Although right ventricular (RV) dysfunction in pulmonary diseases has beenassociated with increased morbidity, tools for RV dysfunction identificationare not well defined.The aim of this study was to evaluate the magnitude of RV dysfunction bymeans of speckle tracking echocardiography (STE) in patients with chronicobstructive pulmonary disease (COPD) and to investigate whether STE could beused as an index of RV improvement after a pulmonary rehabilitation (PR)program.Forty-six patients with COPD undergoing PR program and 32 age-sex matchedhealthy subjects were enrolled. RV function was evaluated at admission andafter PR program by conventional two-dimensional echocardiography (2DE) andSTE. In addition, exercise tolerance of subjects was evaluated using thesix-minute walk test (6MWT).COPD patients had worse RV function according to STE and 2DE as well. STE wasmore sensitive than conventional 2DE in determining RV improvement after PRprogram - RV global longitudinal strain (LS): 20.4 ± 2.4% vs. 21.9± 2.9% p < 0.001 and RV free wall LS: 18.1 ± 3.4% vs. 22.9± 3.7%, p < 0.001). RV free wall LS was directly related todistance walked at baseline 6MWT  and to the changein the 6MWT distance (6MWTD Δ) .We conclude that STE might be as effective as 2DE for evaluation of globaland regional RV functions. STE may become an important tool for assessmentand follow-up of COPD patients undergoing PR program to determine therelationship between RV function and exercise tolerance. The newechocardiographic method of speckle tracking echocardiography (STE) assessesmyocardial deformation on grayscale (B-mode) images and can be used to evaluate bothglobal and regional myocardial strain without being limited by the Doppler beamangle.4The right ventricle plays an important role in the morbidity and mortality ofpatients with signs and symptoms of cardiopulmonary disease.5 Today, is well known that chronicobstructive pulmonary disease (COPD) patients experience substantial mortality andmorbidity from RV function impairment.7Patients with advanced chronic respiratory disease regularly experience distressingsymptoms despite optimal pharmacological treatment. Pulmonary rehabilitation (PR)complements conventional medical therapy, and has been clearly demonstrated toreduce dyspnea, increase exercise performance, and improve RV functions.9 Therefore, we sought to analyze the use of STE in the assessmentof global and regional RV function and impact of PR program on it.A number of studies have used conventional 2DE to evaluate the RV in patients withcardiopulmonary diseases, but there is relatively limited information concerning theassessment of RV performance by means of speckle tracking-derived strain.Subjects were recruited from Sureyyapasa Chest Medicine and Thoracic SurgeryResearch and Training Hospital, Istanbul, Turkey. Fifty-seven patients withmoderate-to-very severe COPD  were enrolled in the study. Six patients wereexcluded from the analyses due to the poor quality of their echocardiographicrecords. In the remaining patients, the apical segment of the RV free wall andthe apical septum could not be analyzed in 3 and in 2 patients,respectively.All patients had a previous diagnosis of symptomatic COPD. The control groupincluded 32 healthy volunteers. Patients with impairment of LV systolic function(ejection fraction < 55%), significant valvular heart disease,cardiomyopathy, history of coronary artery disease, and malignancy wereexcluded. The investigation complies with the principles outlined in theDeclaration of Helsinki. The study was approved by the local Ethics Committeeand written informed consent was obtained from all participants.Adult patients with COPD with medically optimized symptomatic lung disease,admitted to the outpatient PR program, were referred by respiratory physiciansafter an initial multidisciplinary assessment clinic with a respiratory orrehabilitation physician, cardiology physician, nurse, and physiotherapist.Before starting the PR program, we obtained medical histories and performedphysical examination of all patients. Specific measurements recorded at thebeginning and end of PR program included 6-minute walk test (6MWT), mMRC dyspnea scale, the BODE index - body massindex (BMI), degree of obstruction (FEV1), dyspnea , exercisecapacity. The PR program consisted of 2 sessions each day for 6 days per weekfor a total of 4 weeks. Each session lasted 30 minutes and includedsymptom-limited exercise training .11 Two 6MWTs andechocardiographic examinations were performed at the beginning of thepre-rehabilitation and post-rehabilitation assessments at the end of PR programdue to possible learning effect. The best 6MWT was recorded and used foranalysis. The 6MWTDΔ (delta) was determined by the difference betweenpre- and post-rehabilitation of 6MWTs. The effect of the 6MWT after the PRprogram was evaluated by BODE index and the mMRC score.All 6MWTs were performed on a flat surface, enclosed, temperature-controlledcorridor using standardized instructions.12 Estimation ofsystolic pulmonary artery pressure (sPAB) was based on tricuspid regurgitationpeak velocity using the simplified Bernoulli equation: 4x(tricuspidregurgitation peak velocity)2+right atrial pressure (RAP). Estimation of RAP was done on the basis of theinferior vena cava diameter and collapse index.2 Tricuspid annular plane systolic excursion(TAPSE) is defined as the total excursion of the tricuspid annulus fromend-diastole to end-systole, and it is measured typically at the lateral annulususing M-mode Isovolumic relaxation time (IVRT), isovolumic contraction time(IVCT), myocardial performance index (MPI) , and ejection time intervals were measured using either pulsed-waveDoppler (PWD) or Doppler tissue imaging (DTI) at the lateral tricuspid annulus.RV and LV ejection fractions from 2D methods were calculated as (end-diastolicvolume - end-systolic volume)/end-diastolic volume.All echocardiographic examinations of patients and healthy controls wereperformed in accordance with the American Society of Echocardiography guidelinesusing an ultrasound system .14 2D echocardiographic grayscaleapical 4-chamber images and a frame rate of 70 to 80 frames/s were obtained,which seems to be the best compromise between appropriate temporal resolutionand acceptable spatial definition of the LV lateral wall and RV free wall. Inpostprocessing analysis, the region of interest was obtained by tracing the RVendocardial borders at the level of the septum and the free wall in a stillframe at end-systole. An automated software program calculated theframe-to-frame displacements of speckle pattern within the region of interestthroughout the cardiac cycle. Longitudinal strain (LS) curves were obtained fromsix RV segments ; the global RV strain curve was based on the average of the six regionalstrain curves, and longitudinal strain curves of the lateral LV wall wereobtained by repeating the same analysis . The variableswere investigated using visual  and analyticalmethods (Kolmogorov-Smirnov/Shapiro-Wilk test) to determine whether or not theyare normally distributed. In sample size calculation, 46 COPD patients and 32healthy subjects in each group would be needed to detect a 2-point difference inDAN scale, with a power of 80% and 1% of significance level. Categoricalvariables are presented as numbers and percentages and continuous data expressedas mean ± standard deviation. Since all variables were normallydistributed, correlation coefficients and their significance were calculatedusing the Pearson test, and comparisons of quantitative data performed by apaired sample t-test. A p-value of less than 0.05 was set as statisticallysignificant.In our study, 46 patients  with moderate to very severe COPD undergoing PR and 32 healthy subjects were enrolled.Baseline characteristics are shown in In post-rehabilitation echocardiography and 6MWT assessments, there were significantimprovements in RV speckle-tracking measurements  and incrRV free wall LS was directly related to distance walked at baseline 6MWT  and to 6MWTDΔ  . There wIn our study, we evaluated RV dysfunction in patients with moderate-to-very severeCOPD in comparison with healthy subjects and also its improvement after PR program.In determination of both global and regional RV function improvement, STE was shownto be as effective as conventional 2DE. Moreover, RV global longitudinal strain wasdirectly related to exercise tolerance determined by means of 6MWT and BODEindex.16 On the otherhand, RV assessment can be challenging. STE overcomes most of the limitationsinherent in conventional 2DE, given that it is independent of cardiac translation,and it is angle- and load-independent, thus allowing accurate quantification ofmyocardial function.17 STE alsodemonstrates whether reduced RV performance is due to a global failure or tolocalized impaired contraction. Moreover, it identifies discrete and localizedlosses in contractility that are insufficient to affect global systolic function buthave potential diagnostic and prognostic implications. The main result of the studyby Focardi et al.18 was that freewall and global RV LS had a stronger correlation with the RV ejection fraction(RVEF) calculated by CMR (cardiac magnetic resonance) than conventionalechocardiographic indices. Between the two, the highest diagnostic accuracy and thestrongest correlation with the RVEF measured by CMR were observed for RV free walllongitudinal strain.18 In ourstudy, RV free wall LS had higher improvement than RV global LS after PR program.Moreover, it had a statistically significant correlation with exercise toleranceindices of the patients, such as 6MWT