the enhancement was seen in two perpendicular views or two serial slices. The septal midwall LGE pattern was defined as stripe-like or patchy midmyocardial hyperenhancement in the interventricular septal segments. Endocardial contours were manually drawn in end diastolic and end systolic phase on a stack of short axis cine images, using dedicated software (CVIA resting 12-lead electrocardiogram (ECG) of each patient, made in supine position , was collected. Heartrate (beats per minute (bpm)) was automatically assessed. Measurements included the PR-interval and QRS duration, assessed manually from onset of first deflection from baseline  until the end of the S-wave, defined as its return to baseline. Left bundle branch block (LBBB) was defined according to conventional criteria of AHA/ACCF/HRS t-test or Mann-Whitney U test were used for comparison between groups for continuous data, depending on normality, and chi-square test for intergroup comparison of binomial data. Mann-Whitney U test was also used for the comparison of ordinal categorical variables. Pearson and Spearman correlations were calculated as a measure of association between LV volumes, LGE amount and QRS duration, depending on normality. For all these analyses a p-value of <0.05 was considered statistically significant. Determinants of septal midwall LGE and QRS-duration was assessed using respectively logistic regression analysis and linear regression analysis. Data included in regression analysis included demographic data and CMR-derived variables. Parameters with p < 0.1 in univariable regression models were entered in a multivariable regression analysis using a backward elimination procedure with p < 0.05 required for inclusion in the final model. R square and Nagelkerke R were used to assess goodness-of-fit of the linear and logistic regression model. Collinearity was assessed for multivariable analysis using variance inflation factors. No imputation of missing data was performed. Analyses were performed using SPSS .Continuous variables are presented as mean ± SD, or as median and interquartile range (IQR), depending on whether distribution was normal or not. Categorical data are summarized as frequencies and percentages. The independent samples 3We included 165 patients with DCM. Patient with septal midwall LGE had significantly more severe LV dilation  and worse LV systolic function  compared to patients without septal LGE . LGE-extThe mean PR-interval was 176 ± 15 ms and was significantly longer in patients with midwall LGE present . HoweveMedian QRS duration was not found to differ between patients with and without septal midwall LGE . The majority of the 74 patients with QRS ≥ 120 ms had an LBBB pattern (76%). The prevalence of LBBB did not differ significantly between patients with and without septal midwall LGE  and neither did the prevalence of narrow QRS-complex . We found a moderate positive correlation between QRS duration and LV dilation, expressed as LVEDV (r = 0.35, p < 0.001. 4In the present study, both septal midwall LGE on CMR and QRS-prolongation on ECG were frequently observed and often co-existed in patients with DCM. Although both parameters were significantly related to the extent of LV dilation and severity of LV systolic dysfunction, ventricular conduction delay was not correlated to the presence nor the extent of septal midwall LGE.In patients with cardiomyopathy, left ventricular remodelling occurs to maintain cardiac output and is accompanied by myocyte hypertrophy and an increase of interstitial fibrosis The present study showed that in the presence of midwall LGE, LV volumes were larger, LV mass was increased and LV function was significantly lower. This is in line with earlier studies Interstitial fibrosis is assumed to reduce conduction velocity QRS-prolongation with LBBB is found in approximately 1% of the general population and up to 30% of heart failure patients. The prevalence of LBBB is increasing with age, and in patients with structural heart disease LV dilation, resulting from prolonged LV remodelling in heart failure, was moderately correlated to QRS-prolongation in the present study. This finding is in line with previous work This study demonstrates that QRS-prolongation and septal midwall LGE are different entities in patients with DCM. Since all these findings are individually associated with structural changes in LV dimension and function, and all have prognostic consequences 5There are several limitations to this study. This was a single-centre, retrospective, observational study, which is associated with potential selection bias and the rather small sample size limits the power of these results. Furthermore, LGE-quantification was performed after visual assessment of presence or absence of septal midwall LGE. However, the interobserver variability of a certified cardiologists assessing the presence of midwall LGE is known to be small 6In patients with DCM, QRS-prolongation, with or without LBBB pattern, is frequently present and often co-exists with septal midwall LGE on CMR. Both markers are significantly associated with structural LV changes in myocardial remodelling. However, they are not directly correlated. This suggests assessment of both QRS duration and septal midwall LGE on CMR to be of complementary value for risk-stratification o patients with DCM.Marthe A.J. Becker: Conceptualization, Data curation, Investigation, Formal analysis, Methodology, Project administration, Visualization, Writing - original draft. Cornelis P. Allaart: Conceptualization, Resources, Software, Supervision, Writing - review & editing. Alwin Zweerink: Conceptualization, Investigation, Writing - review & editing. Jan H. Cornel: Resources, Supervision, Writing - review & editing. Peter M. Ven: Methodology, Formal analysis, Writing - review & editing. Albert C. Rossum: Resources, Supervision, Writing - review & editing. Tjeerd Germans: Conceptualization, Methodology, Supervision, Visualization, Writing - review & editing.No conflict of interest. No grants or other form of financial support received.


PAH) due to systemic sclerosis (SSc) have high mortality. Left ventricular (LV) peak global longitudinal strain (GLS) is decreased in SSc. It is unknown whether low GLS is due to SSc or PAH. Therefore, our primary aim was to evaluate both LV and right ventricular free wall GLS (RVFW GLS) in SSc, with and without PAH, using cardiac magnetic resonance with feature tracking. Secondary aim was to relate GLS to invasive mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR).Patients with pulmonary arterial hypertension  for volumetric and strain calculations.Thirty‐eight patients with PAH had lower LV and RVFW GLS than SSc  and controls , with no difference between SSc and controls. LV strain correlated with mPAP  and PVR . RVFW GLS correlated with mPAP  and PVR . ROC curves for predicting PAH had AUC 0·73 for LV strain (P = 0·003) and 0·86 for RVFW GLS (P<0·001).Systemic sclerosis‐GLS is mainly determined by increased pulmonary pressure and not by SSc per se. Low LV and RVFW GLS are indicative of increased mPAP and PVR, which opens for improved non‐invasive methods to select patients eligible for right heart catheterization and to monitor the effects of PAH therapy.Lower  Pulmonaet al., et al., et al., et al., 2015). High negative GLS is a marker for good clinical outcome, while low negative GLS implies poor outcome . Using echocardiography and cardiac magnetic resonance (CMR), RV free wall (RVFW) GLS is usually low in patients with PAH and carries, in itself, prognostic value  by echocardiography has been shown to have prognostic value in SSc and PAH from various aetiologies  evaluate whether LV and RVFW GLS differ between patients with SSc, with and without PAH, compared to healthy controls, and (ii) whether these differences are related to invasive measurements.The outcome may be of great importance to differentiate SSc patients that exhibit PAH, enabling earlier referral for diagnostic right heart catheterization (RHC), and potentially identification at a lower risk status, rendering earlier treatment initiation and improved prognosis.et al., et al., et al., et al., Consecutive patients with SSc examined with clinical indications for CMR at Skåne University Hospital during 2002–2015 were prospectively scanned and data retrospectively analysed. CMR data were analysed from 65 patients diagnosed with SSc, whereof 40 without PAH and 25 with PAH. Nineteen healthy controls, from earlier studies in our group  and pulmonary artery wedge pressures were recorded at free breathing over several heartbeats. Cardiac output was calculated via thermodilution, and PVR expressed as [PACardiac magnetic resonance was performed on two 1·5‐Tesla MRI scanners . Short‐ and long‐axis cine steady‐state free precession images were acquired in supine position Fig. . Typical−1) in short‐axis stack and long‐axis planes using an inversion‐recovery gradient echo sequence. Inversion times were adjusted to null the signal from normal myocardium. Severe renal failure with glomerular filtration rate below 30 mL min−1 1·73 m−2 and allergic reaction to gadolinium was considered contraindications for contrast administration. Two patients with SSc‐PAH had no gadolinium administration due to impaired kidney function and two patients with SSc had termination of examination before gadolinium administration due to anxiety (n = 1) or claustrophobia (n = 1).Late gadolinium enhancement (LGE) was obtained on clinical indications to assess focal fibrosis. LGE images were acquired 10–15 min after intravenous gadolinium‐DTPA .Endocardial and epicardial borders were manually delineated in end diastole and end systole in all short‐axis slices. End‐diastolic volume, end‐systolic volume, stroke volume, LV ejection fraction (EF) and cardiac output were calculated. Endocardial and epicardial borders were manually delineated in long‐axis two‐, three‐ and four‐chamber views in end diastole, and an automated propagation throughout the heart cycle was computed for each view Fig. .Endo‐ and epicardium of RVFW were manually delineated in the four‐chamber view, without including the septum, in end diastole and automatically propagated throughout the heart cycle Fig. . InadequAll image analyses were performed blinded to clinical information by one observer (A.L.), with a second observer as adjudicator (E.O.) of the delineations.In tissue tracking, a myocardial pattern is recognized by the software in the end‐diastolic image with the endocardium and epicardium manually delineated as external borders. The software propagates the delineations over the whole heart cycle.et al., Global longitudinal strain was defined as peak systolic strain. LV GLS was computed from the average of each segment according to a 17‐segment model from the long‐axis views  and controls . LV strain did not differ between SSc and controls (P = 1)  compared to both SSc  and controls . RVFW strain did not differ between SSc and controls (P = 1·0)  compared to both SSc  Fig. .R = 0·62, P<0·001)    and diastolic PAP . LV strain correlated with mPAP  and PVR  . Multivariable linear regression with RVFW strain and RVEF correlated with mPAP  and with PVR .Peak RVFW strain correlated with LV strain (01) Fig. . RVFW st01) Fig.  and withP<0·001). A cut‐off value of RVFW strain at −26·2% gave a sensitivity of 84% and a specificity of 77% for the diagnosis of PAH  and a cut‐off value of LV strain at −20·0% gave a sensitivity 84% and specificity 58% , and a cut‐off of 52·0% gave a sensitivity of 95% and a specificity of 84%. Area under the curved for combined RVFW strain and RVEF was 0·98 with a sensitivity of 90% and a specificity of 90%.Analysis of receiver operating characteristics for RVFW strain predicting the diagnosis of PAH, using mPAP ≥25 mmHg from RHC as reference, showed an area under the curve of 0·86 (P = 0·005 among the groups). RVFW strain was lower in patients with fibrosis (−22 ± 8%) and in patients with infarction (−22 ± 5%) compared to patients without fibrosis . Both LVEF and RVEF were lower in patients with fibrosis or infarction compared to patients without fibrosis (P = 0·004 and P<0·001).Four patients had manifestations of infarction, 16 had focal fibrosis at RV insertion and 33 patients were without visually localized fibrosis and scar. LV strain was lower in patients with insertion fibrosis (−18 ± 3%) and even lower in patients with infarction (−17 ± 4%) compared to those without fibrosis  to our LV values (GLS −20% for both groups). However, in the study by Piccione et al., SSc patients had much lower LV GLS compared to controls  , indicating that their patients were more severely ill at least from a fibrotic point of view, and they found a correlation between GLS and anti‐Scl‐70 antibodies . This would suggest that treatment naivety is not the cause of lower strain values.Another confounder to the strain values could be medical therapy, where patients receiving therapy could have increased longitudinal strain. However, the only differences in cardiac medication between the groups were higher usage of endothelin receptor antagonists and phosphodiesterase type 5 inhibitor in the PAH group Table . There wper se. The correlation between left and right GLS and PAPs could open possibilities for non‐invasive evaluations of PAPs in patients with early signs of SSc‐PAH and to select patients eligible for RHC and monitor effects of PAH therapy. This is of importance as earlier diagnosis of PAH, at a lower risk status, previously has been shown to be related to an improved survival (Kylhammar et al., A decrease in LV and RVFW GLS is more likely associated with PAH than SSc Outside the submitted work, H.A. is a shareholder in Imacor AB, Lund, Sweden.


In acute myocardial infarction (AMI), impaired myocardial salvage and large infarct size result in residual heart failure, which is one of the most important predictors of morbidity and mortality after AMI. Sleep-disordered breathing (SDB) is associated with reduced myocardial salvage index (MSI) within the first 3 months after AMI. Adaptive servo-ventilation (ASV) can effectively treat both types of SDB . The Treatment of sleep apnoea Early After Myocardial infarction with Adaptive Servo-Ventilation trial (TEAM-ASV I) will investigate the effects of ASV therapy, added to percutaneous coronary intervention (PCI) and optimal medical management of AMI, on myocardial salvage after AMI.TEAM ASV-I is a multicentre, randomised, parallel-group, open-label trial with blinded assessment of PCI outcomes. Patients with first AMI and successful PCI within 24 h after symptom onset and SDB (apnoea–hypopnoea index ≥ 15/h) will be randomised (1:1 ratio) to PCI and optimal medical therapy alone (control) or plus ASV  or no LAD lesion). The primary outcome is the MSI, assessed by cardiac magnetic resonance imaging. Key secondary outcomes are change of infarct size, left ventricular ejection fraction and B-type natriuretic peptide levels and disease-specific symptom burden at 12 weeks.TEAM ASV-I will help to determine whether treatment of SDB with ASV in the acute phase after myocardial infarction contributes to more myocardial salvage and healing.ClinicalTrials.gov, NCT02093377. Registered on March 21, 2014. After acute myocardial infarction (AMI), myocardial salvage is central to limiting permanent damage to the heart because large infarct sizes result in enduring heart failure (HF) , which iRecent observational studies suggest that at least a moderate degree of SDB affects up to 66% of patients in the early phase after AMI . PatientEspecially in the early phase after AMI, SDB is associated with increased cardiac workload , prolongPrevious randomised controlled trials in patients with AMI and SDB evaluated the effects of continuous positive airway pressure (CPAP) on major cardiovascular events , 18. BotAdaptive servo-ventilation (ASV) is currently the most effective therapy with respect to normalisation of nocturnal breathing in patients with impaired cardiac function plus CSA and OSA, with or without periodic breathing . HoweverClinicalTrials.gov .TEAM ASV I is a multicentre, randomised, parallel group, open-label trial with blinded assessment of outcomes. It will compare treatment with PCI and optimal medical therapy (control group) with PCI, optimal medical therapy and ASV (ASV group) in patients with AMI and SDB. The trial is an investigator-initiated and run study, funded by the ResMed Foundation ; ResMed Germany  is providing the ASV devices. The trial was approved by the relevant institutional ethics committee  and is being conducted in accordance with the Declaration of Helsinki. All patients will provide written informed consent before undergoing study investigations. This trial has been registered with The trial began enrolment in March 2014 and is expected to end enrolment in December 2020. As of writing, a total of 67 of the 90 target patients have been randomized.The study is monitored by an independent data safety monitoring committee (DSMC), comprising three clinical trial experts (two cardiologists and an independent statistician) who will review serious and non-serious adverse events throughout the study. An interim safety analysis is pre-specified after randomisation of the 35th patient and will include all safety variables related to this trial (study device-related and non-related events).Consecutive patients with their first AMI in a stable haemodynamic condition will be assessed for eligibility according