distance and BODE index. One possibleexplanation for this is that the thin RV free wall contracts against low pulmonaryresistance, thus leading to significantly higher strain improvement after thedecline of pulmonary resistance by means of PR program. On the other hand, theseptum consists of the same fibers as those forming the LV and must handle loadingconditions in the RV, as well as higher LV afterload.16 Nevertheless, thishypothesis must be confirmed by further studies. In addition, we chose to analyzethe septum as part of the RV. It cannot be considered simply a part of the LVbecause its shortening contributes to the ejection phase of the RV, and anyimpairment in its contractility reduces RV performance.19Although the current available prognostic models for COPD do not include RV function,it might serve as a surrogate endpoint for determining mortality and morbidity ratesin a variety of cardiopulmonary diseases.20 showed that RV free wall LS and6MWT distance were increased after the initiation of medical therapy in patientswith pulmonary arterial hypertension (PAH). Motoji et al.21 showed that RV global LS < 19.4% indicates highrisk of adverse cardiovascular events in patients with PAH. In addition, Guendouz etal.22 reported that anabsolute RV global LS value below 21% in patients with congestive heart failureidentifies patients with high risk of adverse cardiac events. However, to the bestof our knowledge, there are no published studies using STE to determine RVdysfunction and its improvement after PR program in patients with COPD.Because of the paucity of data, no reference limits were established in the latestguidelines for RV global LS. Recent studies involving STE have focused on exploringRV function in patients with cardiopulmonary disease. Hardegree et al.8 showedthat TAPSE ≤ 16 mm was an indicator of decreased 6MWT distance at baselineand 6MWT distance change in COPD patients undergoing PR. According to our study, STEwas more sensitive in determining RV dysfunction than 2DE. Tanaka et al.,23 in another 2DE-based study, showedan increase of MPI, and that there was a strong correlation between MPI and the MRCbreathlessness score in COPD patients.23 Our data are in agreement with these 2DE studies of RV functionin COPD patients undergoing PR program.The effect of PR on RV function in patients with COPD has been explored in 2DE-basedstudies. Caminiti et al.24 If we hadfollowed up the study population, we could have investigated the impact of PRprogram on RV function, as well as mortality and morbidity. Finally, we did notcompare our results with those of CMR. However, previous studies of LV speckletracking-derived strain have already validated CMR use. Furthermore, althoughmagnetic resonance imaging is considered the gold standard for determining RVvolume and function, it is currently limited by cost and availability and isdeemed unsuitable after the implantation of a cardiac pacemaker.25Several limitations of our study merit consideration. The main limitation was thesmall size of the study population. Moreover, RV strain was assessed only in the4-chamber view of the six segments of the RV; however, the RV longitudinalfunction measured in the inlet chamber accounts for about 80% of RVfunction.Our study demonstrated that RV dysfunction improved after PR program in patients withCOPD. STE might be as effective as the more established measurements of global RVfunction . RV global and regional strain assessment is asimple and effective tool in the routine clinical assessment of patients with COPDin order to explore the relationship between RV function and exercise tolerance.


Myocardial fibrosis is a key mechanism of left ventricular decompensation in aortic stenosis and can be quantified using cardiovascular magnetic resonance (CMR) measures such as extracellular volume fraction (ECV%). Outcomes following aortic valve intervention may be linked to the presence and extent of myocardial fibrosis.This study sought to determine associations between ECV% and markers of left ventricular decompensation and post-intervention clinical outcomes.Patients with severe aortic stenosis underwent CMR, including ECV% quantification using modified Look-Locker inversion recovery–based T1 mapping and late gadolinium enhancement before aortic valve intervention. A central core laboratory quantified CMR parameters.Four-hundred forty patients  from 10 international centers underwent CMR a median of 15 days (IQR: 4 to 58 days) before aortic valve intervention. ECV% did not vary by scanner manufacturer, magnetic field strength, or T1 mapping sequence . ECV% correlated with markers of left ventricular decompensation including left ventricular mass, left atrial volume, New York Heart Association functional class III/IV, late gadolinium enhancement, and lower left ventricular ejection fraction , the latter 2 associations being independent of all other clinical variables (p = 0.035 and p < 0.001). After a median of 3.8 years (IQR: 2.8 to 4.6 years) of follow-up, 52 patients had died, 14 from adjudicated cardiovascular causes. A progressive increase in all-cause mortality was seen across tertiles of ECV% . Not only was ECV% associated with cardiovascular mortality (p = 0.003), but it was also independently associated with all-cause mortality following adjustment for age, sex, ejection fraction, and late gadolinium enhancement .In patients with severe aortic stenosis scheduled for aortic valve intervention, an increased ECV% is a measure of left ventricular decompensation and a powerful independent predictor of mortality.  Aortic stenosis is a disease of both the valve and myocardium. Progressive myocardial remodeling and hypertrophy occur over time in response to sustained pressure overload, decreasing wall stress, and maintaining cardiac performance. However, if untreated, this hypertrophic response eventually decompensates, and patients transition to symptomatic heart failure and adverse events .Myocardial fibrosis is a key pathological process driving left ventricular (LV) decompensation . Two disSeveral T1 mapping measures have been proposed to date to detect changes in diffuse myocardial fibrosis. Native T1 mapping produces a voxel-based map of the myocardium that estimates absolute myocardial T1 values . ExtraceIn the present study, we investigated CMR T1 mapping in a large international multicenter study of patients with severe aortic stenosis scheduled for aortic valve intervention. In particular, we investigated the association between ECV-based measures and clinical characteristics, markers of LV decompensation and post-intervention clinical outcomes.2), previous valve replacement, and presence of another coexistent myocardial pathology such as cardiac amyloidosis, hypertrophic cardiomyopathy, or myocarditis. The study was conducted according to the Declaration of Helsinki and approved by the relevant local research ethics committees. Written informed consent was obtained from all participants. All patients underwent comprehensive medical history and physical examination. Transthoracic echocardiography was performed according to international clinical guidelines and within accredited tertiary echocardiographic units. Particular focus was placed upon measurement of aortic stenosis severity, which was assessed on the basis of the peak velocity, mean gradient, and aortic valve area  within a core lab according to a standardized analysis protocol  using cvThe presence of noninfarct  and infarct patterns of late gadolinium enhancement were recorded and quantitative analysis performed using the full-width-at-half-maximum technique , with thCore lab T1 mapping analysis was performed using a standardized pre-specified analysis protocol. Epicardial and endocardial contours were manually drawn in the midinferoseptum (segment 9 of the standard 17-segment model ) on scanThe primary outcome measure was all-cause mortality. The secondary outcome measure was cardiovascular mortality, which was defined as death attributable to myocardial ischemia or infarction, heart failure, cardiac arrest (due to arrhythmia or unknown cause), or cerebrovascular accident. Outcome events were adjudicated by review of patient health records (including the U.K. Spine database), and cause of death was adjudicated by 3 observers . Among the centers in the United Kingdom, death certificates were available in all patients. Deaths occurring at international sites outside of the United Kingdom were adjudicated using a combination of medical record review, reports from family members, and death certificates where available.t-test or Mann-Whitney U test as appropriate. We presented all categorical variables as counts and percentages and used the Fisher exact test or chi-square test for comparison. The relationship between 2 continuous variables was assessed using Pearson’s r and Spearman’s rho as appropriate. Comparisons between ECV% and iECV tertiles were performed with 1-way analysis of variance or Kruskal-Wallis test as appropriate.The distribution of all continuous variables was assessed using the Shapiro-Wilk test and presented using mean ± SD or median (interquartile range). Comparisons between groups were performed using the independent 2-sample Student's t-tests and linear regression analysis. Interobserver variability for native T1 and ECV% was determined by calculating the intraclass correlation coefficient on a random sample of 15 scans. Univariable linear regression was also performed to determine associations between clinical and imaging variables with T1 mapping measures. Multivariable linear regression was then performed using variables significantly