to the inclusion and exclusion criteria shown in Table https://www.randomizer.at/) supervised by the Center of Clinical Studies. This tool ensures a secret randomization schedule for all participants and offers a 24/7 online randomization service. Randomisation to the intervention arms will be performed in a 1:1 ratio and will be stratified for infarct location (e.g. left anterior descending artery (LAD) lesion and no LAD lesion) and study site. In addition to PCI, patients randomised to the control group receive optimal medical therapy for the management of AMI according to current guidelines [Randomisation will be performed by using the online randomization tool Randomizer  The patient will use the device during the daytime to achieve acclimatisation and to allow further adjustments to minimise leaks. Daytime device use will take place for 30–120 min until the patient feels comfortable with the mask and the device and leak is minimised. Night time treatment initiation will be performed under polygraphic monitoring. Default device settings include autotitrating expiratory positive airway pressure (EPAP) of 5–15 cmHBaseline assessments are performed in all patients meeting the inclusion and exclusion criteria. These include demographics, medical history, physical examination, ECG, cardiac magnetic resonance imaging (CMR), laboratory testing and completion of the Seattle Angina Questionnaire within 5 days after PCI (in-patient) Fig. .Fig. 1SFollow-up visits are performed after 2, 4 and 12 weeks to assess outcome measures and adverse events and to ensure compliance with the allocated treatment. Details of assessments at each visit are provided in Fig. The primary objective is to evaluate the effects of 3 months of ASV therapy in addition to PCI and optimal medical management of AMI on myocardial salvage ), assessed by CMR. Secondary objectives are listed in Tables Polygraphy  will be performed within 3 days after PCI and repeated at the 12-week follow-up visit in both treatment groups  2012 criteria by one experienced sleep technician blinded to the clinical data . SDB is Myocardial salvage, infarct size and left ventricular function will be examined in both groups using CMR at baseline and after 12 weeks of treatment. The baseline CMR is performed to visualise myocardial oedema (i.e. the area at risk) and baseline infarct size. The second CMR is performed to measure the final infarct size.All CMR images will be acquired with a 1.5 or 3.0 Tesla clinical scanner, as previously described . The scaVenous blood samples  and urine (100 mL) will be collected from every patient participating in the study during the first 2 h after morning awakening at baseline and at 12 weeks ) have to be documented in the CRF and source documents. Safety analyses will be performed in the safety population including participants who will have at least one post-baseline safety assessment. Patient informed consent includes long-term follow-up phone interviews after the 3-month trial period to assess mortality at 1, 3 and 5 years after randomization.13 with a power of 1 − β = 80%, at a two-sided alpha significance level of 0.05, the required sample size for a randomised trial is 37 patients per group . With an estimated loss to follow-up rate of approximately 17% based on previous observational data, 90 randomised patients (45 per group) are required.The maximum possible effect of ASV therapy on MSI would be a reduction of 25, as calculated from a previous prospective observational study  . We consThe point estimate for the primary endpoint (MSI) will be presented as mean and standard deviation (SD) with the corresponding 95% confidence interval (CI). MSI values will be compared between the ASV and control groups by an analysis of covariance (ANCOVA) with treatment (ASV therapy and control) as the fixed factor and infarct size at baseline, infarct location and study centre as an additional covariable. The results will be presented in terms of least-squares means and corresponding 95% CI. The primary analysis will be performed on an intention-to-treat basis . In addition, we will perform a sensitivity analysis in a per-protocol analysis set (PP population) to assess the robustness of the results. The PP population consists of all patients in the ITT population who show no major protocol violations. Major and minor protocol deviations will be identified before database lock. In addition, an on-treatment analysis, including patients with positive airway pressure support use for ≥ 4 h/day and an on-treatment AHI of < 10/h, will be performed. All safety data will be analysed in the safety population . Additional pre-specified subgroup analyses are: LAD versus non-LAD lesions; central versus obstructive sleep apnoea; and PCI < 24 h versus ≥ 24 h after symptom onset.No imputation methods for missing values will be used for the analyses of the primary and secondary endpoints . In case of 5 to 40% missing data regarding the primary endpoint, a multiple imputation method will be used for further sensitivity analyses. If more than 40% of the data are missing, the trial results may only be considered as hypothesis generating results .All secondary endpoints will be analysed in an exploratory manner and summarised using descriptive statistics. Safety variables will be analysed descriptively. The interim analysis after randomisation of the 35th patient will include safety variables only. All efficacy analyses will be performed on the ITT population and will be two-sided at a significance level of 0.05. All statistical analyses will be performed using SAS software version 9.4 or higher.This randomised, controlled clinical trial addresses myocardial salvage after AMI in patients with moderate to severe SDB. MSI, the primary endpoint of the study, is the principal mechanism by which patients with AMI benefit from reperfusion therapies . AvailabIschaemia-affected myocardium, although reperfused, is at risk of necrosis when detrimental influences preventing salvage are present, such as hypoxia or myocardial wall stress . In partMyocardial salvage predicts mortality and major adverse cardiovascular event (MACE) outcomes in acute reperfused STEMI, independent of other known risk factors . In one In this regard, ASV treatment of SDB may alleviate the deleterious effects of SDB after AMI and increase myocardial salvage. This is likely to occur due to the documented beneficial effects of ASV on heart rate, heart rhythm, blood pressure and systolic left ventricular transmural pressure , 31. TreIt is important to determine whether ASV therapy has beneficial effects on myocardial salvage in patients with AMI and SDB. If this is the case, ASV would be a novel concept for AMI treatment. Additional secondary endpoints have been incorporated into this trial to determine the effects of ASV therapy on myocardial function and heart failure parameters, with the goal of determining whether increasing myocardial salvage might contribute to reducing, or even preventing, the development of heart failure after AMI.In conclusion, TEAM-ASV-I is designed to investigate the hypothesis that ASV treatment can improve myocardial salvage after AMI in patients with SDB in a randomised controlled setting, with the goal of improving our understanding of the management of SDB in patients after AMI and its effects on myocardial healing.Randomized controlled, multicentre trial.Hypothesis is to increase myocardial salvage in patients with acute myocardial infarction and sleep-disordered breathing with adaptive servoventilation.Targeting and treating highly common comorbidity sleep-disordered breathing.Sleep-disordered breathing is known to significantly impair myocardial salvage.Myocardial salvage is quantified by cardiac magnetic resonance imaging.This trial is still recruiting patients, protocol version 6.0, March 21st, 2014. Recruitment began after trial registration on March 21st, 2014 and enrolment is estimated to end December 2020.Additional file 1: SPIRIT 2013 Checklist: Recommended items to address in a clinical trial protocol and related documents*