associated with T1 measures as well as important variables  regardless of strength of univariable association. Univariable Cox-regression analysis was performed to determine which variables were associated with all-cause mortality as the primary outcome measure as well as with cardiovascular mortality. Time to event or final status check was taken from the date of valve intervention. For all-cause mortality, variables with a significant association were included in the multivariable Cox regression model. The hazard ratio (HR) per unit increase in the variable of interest and 95% confidence intervals (CIs) were expressed as HR (95% CI). All statistical analyses were performed using SPSS version 24  and GraphPad Prism version 8.0 . A 2-sided p < 0.05 was considered statistically significant.The influence of imaging center, CMR scanner manufacturer, magnetic field strength, and pulse sequence on T1 mapping values was analyzed using independent 2-sample Student's A total of 440 patients across 10 sites in 5 countries were included in the final analysis   with a lIn keeping with previous work ,26, subsECV% values were consistent across the different centers , with noThe mean ECV% was 27.7 ± 3.6%, with good interobserver variability . To explore associations between ECV% and clinical variables, the total cohort was divided into tertiles  . Across 2. Analysis by iECV tertile  (Median iECV was 22.5 (18.1 to 29.6) ml/m9 ml/m2)  demonstr9 ml/m2) . Associa9 ml/m2) . On multClinical outcome data were collected from 440 patients after a median of 3.8 (IQR: 2.8 to 4.6) years. Final status checks were performed between January and August 2018, and no patient was lost to follow-up. Over this time, 52 deaths were observed (12%), of which 7 occurred within 30 days of valve intervention (1 perioperative death). Robust cause of death data was available in 37 of these events (71%), of which 14 (38%) were classified as a cardiovascular death following adjudication.All-cause mortality progressively increased across the ECV% tertiles, being approximately 3 times higher in the top versus the bottom tertile  . This reInclusion of variables in the multivariable models was limited to prevent overfitting. In the first model, ECV% remained predictive of the primary outcome independent of age and sex (p = 0.003) . In the There was no difference between all-cause mortality rates when the cohort was analyzed by iECV tertile (p = 0.72)  nor was In patients with severe aortic stenosis undergoing aortic valve replacement, diffuse myocardial fibrosis quantified by CMR T1 mapping is an independent predictor of all-cause mortality . These dThe 2 ECV-based measures examined in this study provide complementary information regarding diffuse myocardial fibrosis. ECV% provides a surrogate marker of the percentage of myocardium made up by fibrosis and has been validated extensively against histological fibrosis , 11, 12.NCT03094143).In aortic stenosis, prognostic T1 mapping data have been limited to single-center studies ,30. ThisImportantly, our data confirm the feasibility of conducting international multicenter T1 mapping studies and comparing ECV-based values acquired on different scanners. The calculation of ECV% adjusts myocardial T1 for blood pool T1 measurements made on the same scanner. In principle, this should help correct for between-scanner differences in measuring T1 and enable comparison between ECV% values ,25. HereNative T1 has potential advantages as a marker of diffuse myocardial fibrosis, being based upon a single measurement and avoiding the need for gadolinium-based contrast administration. However, in this pragmatic multicenter setting, native T1 was hampered by considerable variation in values on different scanners. Recent studies have demonstrated that this variability can, in part, be addressed using phantom testing . This waAlthough no effect of T1 mapping pulse sequence on ECV% was demonstrated, this result cannot be extrapolated to saturation recovery-based T1 mapping techniques, which were not examined and may produce a lower ECV% value compared with inversion recovery sequences . FinallyPerspectivesCOMPETENCY IN MEDICAL KNOWLEDGE: Increased ECV% measured by cardiovascular magnetic resonance is an objective marker of left ventricular decompensation in patients with aortic stenosis (AS) that predicts mortality.TRANSLATIONAL OUTLOOK: Future research should explore whether changes in ECV% can be used to guide the timing of intervention for patients with AS.ECV-based T1 mapping measurements are associated with multiple measures of LV decompensation in aortic stenosis. ECV% is a strong independent predictor of death in patients after aortic valve replacement, with further work now required to determine how these measures can be used to optimize the timing of aortic valve intervention.


Pressure and volumetric methods were adopted to analyze the results of RHC and cardiac magnetic resonance imaging examination. The P < .05). The right ventricular volume parameter in the PAH group was significantly different from that in the control group (P < .05). For patients with PAH, the end-systolic elastance/effective arterial elastance (Ees/Ea) calculated by the volumetric method was significantly related to the prognosis of patients . When Ees/Ea <0.67 was calculated by the volumetric method, the adverse prognosis of patients with PAH increased significantly (P < .05).The hemodynamic index and right ventricular–pulmonary artery coupling parameter of patients with PAH were significantly higher than those in the control group (Ees/Ea calculated by the volumetric method may be better an independent factor for the prognosis of patients with PAH.The  Clinical studies also confirmed the optimal coupling relationship ensuring that most of the energy pumped from the ventricle was transmitted to blood vessels. Scholars proposed the concept of coupling efficiency coefficient (ηvv) to further quantify the relationship of ventricular and vascular interaction with optimal coupling. The quantitative evaluation of right heart function was performed by calculating the ratio of ventricular elastance (end-systolic elastance [Ees]) and vascular elastance , that is, ηvv = Ees/Ea. The aim of this study was to measure the efficiency coefficient of right ventricular–pulmonary artery coupling (ηvv) in patients with PAH using different methods based on the data obtained from right cardiac catheterization and cardiac magnetic resonance imaging (MRI) examination. It was also performed to explore the significance of right ventricular–pulmonary coupling predicting the long-term prognosis of patients with PAH by evaluating the right ventricular function of patients and comparing its correlations with hemodynamic parameters and right ventricular volume, thereby providing a basis for finding a simple, practical, and accurate clinical index to reflect the changes in condition and the prognosis of patients.Pulmonary arterial hypertension (PAH) is a complex and comprehensive disease, which may cause multiple-organ dysfunction and have a poor prognosis. Therefore, it is regarded as cancer in the field of pulmonary vascular disease. Among many factors related to the prognosis of patients with PAH, the right ventricular function is one of the undoubtedly important reasons. In recent years, some scholars have proposed the concept of “ventricular–vascular coupling” considering the matching of right ventricular function and its circulation.22.1 issued by the European Society of Cardiology in 2015, right cardiac catheterization was performed in all patients with suspected PAH (aged ≥18 years) at Wuhan Asia Heart Hospital in January 2015. The hemodynamic parameters were recorded, including mean pulmonary artery pressure (mPAP), right ventricular end-systolic pressure (RVESP), right ventricular end-diastolic pressure (RVEDP), pulmonary vascular resistance (PVR), and cardiac output (CO). Under the resting state, if mPAP ≥25 mm Hg and PVR ≥3 Wood units, it could be diagnosed as PAH. Patients with absolute contraindications for cardiac MRI examination and those with severe systemic disease were excluded. Cardiac MRI was performed within 48 hours after right heart catheterization (RHC). Also, right ventricular volume parameters were recorded, including right ventricular end-systolic volume, right ventricular end-diastolic volume, stroke volume (SV), and right ventricular ejection fraction. All the patients underwent normative and regular targeted PAH therapy, including endothelin receptor antagonists and phosphodiesterase inhibitor. The clinical endpoint was defined as all-cause death and clinical deterioration. Clinical deterioration included worsening of the patients’ condition. The patients were admitted to the hospital again, their condition worsened, and interventions such as medication adjustment and lung transplantation were needed.This study was approved by the Institutional Review Board of Wuhan Asia Heart Hospital and was in compliance with the Health Insurance Portability and Accountability Act regulations and the Declaration of Helsinki. The Institutional Review Board waived the need for individual patient consent. According to the guidelines for PAH2.2ηvv) was calculated by the pressure–volume loop method. In general, it was calculated using the transient ventricular pressure–volume curve in a specific cardiac cycle. The right ventricular pressure and volume curves were obtained according to the RHC and post-processing of cardiovascular magnetic resonance images. The GetData Graph Digitizer software was used to calibrate time, pressure, and volume, and to digitize pressure and volume curves. Then the MATLAB software was used to draw the pressure and volume curves in the same cardiac cycle  to the end-systolic point, that is, (Pmax – ESP)/SV  could be estimated as ESP/SV. Therefore, coupling efficiency coefficient (ηvv) was calculated using the ratio of Ees to Ea. According to pressure–volume loop, 2 main methods were used to calculate the right ventricular–pulmonary coupling efficiency coefficient: pressure method and volumetric method. of which, Ees = ESP/ESV ; the differences between groups were analyzed by a Student 33.1A total of 64 patients were included in this study, of which 49  were diagnosed with PAH by RHC. Eleven had congenital heart disease–associated PAH , 17 had idiopathic PAH (had excluded other etiology), 14 had connective tissue disease-associated PAH, 1 had chronic thromboembolic pulmonary hypertension, and 6 had other PAH. Further, 32 had the World Health Organization (WHO) cardiac function grades I–II and 17 had grades III–IV. The 6-minutes walking distance was 400 ± 120 (0–552) miles. Also, 3 with WHO cardiac function grade IV were unable to walk; the 6-minutes walking distance was 0. The drug therapy for PAH included 21 patients taking phosphodiesterase type 5 inhibitors, 18 taking endothelin receptor antagonists, 2 taking prostaglandin, 31 taking warfarin, 17 taking diuretics, and 17 taking digitalis.Fifteen patients  in the control group (non-PAH) were treated with patent foramen ovale occlusion. Eleven had WHO cardiac function grades I–II, 3 had grade III, and no patient had grade IV; the 6-minutes walking distance was 443 ± 93 (170–550) m. No significant difference in age, gender, WHO cardiac function classification, and 6-minutes walking distance was found between the 2 groups (Table P < .05). For right ventricular volume parameters, the RVESV, RVEDV, and SV of patients with PAH were much higher than those of patients with non-PAH patients. Their RVEF was less than that of patients with non-PAH, and the differences were statistically significant (P < .05). For right ventricular–pulmonary artery coupling parameters, no difference was observed between the 2 groups, irrespective of the method used (P > .05). The Ea of patients with PAH was about twice that of patients with non-PAH. The Ees/Ea was less than that of patients with non-PAH, and the differences were statistically significant (P < .05). In addition, Ees/Ea calculated by the pressure method was obviously smaller than that calculated by the volumetric method.The data of hemodynamic parameters, right ventricular volume parameters, and right ventricular–pulmonary artery coupling are shown in Table In the PAH group, the correlations of right ventricular–pulmonary artery coupling with baseline hemodynamic parameters and right ventricular volume parameters are shown Table ηp)vv( and ηv)vv( (P < .05); that is, the greater the PVR, the smaller the Ees/Ea. CO was significantly and positively correlated with ηp)vv( and ηv)vv( (P < .05); that is, the greater the CO, the greater the Ees/Ea. Moreover, ηp)vv; that is, the greater the average pulmonary artery pressure, the smaller the ηp)vv(. ηv)vv and 6-minutes walking distance . It was significantly and negatively correlated with cardiac function classification ; that is, the higher the right ventricular ejection fraction, the farther the 6-minutes walking distance, the lower the cardiac function classification, and the greater the ηv)vvvv( and ηv)vv.The results showed a significant negative correlation of PVR with 3.2χ2 = 4.721, P = .030), indicating statistical significance in the test of overall model. The variable included in the equation was ηv)vv, indicating that Ees/Ea calculated by the volumetric method was an independent index to predict survival time.Hemodynamic parameters, right ventricular volume parameters, and right ventricular–pulmonary artery coupling parameters were incorporated into the univariate Cox regression model. Forward logistic regression (maximum-likelihood estimation) was used for analysis. The log-likelihood ratio test was used (3.3ηp)vv( and ηv)vv, grouping was conducted according to ηp)vv( = 1.86 and ηv)vv  vvvv, indicating that ηvv was a new index and its baseline significance was consistent with that of common clinical indexes, such as mPAP, RVESP, RVEDP, RVEDV, RVESV, RVEF, and RVSV. However, no statistically significant difference in Ees was found, reflecting right ventricular elastance calculated by the 2 methods in patients with PAH and non-PAH, which was consistent with CO and 6-minutes walking distance . It was believed that this phenomenon was related to the cardiac function status of selected patients. Considering the compliance of MRI examination, 94% patients with PAH had WHO cardiac function grade above III. With the gradual increase in pulmonary arterial pressure or PVR, the right ventricle of patients with PAH must be enlarged to adapt to the increased after-loading. The increased right ventricular systolic function led to a progressive disorder. ESP and EDP increased. Before decompensation, CO, 6-min walk distance, and Ees, which were used to evaluate the contractile force of the right ventricle, were basically normal, resulting in no statistical difference in Ees at baseline. Takeuchi et al reported ESV and EDV increased significantly with the further enlargement of the right ventricle. When self-regulation could not maintain appropriate SV, the right ventricular function began to collapse; Ees, CO, and 6-minute walk distance decreased at that time. Further, Ea, as an index of effective PA elastance, increased abnormally at baseline (P < .01), indicating that the initial stage of increased pulmonary arterial pressure in patients with PAH, that is, the changes in PA elastance and contractility, was consistent with mPAP and PVR. However, whether the long-term change rate could reflect prognosis needed further investigation.Two methods are used to calculate the efficiency of right ventricular–pulmonary artery coupling based on the pressure–volume loop: pressure method and volumetric method. The ηp)vv( and ηv)vv( with PVR at baseline (P < .05). However, they significantly and positively correlated with CO (P < .05), which was coincident with Kuehne's report. That is, the greater the PVR, the smaller the CO, and the smaller the Ees/Ea of the right ventricular–pulmonary artery coupling coefficient. Also, ηvv could be used to comprehensively evaluate the myocardial contractility and the resistance of pulmonary vascular bed in patients with PAH. Further analysis showed that only ηp)vv. That is, the greater the average pulmonary arterial pressure, the smaller the ηp)vvvv and 6-minutes walking distance , and it significantly and negatively correlated with cardiac function classification vvvvvvvvvv was a new index used to evaluate the long-term prognosis of patients in clinical practice, the parameters (ηp)vv( and ηv)vv measured by the 2 methods also significantly and positively correlated with each other , indicating that the introduction of different indexes using different computational methods resulted in great differences. Therefore, the standardization and calculation of Ees/Ea, besides the correct evaluation of the long-term prognostic value of the aforementioned indexes, were directly related to the clinical application and significance of Ees/Ea.Among the aforementioned indexes, CO, PVR, 6-minutes walking distance, and WHO cardiac function classification were clearly instructive for the clinical prognosis of patients with PAH. Further, ηp)vv( and ηv)vvvv, whereas the efficiency coefficient of coupling (ηv)vv measured by the volumetric method was an independent predictor . While analyzing the survival time, the ηv)vvvv were observed. Further, 5The major limitation of this study is the small sample, which was not from multicenter and different race. The follow-up time was not long enough, which may reduce the persuasion of this study. We could not completely exclude the population from other risk factors that affect survival statue. The absolute correlation between right ventricular–pulmonary artery coupling and the prognosis of patients with PAH in long term still need to be identified furthermore.6In this study, it was assumed that the diagnosis and treatment of patients with PAH could be improved as follows: for the first diagnosis, the right cardiac catheterization and other invasive examinations were needed to confirm the diagnosis of PAH. After 6 months to 1 year, the right cardiac catheterization could be replaced by nuclear magnetic resonance. In recent years, ventricular–vascular coupling indexes were constantly accuralized or even redefined in terms of the prominent features of the right ventricle. The use of noninvasive methods to measure the right ventricular function was expected to monitor the development of the disease and helped to select specific treatment options for patients.7ηvv) is important to define the cardiac function in PAH. The Ees/Ea calculated by the volumetric method may be better to predict the prognosis of PAH. When Ees/Ea <0.67, the patients with PAH were more likely to turn to a rapid deterioration.PAH is a complex disease, which has greatly threatened human health and life. It is urgent to correctly evaluate and predict the prognosis of the patients with PAH. The right ventricular–pulmonary artery coupling (Data curation: Sanping Zhang.Formal analysis: Yaling Dong.Investigation: Menghuan Yan.Methodology: Jun Li.Resources: Ming Xu.Software: Lin Nie.Validation: Gangcheng Zhang.Writing – original draft: Laichun Song.Writing – review & editing: Jun Li, Laichun Song.