Systolic anterior motion (SAM) of the mitral valve is a well-known phenomenon associated with left ventricular outflow tract obstruction and hemodynamic compromise. This finding may occur in patients with or without hypertrophic cardiomyopathy. In this report, a patient with no prior medical history presented to the hospital with left-sided chest pain and high-risk echocardiogram (ECG) findings. Left heart catheterization with coronary angiography was negative for coronary artery disease. His initial examination was significant for a systolic murmur due to the underlying SAM, as demonstrated by transthoracic echocardiogram. During his hospitalization, he developed acute heart failure syndrome as a result of dynamic outflow tract obstruction. He was treated with fluid resuscitation with a resolution of his hemodynamic compromise. On a follow-up examination, there was no murmur and SAM was no longer present on echocardiogram. This case demonstrates the importance of recognizing the clinical manifestations of SAM as well as its role in maintaining an appropriate hemodynamic status. Systolic anterior motion (SAM) of the mitral valve leaflet has been well-described among patients with hypertrophic cardiomyopathy (HCM); however, this phenomenon also occurs in a population of patients without HCM. According to a Japanese study, investigating the incidence of SAM using resting echocardiography, the prevalence of SAM among patients without HCM was 0.3% . In the We present a case of a 34-year-old male with no past medical history who presented to the emergency department (ED) with several hours of left-sided chest pain and headaches. The symptoms were preceded by one week of viral prodrome with rhinorrhea, sore throat, mild fevers, and poor oral intake. He appeared acutely distressed due to chest pain, with a blood pressure of 73/43 mmHg, heart rate 116 bpm, respiratory rate 20/min, oxygen saturation 100% on two liters of supplemental oxygen via the nasal cannula. The cardiac examination was significant for a Grade III/VI pansystolic murmur, best heard at the apex with radiation to the axilla. The ECG revealed high-risk findings with ST elevation in aVR and reciprocal depressions in the remaining leads. Initial labs showed abnormalities of bicarbonate, creatinine, and lactic acid.Due to this constellation of high-risk ECG, hemodynamic instability, and chest pain refractory to medical therapy, the patient was taken for emergent cardiac catheterization. A coronary angiogram and left ventriculography showed only minor luminal irregularities, hyperdynamic systolic function, 2+ mitral regurgitation, and a left ventricular end-diastolic pressure of 22 mmHg. On right heart catheterization, the right atrial pressure was 13 mmHg, the right ventricular pressure was 50/15 mmHg, the pulmonary artery pressure was 50/22 mean 34) mmHg, and the pulmonary capillary wedge pressure was 29 (v wave 51) mmHg. A transthoracic echocardiogram showed moderate mitral regurgitation (MR) with thickened leaflets and an echodensity in the submitral apparatus suspicious for torn chordae tendineae versus ruptured papillary muscle . An additional follow-up examination should include exercise evaluation and auscultation maneuvers  to evaluate for clinical evidence of an LVOT obstruction.It has been previously reported that the finding of chordal SAM during peak exercise and a small LV end-systolic diameter were significant predictors of LVOT obstruction -5. OtherMaron et al. reported that the prevalence of SAM without asymmetrical septal hypertrophy or the transposition of the great vessels was 0.4% among 721 patients with a wide variety of cardiac diseases other than HCM . PearsonThis case demonstrates the importance of recognizing the clinical manifestations of SAM and its role in maintaining an appropriate hemodynamic status. A hyperdynamic ventricle with reduced diastolic filling time and reduced preload predisposes to SAM. Prompt diagnosis is crucial to institute appropriate fluid resuscitative measures and to avoid vasopressors that would worsen LVOT gradients and lead to hemodynamic deterioration. Echocardiography and cardiac MRI are great modalities to diagnose this phenomenon and to follow up hemodynamics. Since there is no HCM, the risk of sudden cardiac death is not the same as in HCM patients and an implantable cardiac defibrillator is not indicated. However, appropriate instructions on maintaining good hydration and instituting negative chronotropic agents are necessary.


The incidence of eLVH increased progressively from the lowest to the highest baseline PC tertile (p < 0.001 for the trend) and the subjects in the former group showed a 76% greater risk of developing eLVH compared to their counterparts. After further adjustment for the potential mediators, PCs carried eLVH odds ) of 1.256 (0.998–1.514), per standard deviation increase. High plasma protein carbonyls levels are a significant independent predictor of eccentric LVH in chronic hemodialysis patients. High prevalence of left ventricular hypertrophy (LVH) and elevated oxidative stress are associated with poor outcomes in chronic hemodialysis patients. Abnormal left ventriculаr geomеtry and different geometric patterns play an important role as well. Our study analyzed the role of oxidative stress on myocardial remodeling in these patients. Plasma malondialdehyde (MDA), protein carbonyl (PC) content, and total antioxidative capacity (TAC) were investigated in 104 hemodialysis patients together with transthoracic echocardiography. Compared to patients with normal ventricular geometry, patients with LVH had increased MDA and PC plasma concentration. Multivariate analysis demonstrated that protein carbonyls, as biomarkers of oxidative protein modification, were an independent predictor of eccentric hypertrophy (eLVH), including higher LV end-diastolic diameter and LV end-diastolic volume, (β = 0.32 and β = 0.28,  Left ventricular hypertrophy (LVH) is a common structural change in chronic kidney disease patients with an estimated prevalence between 40% аnd 75%, dependent upon the chronic kidney disease (CKD) stage ,2 and reOxidative stress, an imbalance between increased production and reduced clearance of oxidants, has been associated with a number of chronic kidney disease and end-stage renal disease complications ,14,15. HAccumulation of ROS promotes vascular oxidative stress and progressive coronary atherosclerosis in hemodialysis (HD) patients . MoreoveMany of the previous studies concerning systemic oxidative stress in HD patients are based on the measurement of plasma malondialdehyde (MDA) levels, which is the biomarker of lipid peroxidation ,23,24. SFinally, various antioxidant defense systems, both non-enzymatic and enzymatic are expected to limit the damage caused by ROS production. However, these intrinsic antioxidant capacities may become overwhelmed due to persistently high levels of ROS. Unfortunately, the vast majority of published studies did not investigate the possible role of the antioxidative defense system in cardiac hypertrophy.Considering the high prevalence of LVH among chrоnic HD pаtiеnts, paralleled by elevated oxidative stress linked to poor outcomes, our aim was to evaluate different left ventricular (LV) geometric patterns in HD pаtiеnts аnd tо investigate thе rоlе оf оxidаtivе strеss аs а pоssiblе risk fаctоr for myоcаrdiаl rеmоdеling in these pаtiеnts.Inclusion criteria were clinically stable patients aged 18 years or older on chronic maintenance HD for more than 12 months who were able to give their written informed consent. Exclusion criteria were any concomitant myocardial pathology that may confound hypertrophy , history of myocardial infarction and congestive heart failure in addition to a multisystemic disease, active infection, hepatitis of any form, and a poor acoustic window with poor image quality for optimal visualization and assessment of cardiac structures and function. We initially evaluated 145 patients, but after considering the exclusion criteria, only 104 patients were included in the final analysis. The study was carried out in accordance with the Declaration of Helsinki and approved by the local Ethics Committee.2. Duration of dialysis (4–4.5 h) and blood and dialysate flow (500 mL/min) was prescribed to a Kt/V >1.3. Blood samples were collected from all patients from the arteriovenous fistula before the start of hemodialysis on the mid-dialysis day. Patients data , and treatment-related characteristics  were collected. Interdialytic weight gain (IDWG) was calculated as the mean net ultrafiltration (UF) of three consecutive dialysis sessions. The mean of three consecutive post-dialysis weights was used to calculate “dry” weight.Patients were receiving routine HD treatment using synthetic high-flux filters >1.6 m2 for women and 115 g/m2 for men) [Echocardiographic measurements were conducted based on the criteria suggested by the American Society of Cardiovascular Imaging and the European Echocardiography Association . Transthfor men) . The sumfor men) . PatternLV ejection fraction (LVEF) was computed by [LV end-diastolic volume (LVEDV) − LV end-systolic volume (LVESV)]/LV end-diastolic volume (LVEDV) × 100%.To clarify the role of oxidative stress on cardiac hypertrophy in HD patients, we investigated the two markers of oxidative damage concurrently with antioxidative defense system and compared them with echocardiographic