The various conditions causing a chronic increase of RV pressure greatly differ in the occurrence of RV failure, and in clinical outcome. To get a better understanding of the differences in outcome, RV remodeling, longitudinal function, and transverse function are compared between patients with pulmonary stenosis (PS), those with a systemic RV and those with pulmonary hypertension (PH).This cross-sectional study prospectively enrolled subjects for cardiac magnetic resonance imaging (CMR), functional echocardiography and cardiopulmonary exercise testing. The study included: controls (n = 37), patients with PS (n = 15), systemic RV (n = 19) and PH (n = 20). Statistical analysis was performed using Analysis of Variance (ANOVA) with posthoc Bonferroni.2 peak/kg% (p<0.001) compared to systemic RV patients. Mean apical transverse RV free wall motion was lower and RV free wall shortening (p<0.001) was prolonged in PH patients–resulting in post-systolic shortening and intra-ventricular dyssynchrony. Apical transverse shortening and global longitudinal RV deformation showed the best correlation to RV ejection fraction .PS patients had smaller RV volumes with higher RV ejection fraction  compared to controls (53.8±4.8%). PH and systemic RV patients exhibited dilated RVs with lower RV ejection fraction . PH patients had lower RV stroke volume (p = 0.02), RV ejection fractions (p<0.01) and VORV remodeling and function differed depending on the etiology of RV pressure overload. In contrast to the RV of patients with PS or a systemic RV, in whom sufficient stroke volumes are maintained, the RV of patients with PH seems unable to compensate for its increase in afterload completely. Key mediators of RV dysfunction observed in PH patients, were: prolonged RV free wall shortening, resulting in post-systolic shortening and intra-ventricular dyssynchrony, and decreased transverse function. Pulmonic valve opening, acceleration time, pulmonic valve closure, and ejection time were measured from a pulsed wave Doppler tracing taken in the RV outflow tract. Measurements were taken at an inter-beat (RR) interval similar to that of the strain analysis. Two measures of RV dyssynchrony were included: the time difference between peak septal and peak free wall strain, and the standard deviation of the basal-RV free wall, mid-RV free wall, basal septal, and mid septal segment time to peak (RV-SD4).  as appropriate. Categorical variables are shown as frequency (%) and compared with Chi-square. All patient groups were compared to controls using Analysis of Variance (ANOVA) with posthoc Dunnet’s–for normally distributed parameters–or Kruskal-Wallis with Mann-Whitney U test–for non-normally distributed parameters. Patient groups were compared to each other using Analysis of Variance (ANOVA) with posthoc Bonferroni.2 for the model and beta-coefficient for the individual parameter.The Pearson correlation coefficient (r) was used to correlate conventional echocardiographic measurements, deformation imaging and transverse measures to RVEF. Multivariable linear regression analysis included all imaging parameters that were correlated significantly with RVEF. If parameters were suspected to be collinear, the multivariable analysis only included the parameter with the highest univariable correlation. Multivariable linear regression, including underlying disease as an additional variable, was also used to associate the same measurements to % of predicted VO2max/kg. For multivariable linear regression, we report the adjusted RIntra- and interobserver reproducibility were assessed by re-analyzing 15 datasets >1 month apart. The agreement was assessed using intra-class correlation coefficients, mean difference with limits of agreement and a paired Student T-test. Our group and Kind et al. have previously published reproducibility of the CMR measurements. ,18 An alThe study included 91 subjects: 37 controls, 15 PS, 19 systemic RV , and 21 PH patients . RVSP was significantly higher in systemic RV patients than PH and PS patients (p<0.001) but did not differ significantly between PS and PH patients (p = 0.111). Percentage of predicted pVO2/kg and pVO2/heart rate were significantly lower in PH patients than PS and systemic RV patients (both p<0.01). VE/VCO2 slope was significantly higher in PH patients (both p<0.001). Lastly, % of predicted peak HR was lower in PH patients and systemic RV patients compared to PS patients (respectively p = 0.003 and p = 0.015).Measurements of longitudinal RV free wall motion, by both CMR  and specTiming measurements are shown in 2 = 0.828), i.e. together explaining 82.8% of the variation in RVEF.2 increasing from 0.349 to 0.392).Global systolic RV longitudinal deformation by STE was the only parameter associated to % of predicted pVO2max/kg in multiple linear regression , independent of underlying disease entity  The RVs of patients with PS are hyperdynamic, with low RV volumes and supra-normal RVEF, despite sustaining substantially elevated RV pressures for several decades. 2) In contrast, patients with a systemic RV or with PH show RV dilation, spherical RV geometry, and decreased ejection fraction. Of the latter two patient groups, PH patients have a poorer global function, reflected by a lower RVEF and RV stroke volume. This is probably mediated by a higher degree of intra-ventricular dyssynchrony, resulting in post-systolic shortening, and by decreased transverse RV free wall function. In pressure-loaded RVs apical transverse function and global RV systolic strain by STE were able to predict 83.8% of the variance in RVEF. The correlation of TAPSE and TDI S’, the most frequently used conventional echocardiographic parameters, to RVEF was poor.Higher systolic ventricular pressure needs to be met by proportional RV hypertrophy to reduce afterload and/or increase contractile strength. If this hypertrophy is sufficient, acceptable stroke volumes can be maintained. If this hypertrophy is insufficient, RV dilation will ensue to maintain stroke volume through the Frank-Starling mechanism: a phenomenon that is known as pre-load recruitable stroke work. If both mechanisms are not sufficient to compensate for the elevated afterload, myocytes remain stretched throughout systole, which increases the duration of contraction and ultimately decreases systolic function.This theoretically translates into three types of adaptation: 1) increased afterload compensated by adequate RV hypertrophy. 2) Increased afterload compensated by hypertrophy and RV dilation . 3) Increased afterload compensated insufficiently despite hypertrophy and RV dilation, resulting in an increased duration of contraction and a drop in stroke volume . Patients with valvular stenosis have low RV volumes, high mass-volume ratios and (supra)normal function, corresponding to the first pattern of adaptation. The RV of systemic RV patients and PH patients, facing high vascular resistance, dilates to maintain its stroke volume . SystemiMeasures of RV free wall longitudinal shortening, which is believed to be most important for global RV function in the normal RV, were decreased in all patient groups compared to controls . In patiIncreased intra-ventricular dyssynchrony mediated by prolonged RV free wall contraction, present in PH but not CHD patients, is a second important mechanism of RV dysfunction in PH patients. The RV fThe ultimate goal of RV adaptation is for the RV to stay coupled to its afterload. The diffThe ventricular load is most often estimated using calculations of end-systolic wall stress (static load), but oscillatory load  also determines the total RV load. AlthoughFurthermore, the myocardial response, regarding RV hypertrophy, differs substantially between groups. Both CHD patient groups show superior mass-volume ratios compared to the PH patients, indicating a higher degree of hypertrophy, which has been reported in previous studies as well.,27 This Lastly, myocardial damage might progress faster in PH, as studies have demonstrated relative RV ischemia, causing fibrosis–which aggravates RV dilation and reduces contractility. 2 = 0.83. Their value in daily practice will require further study, as they are less simple and straightforward than TAPSE and fractional area change. Our results complement previous studies in PH, showing global RV strain[CMR-derived RVEF is considered the reference standard for assessment of RV systolic function. However, it is expensive, not very patient-friendly, and therefore, not used as the sole imaging modality for follow-up in these patients. In daily practice, most institutions will use echocardiography for serial follow-up. The echocardiographic measurements most frequently used for quantification of RV systolic function are TAPSE, TDI S’ and fractional area change. In accordance with recent studies, correlation of TAPSE to RVEF was poor in our study.,32 FractRV strain,35 and tRV strain are of aPA acceleration time also correlated well to RVEF, with a shorter acceleration time corresponding to a poorer RVEF. The fact that not RVSP but PA acceleration time correlated to RVEF may indicate acceleration time–like the pulsed wave Doppler shape–better reflects the interaction between ventricular and pulmonary vasculature .Global longitudinal deformation by STE was the only measurement related to % of predicted VO2max/kg independent of underlying disease. Different determinants of aerobic exercise capacity in CHD vs. PH patients likely explain this. In patients with CHD, aerobic capacity is mainly related to cardiac output, either a decreased O2 pulse (representing reduced stroke volume) or–as seen in the systemic RV group–reduced peak HR. Contrarily, in PH patients both cardiac function and decreased ventilatory efficiency contribute to the decreased aerobic capacity , as illuNo invasive pressure measurements were available–as they are not routinely performed in many CHD patients. Furthermore, RVSP was inevitably higher in systemic RV patients. However, our goal was to have comparable RVSP in PH and PS patients. As all imaging measurements of RV function are load dependent, it is important to note that differences in ejection/deformation do not always reflect contractility, but may be a result of different afterload.Although we attempted to reduce heterogeneity to a minimum, sex and age distribution were different between the groups, concordant with the differences in epidemiology. However, it is unlikely that the differences in age importantly influenced our results, as the normal effect of age on RV function and volume is opposite to the change observed in PH patients. Lastly, There is no agreed-upon way to calculate wall stress for the RV. We estimated end-systolic wall stress with a modified Laplace’s law; using wall mass and end-systolic volumes to obtain a more global estimate of wall stress as RV geometry varies greatly between patient entities.Patient groups with high RV pressures greatly differ in presence and degree of RV dilation, RV mass to volume ratio, magnitude of transverse motion, and timing of RV contraction–which corresponds to the degree of RV dyssynchrony. This ultimately leads to differences in stroke volume and global function. Concurrent to their poor clinical outcome, PH patients showed unfavourable RV remodeling and function. This indicates that their RV, unlike that of PS and systemic RV patients, is unable to compensate for its increase in afterload completely. In the studied cohort with RV pressure overload, global RV systolic longitudinal deformation by STE, transverse motion, and fractional area change correlated highly to RVEF, while TAPSE and TDI S’ did not.S1 TableReproducibility measurements. ‡mean difference and limits of agreement.; ‡mean difference and limits of agreement; II significance of paired T-test. ICC = intra-class correlation coefficient; RV = right ventricular.(DOCX)Click here for additional data file.S1 Data(SAV)Click here for additional data file.