indices of ventricular remodeling.Plasma MDA was determined as a biomarker of oxidative stress-induced lipid peroxidation, and protein carbonyls (PCs) as a marker of oxidative modification of proteins. The antioxidative defense system was estimated by total antioxidative capacity (TAC). The MDA concentration was determined according to Andreeva et al.  by the tn = 12) based on medium standardized effect sizes (0.5) for a main trial designed [2 test for categorical data. When results suggested differences, pairwise differences were assessed by Bonferroni’s post hoc test. Correlation analyses were performed using a Pearson correlation test.Since there was no other similar study regarding the effects of protein carbonyls on myocardial remodeling pattern, which could provide data to calculate sample size, we had to estimate the minimal sample size per group  of LV geometric patterns. The area under the curve (AUC) was calculated by the receiver operating characteristic (ROC) analysis to estimate the diagnostic ability of MDA and PCs to identify abnormal LV geometry. All statistical analysis was performed using the statistical package for social sciences (SPSS) software version 20.0 .A multivariable logistic regression model was applied to examine the independent relationship between demographic and clinical data and the type of LVH. Variables were selected for the multivariable model if they were related to the type of LVH in the univariable regression model, using a cut-off value of One hundred and four patients  were included in the final analysis.Left ventricular hypertrophy was present in 78/104 (75%) patients. The most common type of LV geometry was eccentric LVH (eLVH) (32.14%), followed by concentric LVH (cLVH) (31.7%), and concentric remodeling (CR) (13.5%). Normal LV geometry (NG) was found in only twelve patients (11.5%). Counting only patients with LVH, 57% had eLVH, and 43% had cLVH. Clinical and laboratory characteristics of patients with four different LV geometric patterns are presented in Differences between the patients’ groups were found for systolic (sBP) and diastolic (dBP) blood pressure, hemoglobin, IDWG, and LDL cholesterol. Age, gender, body mass index (BMI), HD vintage, serum albumin level, C-reactive protein (CRP), Kt/V were similar between the groups. p < 0.001). Additionally, we noted a statistically significant difference between MDA levels in cLVH, and eLVH patients (p < 0.05).Patients with left ventricular hypertrophy had elevated oxidative stress measured by MDA, PCs, and TAC, regardless of LVH type. As shown in p < 0.001, respectively). A significant difference in PC concentration between cLVH and eLVH (p = 0.005) was also observed.Similarly, as shown in r = 0.234, r = 0.017).As eccentric hypertrophy is largely due to volume overload, we further examined the correlation between the protein carbonyl level and IDWG and found a significant positive correlation (p < 0.001).Additionally, TAC was significantly related to abnormal left ventricular geometry c. In allp < 0.001), as shown in p < 0.05).When indices of cardiac remodeling were correlated with the markers of lipid peroxidation, no relations were found between MDA levels and the indices of concentric  nor eccentric hypertrophy (LVEDD and LVEDV). However, protein carbonyls showed a significant positive correlation to LVMI, LVEDD, and LVEDV , LVEDD , LVEDV , in addition to LVWT . TAC did not correlate to RWT.Finally, TAC showed a significant, negative correlation with LVMI (p < 0.001) while MDA correlation with these parameters was modest (p < 0.05). After multivariable adjustments for covariates, serum protein carbonyls remained statistically significant as a prognostic factor for eccentric LVH type, including greater LVEDD and LVEDV  (p < 0.05 in both cases).In unadjusted linear regression analyses, PC significantly correlates with LVEDD and LVEDV (or both) . TAC negp < 0.001 for the trend). The predictive role of PCs was anything but marginal, as 2.35 mmol/g of protein of PC increase was associated with a 45% increased risk of eLVH. This negative trend was even more clear when eLVH incidence in the highest PC tertile was compared to that in the lowest tertile, as subjects in the former group exhibited a 76% greater risk of developing eLVH compared to their counterparts. After further adjustment for the potential mediators (Model 2), PCs carried eccentric LVH odds (95% CI) of 1.256 (0.998–1.514), per standard deviation increase. Tertile analysis of the PCs and eccentric LVH showed excess risk with the highest tertile .As shown in p < 0.001)  0.77–0.92; < 0.001) . A cutofWe found that end stage renal disease (ESRD) was associated with an alarmingly high prevalence of cardiac remodeling and LVH. In our study, 88.6% of the patients had an abnormal left ventricular chamber, and 75% of them had LVH. These data correlate with the data publicized by several authors ,34,35. MEmerging data suggest that chronic hemodialysis patients experience heightened oxidative and “carbonyl” stress, which have been proposed as the critical proof linking uremia to cardiovascular complications ,43,44,45As the intensification of oxidative stress poses a risk of myocardial mass gain, echocardiographic indices of cardiac remodeling were correlated with biomarkers of oxidative stress.We showed that oxidative damage of proteins has a significant role in the pathogenesis of eccentric left ventricular hypertrophy. As all four groups of patients had comparable CRP, iron, albumin, and uric acid and all were on bicarbonate dialysis, observed differences between them in terms of oxidative stress and protein carbonyl content could not be linked to varying degrees of inflammation. Exposure of proteins to ROS leads to alteration of amino acid residues, protein damage, and an increase in protein carbonyl groups. Massive carbonyl stress affects circulating, cellular, and tissue proteins , resultiMost of our patients have eccentric hypertrophy, which may indicate poor volume control. As expected, interdialytic weight gain, one of the putative determinants of fluid balance, showed a positive relationship with eLVH. However, the probability of eccentric LVH only modestly increased in the presence of high interdialytic weight gain. After taking into account a number of confounders, protein carbonyls emerged as the most powerful predictor of eccentric LVH.As previously stated, the presence of protein carbonyl content in patients with eLVH is undoubtedly the consequence of oxidative modifications of proteins. However, based on literature data, it is difficult to conclude which oxidative pathway is responsible for triggering eccentric geometric remodeling of the left ventricle. In many cases, oxidatively modified proteins and advanced glycation end products (AGE) share structural homology; thus, oxidatively modified proteins may serve as candidate ligands for AGE receptors (RAGE) .Conditions with elevated carbonyl stress increase the concentration of RAGE ligand. RAGE signaling activates pathways related to cardiac remodeling ,53 by acFinally, the failure to boost the endogenous antioxidant system additionally generated oxidative stress in our study group. Endogenous antioxidants serve as “sacrificial” substances in plasma and extravascular spaces by blocking chain reactions of free radical production. Our study demonstrated that antioxidant defense systems, measured by TAC, were severely affected in patients with abnormal LV geometry probably due to the fact that these systems were overburdened under the state of persistently high levels of ROS in HD patients.Protein carbonyls have been studied in pediatric patients  and for Our study has certain limitations. First, this is a single-center study with a relatively small sample size; second, we did not compare MDA and PC levels to a non-dialysis population with cLVH and eLVH. We also lack data on diastolic function as we did not perform mitral inflow E- and A-wave velocities. Finally, our findings should be interpreted in light of the cross-sectional design, which limits our ability to assume causation.Data on the prognostic potential of biomarkers of oxidative stress on cardiac remodeling are still lacking. The results obtained in this investigation confirmed that oxidative stress parameters might be related to the prognosis of the morphological alterations of LV geometry. High plasma protein carbonyls were associated with increased risk of eccentric LVH in a dose–response fashion. The recognition of the pathophysiological mechanisms which are associated with the cardiac hypertrophy and remodeling process is fundamental for the development of new treatment strategies, primarily because the mortality rates related to cardiac remodeling prevail.