Background: 3D speckle-tracking echocardiography (3D-STE) is a novel method to quantify left ventricular (LV) mechanical dyssynchrony. 3D-STE is influenced by image quality, but studies on the magnitude of its effect on 3D-STE derived LV systolic dyssynchrony indices (SDIs) and their test-retest reproducibility are limited.Methods: 3D-STE was performed in two groups, each comprising 18 healthy volunteers with good echocardiographic windows. In study 1, optimal and inferior-quality images, by intentionally poor echocardiographic technique, were acquired. In study 2, sub-optimal quality images were acquired by impairing ultrasound propagation using neoprene rubber sheets  mimicking mildly, moderately, and severely impaired images, respectively. Measures  were volume- and strain-based SDIs defined as the standard deviation of time to minimum segmental values, and volume- and strain-derived dispersion indices. For both studies test-retest reproducibility was assessed.Results: Test-retest reproducibility was better for most indices when restricting the analysis to good quality images; nevertheless, only volume-, circumferential strain-, and principal tangential strain-derived LV dyssynchrony indices achieved fair to good reliability. There was no evidence of systematic bias due to sub-optimal quality image. Volume-, circumferential strain-, and principal tangential strain-derived SDIs correlated closely. Radial strain- and longitudinal strain-SDI correlated moderately or weakly with volume-SDI, respectively.Conclusions: Sub-optimal image quality compromised the reliability of 3D-STE derived dyssynchrony indices but did not introduce systematic bias in healthy individuals. Even with optimal quality images, only 3D-STE indices based on volume, circumferential strain and principal tangential strain showed acceptable test-retest reliability. Synchronous contraction is important for overall left ventricular (LV) systolic performance . WideninLVMD can be measured by several echocardiographic imaging modalities such tissue-Doppler imaging (TDI), 2D speckle-tracking echocardiography (STE), 3D echocardiography (3DE), and 3D-STE . TDI-bas3D-STE has also emerged as a promising method for quantifying LVMD, with 3DE systolic dyssynchrony index (SDI-volume) having been proposed as a useful measure to assess LVMD and guide CRT . In addiFor a test to be useful it must be reproducible, i.e., show acceptable variability between measures (good reliability) and demonstrate no systematic differences between measurement occasions (no bias) . Good reWe aimed therefore to (1) quantitate the impact of intentionally distorted image quality on reliability and bias of LV dyssynchrony indices by 3D-STE; (2) assess the association between SDI-volume and strain-based LV SDIs. By design, the study was conducted in healthy individuals with good echocardiographic windows since this allowed us to achieve a realistic degree of intentional image impairment to compare with good quality reference images. Some of these data have been presented previously in abstract form , 25.Two prospective sub-studies  were performed. In study 1, 23 healthy individuals with no previous cardiac medical history were recruited to undergo 3DE. Only individuals with excellent/optimal echocardiographic windows were included in these studies, so 5 individuals were excluded in study 1 due to sub-optimal echocardiographic windows, leaving a final sample size of 18. In study 2 study, an additional 21 healthy individuals were recruited to further quantify the impact of sub-optimal image quality. Eighteen participants were finally included after excluding 3 participants with sub-optimal echocardiographic windows. The institutional review board approved the study protocol and informed consent was obtained from all participants at the time of examination.3DE examination was perfumed using an EPIQ7 ultrasound machine  equipped with a X5-1 Xmatrix-array transducer by an experienced, British Society of Echocardiography accredited sonographer as previously described . FollowiIn study 1, two gated wide-angled 3DE LV full-volume datasets were obtained per participant. The acquisition of the first dataset was performed according to EAE/ASE recommendations . MachinePoor visualization of the endocardium of up to 7 segments throughout the cardiac cycle in a 16-segment LV model.The presence of echo dropout.Shadow artifacts.An identical acquisition protocol  under the same conditions was repeated on the same day  to assess the test-retest reproducibility of optimal and sub-optimal images.In study 2, the quality of the 3DE images was impaired by attenuating ultrasound propagation in a graded and reproducible manner to better quantitate the impact of sub-optimal image quality. In achieving this, we used three sheets of ultrasound-attenuating material called neoprene rubber with different thicknesses  to mimic mild, moderate, and severe impairment in image quality, respectively . NeoprenImage analysis was perfumed using 4D LV-Analysis software  by a single blinded reader. In total, 4 datasets per participant for each sub-study were analyzed. To quantify read-to-read variability a second read of scan was performed ~2–3 months after the initial read. At the start of each analysis, three standard apical views and one short-axis view were automatically selected and displayed by the software. The longitudinal axis of the LV in all apical views were further aligned manually if needed using the mitral valve annulus and the apex as anatomical landmarks. The LV endocardial borders in all three apical views were then automatically defined by the software at end-diastole and tracked throughout the cardiac cycle in 3D space from which the 3D LV endocardial shell was constructed. Further, manual adjustments were kept as minimal as possible. The software then subdivided the LV into 16 segments using a standard model  and prov- Volume-based SDI, defined as the SD of time to minimum segmental volumes over 16-LV segments.- Strain-based SDI, calculated as the SD of time to peak segmental strain over 16 LV-segments from LS, CS, RS, and principle tangential strain (PTS) which is a composite 3D measure of CS and LS.- Volume- and strain-derived dispersion indices (Di), calculated as the difference between minimum and maximum time to peak of segmental volume/strain values over 16-LV segments.LV dyssynchrony indices were the following :- VolumAll indices were normalized to cardiac cycle length and reported as %.r. The sample size was chosen to ensure a lower limit of the one-sided confidence interval ≤ 0.15 assuming a ICC = 0.8 . Test-retest reliability was quantified by intraclass correlation coefficients (ICC). Reliability was classified as follows: ICC < 0.4 = poor, 0.4 ≥ ICC < 0.75 = fair to good, and ICC ≥ 0.75 = excellent . MeasureCC = 0.8 . With thCharacteristics of participants in study 1 and 2 are summarized in Under optimal conditions , only volume, CS and PTS 3D-STE derived dyssynchrony indices achieved fair to good test-retest reliability, whereas LS and RS derived dyssynchrony indices showed poor test-retest reliability . ReducedThere was no evidence of systematic bias due to sub-optimal image quality in any of 3D-STE derived LV dyssynchrony indices in study 1 . In studIntra-observer reproducibility based on re-reading the same  scans showed good to excellent reproducibility of all dyssynchrony indices except for LS derived dyssynchrony indices . Reprodur = 0.70, p < 0.0001 for PTS-SDI; and r = 0.66, p < 0.0001 for CS-SDI) , whereas LS-SDI correlated weakly  (PTS-SDI and CS-SDI correlated well with SDI-volume ( CS-SDI) . RS-SDI  0.0025) .3D-STE has theoretical advantages over other ultrasound-based methods for quantification of LVMD as it allows comprehensive evaluation of active contraction of the myocardium along different myocardial vectors simultaneously, and may therefore provide a better representation of LVMD . HoweverSDI-volume by 3DE has previously been reported to be a feasible and reliable measure to assess LVMD , 35. In Comprehensive evaluation of LVMD from different myocardial vectors including LS, RS, CS, and more recently AS  may provide a better representation of the active contraction of the myocardium than volume changes . DespiteDifferent components of myocardial mechanics reflect the contributions of different layers of the myocardium ; these mWe acknowledge a number of limitations in this study. We only examined short-term test-retest reliability of 3D-STE derived LV dyssynchrony indices, and how they are influenced by sub-optimal image quality in healthy individuals. The use of healthy individuals makes generalization to specific cardiac pathologies difficult but at least some of our findings are likely to be relevant to studies of diseased populations since sub-optimal image quality is more likely in unhealthy individuals. Image quality is only one factor influencing the clinical utility of 3D-STE in assessing LVMD. While our approach produced impairments of image quality that were qualitatively similar to that seen in older or more obese patients, echocardiographic images may impaired by other factors such as emphysema or surgical scars which may be more difficult to simulate. 