Pulmonary pulse wave velocity (PWV) allows the non-invasive measurement of pulmonary arterial stiffening, but has not previously been assessed in COPD. The aim of the current study was to assess PWV in COPD and its association with right ventricular (RV) remodelling.Fifty-eight participants with COPD underwent pulmonary function tests, 6-min walk test and cardiac MRI, while 21 healthy controls (HCs) underwent cardiac MRI. Thirty-two COPD patients underwent a follow-up MRI to assess for longitudinal changes in RV metrics. Cardiac MRI was used to quantify RV mass, volumes and PWV. Differences in continuous variables between the COPD and HC groups was tested using an independent t-test, and associations between PWV and right ventricular parameters was examined using Pearson’s correlation coefficient.p=0.021), pulmonary acceleration time , higher PWV , lower RV end diastolic volume  and RV stroke volume  with no difference in mass (p=0.53). PWV was not associated with right ventricular parameters.Those with COPD had reduced pulsatility (COPD (mean±SD):24.88±8.84% vs. HC:30.55±11.28%, While pulmonary vascular remodelling is present in COPD, cardiac remodelling favours reduced filling rather than increased afterload. Treatment of obstructive lung disease may have greater effect on cardiac function than treatment of pulmonary vascular disease in most COPD patients• Pulmonary pulse wave velocity (PWV) is elevated in COPD.• Pulmonary PWV is not associated with right ventricular remodelling.• Right ventricular remodelling is more in keeping with that of reduced filling.The online version of this article (10.1007/s00330-018-5346-x) contains supplementary material, which is available to authorized users. COPD is the second most common cause of pulmonary hypertension after left-sided heart disease, with the prevalence of this increasing with increasing severity of COPD . In compThe role of pulmonary arterial stiffness in COPD was highlighted in a recent study where an increase in pulmonary arterial stiffness was observed during exercise with a greater contribution from this to changes in the mean pulmonary arterial pressures (mPAP) than the peripheral vascular resistance (PVR) . PulmonaTo date the examination of pulmonary vascular stiffening has been limited due to the need for right heart catheterisation. However, advances in MRI technology have allowed the measurement of pulmonary arterial pulse wave velocity – a direct measure of pulmonary arterial stiffness, which does not require the knowledge of the underlying pulmonary pressures to calculate . PulmonaThus, the aim of the current study was to examine pulmonary arterial PWV in COPD and establish its association with right ventricular remodelling with the hypothesis that: (1) PWV would be elevated early in the disease process of COPD and (2) that elevated PWV would be associated with right ventricular hypertrophic remodelling.Between July 2014 and May 2016 participants were recruited from a database of community spirometry readings, and directly from general practitioner surgeries, clinics and previous research participants. Inclusion criteria for the study were a diagnosis of COPD, based on the current Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines of post-bronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) <0.7 with a history of smoking; and aged 40–85 years. Exclusion criteria were: History of cardiac condition, including but not limited to ischaemic heart disease, valvular disease , arrhythmia, cardiomyopathy, congestive cardiac failure or congenital cardiac disease; previous cardiac or thoracic operation; other co-existent lung condition; connective tissue disease or systemic vasculitis; severe renal impairment (estimated glomerular filtration rate (eGFR) < 30 ml/min) or contraindication for MRI. All recruited participants underwent a screening echocardiogram to exclude significant silent left ventricular systolic dysfunction (ejection fraction < 45 %).A healthy control (HC) group was recruited to be approximately age and sex matched, with no prior history of cardiac or pulmonary pathology. All participants gave written informed written consent for the study, which was conducted in accordance with the Declaration of Helsinki and was approved by the East of Scotland Research Ethics Committee 1.All COPD participants underwent spirometry, DLCO, body plethysmography, a 6-min walk test and a cardiac MRI on the same day. A subset returned at 1 year after their baseline visit for repeat cardiac MRI (CMR). All healthy controls (HCs) underwent a baseline cardiac MRI. Plethysmography and Diffusing Capacity of the Lungs for Carbon Monoxide (DLCO) were performed using a VMax Encore V22 bodybox . These were performed at rest, prior to the 6-min walk test with a minimum of 24 h free from inhaler therapy by dedicated pulmonary function laboratory technicians following ERS/ATS guidelines . The 6-mOne hundred and four COPD participants were screened, with 37 excluded due to co-existent coronary artery disease, atrial fibrillation, prior thoracotomy, co-existent lung condition, left ventricular systolic dysfunction on echo or no history of smoking. This left 67 in the cohort. Of these, 58 were included in the final analysis . All participants recruited and scanned for the main study before August 2015 went on to have a 1-year follow-up scan. Of the 49 who were scanned prior to this date, 35 underwent their follow-up examination. Sixteen were lost due to: pacemaker insertion (n=1), lung cancer diagnosed on initial CMR and receiving treatment for this (n=2), interval diagnosis of bladder cancer (n=2), unwilling to undergone repeat CMR (n=1), recurrent chest infections (as needed to be free from exacerbations for 2 months) (n=2), withdrawal from the study (n=2), and unable to contact (n=6). Of the 35 scanned, onr had to be abandoned due to claustrophobia despite having successfully completed their CMR the preceding year, and two had images of insufficient quality to analyse, leaving 32 in the final follow-up analysis.2, FOV phase 84.4 %, matrix 256 × 256, parallel acceleration factor 2. To plan the main pulmonary artery phase contrast sequence, a bSSFP sequence of the right ventricular outflow tract was performed following which an orthogonal plane was acquired to optimally visualise the main pulmonary artery and pulmonary valve. A breath-hold bSSFP sequence was then performed through the MPA slice and was positioned mid-way between the valve and the bifurcation of the pulmonary artery in order to avoid both structures throughout the cardiac cycle. A free-breathing phase-contrast sequence  320×320 mm2, matrix 512×512) was then performed in the same position as previously described [Images were acquired with a 3T MR scanner . A 32-element cardiac phase-array was used for signal reception. For ventricular quantification a balanced steady-state free precession (bSSFP) stack was performed in breath-hold from the atrioventricular ring to the apex using the following acquisition parameters: Slice thickness 6 mm, interslice gap 4 mm, TR/TE 47.6/1.49 ms, no. averages 1, phases 25, bandwidth/pixel 446 Hz, flip angle 53°, field of view (FOV) 360 × 360 mmescribed .Image analysis was performed using CVI 42 .1.7. Twenty scans were analysed twice for reproducibility, with excellent reproducibility for all measures (intraclass correlation (ICC) > 0.8 for all; see Supplementary Material for full ICC .Pulmonary stiffness was measured using PWV, pulmonary acceleration time (PAT) and pulsatility see Fig. . For PWVThe reproducibility of this technique has been described in detail previously , 20. Pulp=0.05. Further work by Bradlow et al. has shown a group size of 17 will allow detection of a 10-ml change in RV end-diastolic volume, which correlates with changes of 9–15 ml seen in the placebo arm of drug intervention studies [The study was powered to examine the longitudinal effects of PWV on right ventricular remodelling. Due to a lack of prior work on the longitudinal follow-up of ventricular remodelling in COPD, the primary study outcome – change in right ventricular mass – was powered according to the placebo arms of randomised control trials in pulmonary hypertension as this was the only data available. These describe an increase in mass of 5–8 g  , 23. Bas studies –24.p < 0.05.Descriptive statistics were used for the analysis of the demographic and clinical features of the cohorts with data expressed as mean ± SD. Normality and equality of variances of the variables was tested. An independent sample t-test was used to compare the differences in continuous variables between the HC and COPD cohort. To assess the longitudinal impact of PWV on RV remodelling in COPD, this cohort was divided into three according to the tertile of their baseline PWV, and an independent sample t-test was used to compare the difference in change in the RV mass and volumes between those in the top and bottom tertiles of PWV. Chi-square and Fisher’s exact tests were used as appropriate to compare differences in ordinal and nominal data between the groups. Pearson’s correlation coefficients were used to assess the correlation between PWV and demographic, spirometric and MRI factors. Analysis of covariance was performed to further analyse differences in RV metrics and PWV between the HC and COPD cohorts correcting for differences in baseline demographics. Paired-sample t-tests were used to examine differences in metrics between baseline and follow-up. Reproducibility of measures was examined using a two-way absolute agreement fixed effect ICC and Bland-Altman plots. All data were analysed using SPSS statistical package . Significance was assumed when p<0.001), had a higher BMI , and a higher resting heart rate . Of those with COPD, the majority had moderate COPD, with n=12 with GOLD I, n=32 with GOLD II, n=13 with GOLD III and n=1 with GOLD IV COPD. Using the modified British Medical Research Council (mMRC) breathlessness score [Fifty-eight COPD patients  and 21 HCs  completed the study protocol. Despite approximate age and sex matching, those with COPD were significantly older , reduced pulsatility , reduced PAT  and higher PWV . Given that the COPD cohort were older with a higher rate of smoking and a higher BMI, an ANCOVA was performed with PWV and these variables. A small-to-moderate group effect size was seen between COPD and HCs for PWV, although this did not quite reach significance  , stroke volume  (see Table p=0.035) and RVSV   and diastolic blood pressure , and total lung capacity , with a trend towards an association with residual volume , but did not demonstrate any significant association with any right ventricular parameters . Both RVEDV and LVEDV demonstrated significant correlations with heart rate  and DLCO  and either a trend or a significant correlation with KCO  and BMI .As the pulmonary stiffness did not appear to affect cardiac remodelling and the cardiac remodelling appeared to be that of a reduced preload (with reduced ventricular volumes) rather than an increased afterload (which would be associated with an increase in right ventricular mass) the determinants of the cardiac volumes were examined as detailed in Table At follow-up there was no significant change in right ventricular mass or volumes


Tricuspid annular systolic excursion (TAPSE) or velocities (s′) and right ventricular (RV) end‐systolic dimensions are predictors of outcome in patients with pulmonary hypertension (PH). We explored the value of combining peak s′ and RV end‐systolic area index (RVESAi) as a surrogate of RV‐pulmonary artery (RV–PA) coupling in a large animal of precapillary PH as well as clinically.n = 141) and acutely decompensated pulmonary arterial hypertension (n = 48).The first experimental group included four control and four piglets with thromboembolic disease. RV–PA coupling was assessed by ventricular to arterial elastance ratio (Ees/Ea) at baseline, after esmolol and dobutamine administration. Echocardiographic metrics included s′, TAPSE, fractional area change (RVFAC), and RVESAi. The findings were validated in six piglets with severe PH. Clinical cohorts were stable outpatients  and RVESAi , while RVFAC  and TAPSE showed weaker association . The ratio s′/RVESAi showed nominally but not significantly (higher) association with Ees/Ea . The association between changes in s′/RVESAi and Ees/Ea was strong . In more severe PH, Ees/Ea and changes in Ees/Ea correlated significantly with s′/RVESAi and changes in s′/RVESAi . In the two clinical cohorts, the s′/RVESAi did not emerge as a stronger predictor of outcome than RVESAi.In the first experimental group, the best linear correlates of Ees/Ea were s′ . We concluded that peak velocity of the tricuspid annulus (s′), end‐systolic area, as well as there ratio, may represent interesting surrogate of right ventricle ‐ pulmonary artery coupling. It is considered as a major determinant of functional capacity and survival in patients with precapillary pulmonary hypertension (PH)  to end‐systolic dimension would constitute a marker of ventriculo–arterial coupling. Compared with the SV/ESV ratio, integrating annular velocities and end‐systolic dimension into a single marker would offer the advantage to combine two well‐established echocardiographic prognostic factors in PH  and invasive ventricular contractility or ventriculo–arterial coupling in the piglet PH model, at baseline and after modulation of loading and contractility. The second objective was to validate s′/RVESAi in another piglet model of PH with severe pressure‐overloaded right ventricle. The third objective was to assess the prognostic value of s′/RVESAi for prediction of long‐term outcomes in two cohorts of patients with PAH: a first cohort of stable outpatients and a second cohort of acutely decompensated symptomatic patients.22.1Marie Lannelongue Hospital institutional animal care committee approved all procedures that were performed according to institutional guidelines complying with national and international regulations.sus scrofa) of 6‐week‐old at time of study enrollment divided into two groups: a first group of four healthy pigs (controls) and a second group of four pigs in whom mild PH was induced by performing an extra‐pericardial left pulmonary artery ligation followed by right lower lobe embolizations with embucrylate  once a week for 3 weeks, as previously described and illustrated in Figure −1 min−1, after esmolol infusion cessation (“second stable baseline” before dobutamine infusion), during 2.5 μg kg−1 min−1 of dobutamine infusion, and then during 5 μg kg−1 min−1 of dobutamine infusion. We also evaluated animals at baseline and after volume loading of 500 ml of saline in order to explore changes with volume loading. A period of 15 min of hemodynamic stabilization was observed during each condition prior to data acquisition.All the experimental procedures and data acquisitions were performed under general anesthesia as previously described  was positioned into the right ventricle through a jugular vein under fluoroscopic control for PV loops acquisitions. Pressures and ECG signals were amplified and transmitted to a Powerlab 16/35 (AD instrument Pty Ltd) and continuously recorded at a rate of 1,000 Hz using LabChart 7 pro . The conductance catheter was calibrated for pressure, volume, and blood electric resistivity (Rho cuvette) with the MPVS ultra® system according to the manufacturer instructions. Parallel volume conductance was determined by infusion of 10 ml of 10% saline serum repeated thrice. The alpha calibration of stroke volume was performed at each dataset acquisition using a thermodilution method . The balloon for inferior vena cava occlusion was positioned at the level of the diaphragm under fluoroscopic control through a transfemoral approach. Inferior vena cava occlusions were repeated at least three times for each dataset acquisition. All acquisitions were performed during stable end‐expiration periods. Stroke volume was determined as the ratio of cardiac output over heart rate acquired by thermodilution methods, with three boluses per measurement. Total