3D-STE is also constrained by limited temporal resolution and the effect of frame rate on reproducibility was not studied as this has been described by others , but we Under optimal conditions in healthy individuals, the reliability of volume-derived and some 3D-STE strain-based LV dyssynchrony indices by test-retest was fair to good, but reliability was substantially compromised by poor image quality. Previous studies using re-reading of images as a measure of reliability have probably over-estimated the reliability of 3D-STE derived LV dyssynchrony indices.All datasets relevant to this study are included in the manuscript/This study was carried out in accordance with the recommendations of World Medical Association (WMA). All subjects gave written informed consent in accordance with the Declaration of Helsinki. The protocol was approved by the UCL REC.Each author has contributed extensively to the manuscript. LA and AH conceived and designed the study. LA performed the data collection and the statistical analysis and drafted the manuscript. CP and AH assisted in data interpretation, critically reviewed, and amended the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Left ventricular apical hypertrophic cardiomyopathy is a rare presentation of hypertrophic cardiomyopathy associated with thickening of the apical segment of the left ventricle. It was initially described in Japan in 1976 and is characterized by electrocardiogram findings showing giant T wave inversions in the precordial leads as well as a spade shaped appearance of the apical cavity on imaging .In this case, we present a patient with a heart transplant with a stable post-transplant course who was found to have apical hypertrophic cardiomyopathy. There have been a few cases of apical hypertrophy in a transplanted heart documented in the literature. Making this case even more unique is that this presentation is evident 17 years after heart transplantation.Fifty-four year-old male with a history of orthotropic heart transplant in 2001 on immunosuppressive therapy presented with palpitations and associated lightheadedness. He had a blood pressure of 184/89 mmHg on arrival but otherwise had stable vital signs and physical examination. Cardiac biomarkers revealed a CK of 59 U/L and a troponin of 0.11NG/ML. B type natriuretic peptide was 371 PG/ML. Routine laboratory studies demonstrated normal sodium, magnesium, serum creatinine, and a potassium of 3.3 mmol/L. His hemoglobin and hematocrit were normal. His EKG showed sinus rhythm with old T wave inversions in the anterior and lateral leads. Echocardiogram revealed a left ventricular ejection fraction of 55–65%, left posterior wall of 1.3 cm and interventricular septal wall 1.2 cm, thickened trabeculated apex, with severely dilated left atrium. He had a stress test that showed mild inferior wall thinning and a cardiac MRI performed to further evaluate apical hypertrophy revealed prominent apical hypertrophy of the left ventricle with near obliteration of the apical cavity. He had no events on cardiac monitoring and was discharged with close followup with the transplant team.While there are many etiologies of ApHCM, it has not been well described in transplanted patients who are on chronic immunosuppressive therapy. It is unclear if these groups of patients are at an increased risk of developing this condition. The literature suggests that ApHCM is associated with a being prognosis but there is new data suggesting increased mortality in a subset of patients with this condition. Left ventricular apical hypertrophic cardiomyopathy is a rare presentation of hypertrophic cardiomyopathy associated with thickening of the apical segment of the left ventricle. It was initially described in Japan in 1976 . In westIn this case, we present a patient with a heart transplant with a stable post-transplant course who was found to have apical hypertrophic cardiomyopathy. There have been a few cases of apical hypertrophy in a transplanted heart documented in the literature. Making this case even more unique is that this presentation is evident 17 years after transplantation.A 54 year-old male with a history of orthotropic heart transplant in 2001 for non-ischemic cardiomyopathy presented to the hospital after experiencing intermittent palpitations with associated lightheadedness of one hour duration. He denied any chest pain or shortness of breath, orthopnea or paroxysmal nocturnal dyspnea. At baseline, he described activities consistent with New York Heart Association Class 2. He had recently completed a 4 day course of Prednisone for a gout flare-up. Additional medical history was notable for benign prostatic hyperplasia and hyperlipidemia. Medications included Atorvastatin, Cyclosporine, Finasteride, Levothyroxine, Mirtazapine, Mycophenolate, Omeprazole, Prednisone, Quetiapine, Ranitidine, Tamsulosin, Zolpidem. He had allergies to Azithromycin. He denied tobacco or illicit drug use and alcohol consumption.On arrival, he was afebrile, heart rate was 54 bpm, blood pressure was 184/89 mmHg, and oxygen saturation was 98% on ambient air. His physical examination was unremarkable and he appeared clinically euvolemic. Cardiac biomarkers revealed a CK of 59 U/L and a troponin of 0.11NG/ML. B type natriuretic peptide was 371 PG/ML. Routine laboratory studies demonstrated normal sodium, magnesium, serum creatinine, and a potassium of 3.3 mmol/L. His hemoglobin and hematocrit were normal. An electrocardiogram revealed a normal sinus rhythm with T wave inversions in the anterior and lateral leads which were unchanged compared to prior ECG Fig. . He undeApical Hypertrophic Cardiomyopathy (ApHCM) is a relatively rare variant of hypertrophic cardiomyopathy associated with thickening of the apical segment of the left ventricle leading to a ‘spade-shaped’ small cavity. Initially described in Japan, it makes up approximately 15–25% of all hypertrophic cardiomyopathies and is more commonly seen in men .The hallmarks include giant T wave inversions in the precordial leads on electrocardiogram and the aforementioned spade like appearance of the left ventricular cavity , 2. MostIn a transplanted heart, various causes of hypertrophy exist. These include long standing hypertension and pressure overload, medications like tacrolimus, metabolic disorders and donor hypertrophic cardiomyopathy .This patient’s case is rather peculiar because he had a heart transplant seventeen years ago and has been maintained on immunosuppressive therapy with a rather benign post-transplant course. He had an echocardiogram dating back five years ago that had no evidence of ApHCM so it is safe to assume that the pre-transplant donor echo was unremarkable. It is unclear if there was any history of HCM or sudden cardiac death in donor’s family. He had well controlled blood pressures and had no evidence of ischemia or valvular disease on non-invasive testing. It is certainly possible that this is an idiopathic finding.The finding of apical hypertrophic cardiomyopathy in this patient likely does not suggest an increase in mortality or morbidity due to its historically benign course. However, recent studies have shown increased morbidity and mortality in this subset of patients . FactorsIn conclusion, apical hypertrophic cardiomyopathy is a well described benign variant of hypertrophic cardiomyopathy. However, it has not been well described in a patient with previous heart transplant. The etiology of ApHCM in this patient is thought to be idiopathic and less likely related to his long term immunosuppressive therapy. It is unclear if the prognosis differs in this group of patients but studies done to assess long term outcome have shown a benign prognosis in terms of cardiovascular mortality.


Histone deacetylases (HDACs) play a critical role in modulating myocardial protection and cardiomyocyte survivals. However, Specific HDAC isoforms in mediating myocardial ischemia/reperfusion injury remain currently unknown.We used cardiomyocyte-specific overexpression of active HDAC4 to determine the functional role of activated HDAC4 in regulating myocardial ischemia and reperfusion in isovolumetric perfused hearts.In this study, we created myocyte-specific active HDAC4 transgenic mice to examine the functional role of active HDAC4 in mediating myocardial I/R injury. Ventricular function was determined in the isovolumetric heart, and infarct size was determined using tetrazolium chloride staining.Myocyte-specific overexpressing activated HDAC4 in mice promoted myocardial I/R injury, as indicated by the increases in infarct size and reduction of ventricular functional recovery following I/R injury. Notably, active HDAC4 overexpression led to an increase in LC-3 and active caspase 3 and decrease in SOD-1 in myocardium. Delivery of chemical HDAC inhibitor attenuated the detrimental effects of active HDAC4 on I/R injury, revealing the pivotal role of active HDAC4 in response to myocardial I/R injury.Taken together, these findings are the first to define that activated HDAC4 as a crucial regulator for myocardial ischemia and reperfusion injury.The online version of this article (10.1186/s10020-018-0037-2) contains supplementary material, which is available to authorized users. Histone deacetylases (HDACs) are a group of enzymes that regulate gene expression by the modulation of their interactions with chromatin through the deacetylation of histones. The acetylation and deacetylation of chromatin histones are considered to be critical in the regulation of transcription in in the biological responses. Acetylation of histone is caused by histone acetyl transferase, which leads to nucleosomal relaxation and altered transcriptional activation. In contrast, histone deacetylase result in deacetylation and transcriptional repression Turner .Since the identification of HDAC 1 ; a sense primer specific to MHC promoter exon 2) and antisense primer B (5-AGCGCCAGGAGCTCCTGCTGC-3); specific to HDAC4 cDNA. The protocol for the animal experiments in this study was approved by IACUC, which is fully in agreement with the guidance for the Care and Use of Laboratory Animals published by the US National Institutes of Health.Creation of the mice carried out in Boston University transgenic core facility. A cDNA encoding an activated HDAC4 was cloned into an expression vector encoding alpha-myosine heavy chain , a cardiomyocyte-specific promoter at the multiple cloning site. After ligation, the construct was purified and verified by restriction enzyme digestion and sequencing. Transgenic mice were generated by microinjection of the α-MHC-HDAC4 DNA construct into fertilized FVB/n mouse eggs FTm , and primary active caspase 3 were purchased from Abcam . SOD-1 and LC3 poly clonal primary antibodies was purchased from Santa Cruz biotechnology . All chemicals for perfused hearts were purchased from Aldrich-Sigma .Trichostatin A, 3--2,5- diphenyltetrazolium bromide (MTT) and 4,6-Diamidino-2-phenylindole (DAPI) were obtained from Life Technologies . Primary antibodies including HDAC4 rabbit polyclonal and β-actin antibodies  of about 10 mmHg. Left ventricular function was assessed by inserting a water-filled latex balloon into the left ventricle, which was connected to a pressure transducer and recorded through Power Lab recording system . Ventricular functional parameters were measured, which include left ventricular end-diastolic pressure (LVEDP), left ventricular systolic pressure (LVSP), left ventricular developed pressure (LVDP), rate pressure product (RPP), heart rate (HR), and coronary flow (CF).The methodologies of Langendorff perfused system, ventricular function detection, and