pulmonary resistance was calculated as the ratio of MPAP over cardiac output. Cardiac output and total pulmonary resistance were indexed to the body surface area (BSA) using the following formula 0.0734*weight(kg)(2/3)  was determined as the slope of the linear regression of the end‐systolic pressure–volume relationship during inferior vena cava occlusion; the end‐systolic pressure–volume point corresponded to the ECG T wave. The pulmonary artery elastance (Ea) was the ratio of RV end‐systolic pressure over stroke volume; the RV–PA coupling was the Ees/Ea ratio. The end‐systolic pressure–volume relationship linear regressions was performed by the least square method using manually validated pressure and volume values from at least five cardiac cycles during inferior vena cava occlusion. Each Ees value was derived from the mean of two values from the analysis of two different inferior vena cava occlusions. For each regression, if the 2.3Resting echocardiograms were acquired using a Vivid 9 console and a 5S probe , including RV focused apical 5‐chamber views, parasternal long‐ and short‐axis views. In pigs, the 5‐chamber view was used instead of the human 4‐chamber view as previously published  and patients admitted for acutely decompensated PAH (cohort 2). Stanford University Institutional Review Board approved the study, which was conducted in agreement with the Helsinki‐II declaration. All patients gave written informed consent.The first cohort was selected from the previously published prospective Vera Moulton Wall Center Pulmonary Hypertension Registry at Stanford of patients with incident or prevalent idiopathic, familial, drug and toxins, or connective tissue disease‐related PAH   if parametric (as assessed using the Kolmogorov–Smirnov test). Qualitative variables are expressed as number and percentage, and compared using Chi‐square test. Linear correlations between two quantitative variables are expressed using Pearson correlation coefficients (R2), slopes, Y intercepts absolute values and 95% confidence intervals. RV metrics were remeasured blindly by a second observer (DB) in the derivation piglet cohort to determine the inter‐observer variability (assessed using Bland–Altman test). Cox proportional hazard models were used to determine correlates of outcome in the clinical cohorts; hazard ratios were normalized for one SD. Results were considered significant when two‐sided p‐values were <.05. Statistical analysis was performed using SPSS® statistical software  or GraphPad Prism 6 .Quantitative variables are expressed as median and interquartile range and compared using Mann–Whitney test if nonparametric, or mean and standard deviation (33.1p < .05). In contrast, s′ wave and TAPSE did not significantly change with esmolol. With a low dose of dobutamine (2.5 μg kg−1 min−1), cardiac output, heart rate, Ees/Ea and the three indices of RV contractility  significantly improved . Among echocardiographic indices, RVESA decreased in size while RVFAC and s′ increased . With higher dose of dobutamine (5 μg kg−1 min−1), IVA and TAPSE also significantly increased . The noninvasive ratio s′/RVESAi was the only one that significantly decreased with esmolol and significantly increased with both dobutamine doses .The baseline characteristics of the eight pigs are presented in Table 3.2R2 = .11, p = .04) and did not correlate with Eesi . The significant correlations between absolute value changes of s′/RVESAi, IVA and Ees/Ea are also presented in Figure The Figure 3.3https://figshare.com/articles/Figure_S2/9946883].Volume loading of 500 ml of saline did not induce significant changes in Ees/Ea or s′/RVESAi in the derivation cohort, as shown in Figure 3.4https://figshare.com/articles/Figure_S3/9946892]) with a correlation of R2 = .94 (p < .01). The mean difference  of s′/RVESAi between the two readers was −0.08 , of s′ was −0.02  and of RVESAi was −0.23 .There was a good reproducibility of s′/RVESAi measurement between the two readers . The median age was similar in the two groups , with a majority (80%) of female sex. The “acute” cohort (n = 48) was slightly more severe than the “stable” cohort (n = 141) as illustrated by a trend toward higher pulmonary vascular resistance , lower cardiac index  and higher NT‐proBNP levels. The mean (±standard error) survival rates were 92.0 ± 2.3% at 1 year and 79.3 ± 3.6% at 3 years for the “stable” cohort and 93.6 ± 3.6% at 1 year and 78.7 ± 6.0% at 3 years for the “acute” cohort. Using univariable analysis (Table Baseline characteristics of the two clinical cohorts are presented in the Table 4The original contribution of our study is to quantify the association between commonly used noninvasive indices of RV function and ventricular arterial coupling in a large animal model of PH. From our experimental data, we confirm that commonly used indices of ventricular function relate more to ventriculo–arterial coupling than to ventricular elastance. Despite the small experimental size, the s′/RVESAi had the stronger nominal association with ventriculo–arterial coupling, and was the only metric that decreased significantly with esmolol infusion. In the clinical cohort, the point estimate for prediction of outcome of s′/RVESAi was higher than RV end‐systolic dimension alone, but its incremental value in clinical practice will likely be small. The index may, however, play a role in assessing acute changes of ventriculo–arterial coupling at bed side.Few studies have analyzed noninvasive metrics of RV–PA coupling in large animal models of PH. The study of Vogel et al. validating IVA as a promising index of RV contractility was conducted in healthy pigs (Vogel et al., Because the gold standard for Ees/Ea determination requires invasive PV loop conductance studies, efforts have focused on identifying surrogate end points. These often can be divided into three main categories. First, the single beat method measures ventricular elastance by extrapolating maximal RV pressure during isovolumic contraction and using the end‐systolic pressure–volume point derived from the single pressure volume loop (Brimioulle et al., The main advantage of our study is to critically evaluate simple indices of RV–PA coupling. We first validate our previous observation that measures of systolic function mainly reflect RV–PA coupling and not right ventricular contractility but now across the spectrum of severity of PH (Guihaire et al., The clinical implication of our study is physiological at this stage. As illustrated in our experimental section, the s′/RVESAi is a good metric of RV–PA coupling reflecting acute changes in volume loading and contractility. A potential application could be serial evaluation of RV adaptation to its afterload patients with PH, or, for example, for evaluation of the response to catecholamine infusion in patients in the intensive care unit or experiencing clinical worsening. The s′/RVESAi ratio has the clinical bedside strong advantage of being derived from a single echocardiographic view. Regarding the prognostic value, in our clinical cohorts, while the s′/RVESAi was strongly associated with outcomes, the confidence interval of its hazard ratio overlapped with the RVESAi′s, requiring further clinical validation to determine its potential incremental value.The main limitation of our study is the angle‐dependency of s′ and RVESA measurements. Reproducibility of these metrics can be improved by using the RV‐focused apical view as previously reported (Amsallem et al., 5Our study validates using a large animal model of progressive RV pressure overload that annular indices as well as end‐systolic indices mainly reflect RV–PA coupling. While providing physiological basis for the use ratio of s′/RV end‐systolic dimension ratio, future studies will be needed to validate its incremental value in clinical practice.None of the authors have any conflict of interest relative to the study. Click here for additional data file. Click here for additional data file. Click here for additional data file. Click here for additional data file.