infarct size measurement has been described previously  with TSA 24 h before ischemia. Animals were divided into two additional groups: TSA + Wild type mice (n = 5), Wild type mice were injected with TSA (0.1 mg/kg ip); TSA + α-MHC-HDAC4 mice (n = 5), α-MHC-HDAC4 mice were injected with TSA (0.1 mg/kg ip). Twenty-four hours later, the hearts were subjected to 30 min of ischemia followed by 30 min of reperfusion.Mice about 2 month old were randomized into four experimental groups that underwent the following treatments, as shown in the experimental protocol(TTC) staining was employed to detect infarct size. After Langendorff perfusion, the hearts were then frozen in the refrigerator for a short period. Then, the frozen hearts were cut from apex to base into 1 mm thick slices. These slices were then placed in 10% TTC for 20 min. The cardiac sections were fixed in paraformaldehyde (4%) for photography. NIH ImageJ software was utilized to measure the area of viable and dead portion of tissues. The infarct size of each heart was determined and shown as the percentage of risk area, defined as the sum of total ventricular area minus cavities ; fractional shortening (FS) and ejection fraction (EF), which were described previously .t test was conducted to compare the difference between groups. p < 0.05 was considered to be a significant difference between groups.All data, including ventricular function, infarct size, protein density, and immunostaining signals are expressed as mean ± SE. Differences among the groups were analyzed by one-way analysis of variance (ANOVA) followed by Bonferroni correction. Student’s unpaired The HDAC4 proteins in the heart from MHC-HDAC4 levels were significantly higher than that of control wild type. In adult 2-month old mice, there was no differences in HDAC4 on other organs Fig. . The HDABaseline functional parameters, including left ventricular developed pressure (LVDP), LV-dP/dt max LV-dP/dt min, heart rate, and coronary effluent were recorded among control wild type and HDAC4 transgenic mice before subjection to I/R. The experimental protocol for I/R was shown in Fig. Myocardial infarct size, an index of irreversible myocardial injury, was measured. As shown in Fig. p < 0.05 vs Wild type), which was also accompanied with the reduction of RPP recovery MHC-HDAC4 at both 15 min  This is the first study to identify that overexpression of activated HDAC4, a major class II HDAC isoform in the heart exacerbates myocardial I/R injury, as indicated by the increase in infarct size and the reduction of myocardial function; 2) Over-expression of HDAC4-induced I/R injury was attenuated by delivery of HDAC inhibitor, TSA; 3) Furthermore, activated HDAC4 promoted I/R injury was associated with increased in autophagy, apoptosis and decreased SOD-1. These findings indicate that cardiac-specific activated HDAC4 reduces myocardial function and increases cardiac injury following I/R, which is associated with increased autophagy and apoptosis.The roles of class II HDACs in cardiac development and hypertrophy were assessed in previous observations


Cardiovascular disease is the major cause of death, accounting for approximately 40 percent of all-cause mortality in patients receiving either hemodialysis or peritoneal dialysis. Cardiovascular risk stratification is an important aspect of managing dialysis patients as it enables early identification of high-risk patients, so therapeutic interventions can be optimized to lower cardiovascular morbidity and mortality. Biomarkers can detect early stages of cardiac injury so timely intervention can be provided. The B-type natriuretic peptides  and troponins have been shown to predict mortality in dialysis patients. Suppression of tumorigenicity 2 (ST2) and galectin-3 are new emerging biomarkers in the field of heart failure in both the general and dialysis populations. This article aims to discuss the current evidence regarding cardiac biomarker use to diagnose myocardial injury and monitor the risk of major adverse cardiovascular events in patients undergoing dialysis. There is a high prevalence of traditional cardiovascular risk factors, particularly diabetes mellitus and hypertension, in individuals with end-stage kidney disease (ESKD) compared with the general population Sudden cardiac death (SCD) is the single leading cause of death in dialysis populations 2.B-type natriuretic peptide (BNP) is a member of the natriuretic peptide system, which additionally consists of the A-, C-, D- and V- type natriuretic peptides and urodilatin 2.1.BNP and NT-proBNP have a number of proven clinical applications in the general population, including improving the accuracy of clinical assessment for diagnosing cardiac failure in patients presenting with dyspnea A recent meta-analysis reported that BNP/NT-proBNP-guided heart failure pharmacotherapy resulted in significant reductions in mortality in patients under 75 years of age compared to specialist care alone  2.2.Both peptides are partially excreted unchanged renally with a fractional renal excretion of 15–20% Biologic or within-person variation of NT-pro-BNP in dialysis patients is an important consideration during interpretation of serial measurements of this cardiac biomarker. Fahim et al. The hemodialysis procedure has also been shown to affect serum concentrations of BNP and NT-proBNP, with low-flux hemodialysis resulting in 2–16% reductions in serum BNP concentrations and 0–12% increases in serum NT-proBNP concentrations In contrast to hemodialysis, the effect of peritoneal dialysis on the clearance of plasma BNP and NT-proBNP remains unclear. A recent study of eight peritoneal dialysis patients demonstrated that BNP was present in peritoneal dialysis fluid at mean concentration of 19 ± 4% that of circulating BNP concentrations, suggesting that BNP is cleared by peritoneal dialysis 2.3.BNP/NT-proBNP concentrations have not been shown to correlate with short-term changes in volume state 2.4.β = −0.48, p < 0.0001) and LV mass indexed to height  after adjusting for blood pressure, age, diabetes, albumin, hemoglobin, treatment modality, small molecule clearance, and time on renal replacement therapy p = 0.01). A cohort study of 199 dialysis patients investigated the relationship between baseline BNP as the exposure and increase in left atrial volume as the outcome. The study demonstrated that baseline BNP concentration was a powerful, independent predictor of increase in left atrial volume p < 0.001) Several studies in dialysis populations have demonstrated that BNP/NT-proBNP have an independent and powerful direct correlation with left ventricular (LV) mass 2.5.In addition to the important cardiac and physiological correlations discussed previously, cohort studies using a single baseline serum concentration of BNP/NT-proBNP as the exposure have demonstrated that it is a powerful, independent predictor of heart failure The strongest support for the potential role of the B-type natriuretic peptides as biomarkers of cardiac risk in the renal dialysis population comes from longitudinal studies employing limited numbers of repeated natriuretic peptide measurements to investigate the relationship between change in peptide concentration and change in risk of mortal events. These studies demonstrated that change in B-type natriuretic peptide concentration correlated directly with change in risk of cardiovascular and all-cause mortality in both incident and prevalent hemodialysis patients 3.The troponin complex is composed of three subunits—Troponin C (TnC), Troponin I (TnI), and Troponin T (TnT)—which work in concert to regulate the interaction between actin and myosin required for myofibrillary contraction. Approximately 6% of cTnT and 4% of cTnI are present unbound in the cytoplasm of cardiac myofibrils 3.1.Troponin is one of the biologically active structural proteins released into the circulation when cardiac injury occurs with disruption of normal cardiac myocyte membrane integrity. The precise mechanism by which cardiac troponins are cleared from the circulation has not been elucidated, although accumulating evidence suggests that renal clearance plays little, if any, role in the elimination of troponins. Firstly, several cohort studies have demonstrated that a large proportion of renal transplant recipients with elevated pre-transplant cardiac troponin concentrations continue to have elevated concentrations in the first year post-transplant despite a substantial improvement in their glomerular filtration rate th centile upper reference limit of troponin assays despite being asymptomatic , which are a leading cause of emergency presentations, hospitalization and death in this population change in serial troponin concentrations with at least one concentration exceeding the 99th centile upper reference limit, occurring in an appropriate clinical context, in order to confirm a diagnosis of acute myocardial injury in dialysis patients In an effort to address this conundrum, the current consensus guideline on the diagnosis of acute myocardial injury requires demonstration of a Guidelines for interpreting serial troponin measurements should incorporate data on both the biological variation of cardiac troponins in stable dialysis patients and serial changes in troponins associated with adverse outcomes in dialysis patients. Biological or within-person variation describes the random fluctuation of biomarker levels around a homeostatic set point in healthy individuals or those with stable disease; such fluctuations are of no clinical significance and must be distinguished from pathological changes. Fahim et al. 3.3.Michos et al. 4.Based on the evidence presented and discussed in this review, troponin has been validated as a useful biomarker in the acute care setting and should be used to diagnose myocardial injury in ESKD patients using a relative change strategy. Consequently, in an ESKD patient with a compatible clinical history, an acute increase in serial serum hs-cTnT concentrations of greater than 33% is sufficient to diagnose acute myocardial injury. On the other hand, we do not recommend the use of cardiac troponin in the chronic care setting in these patients. Chronically elevated cardiac troponin concentrations in clinically well dialysis patients reflect long term risk of mortality, but are not well characterized enough for use in clinical practice. Elevated troponin concentrations in dialysis patients have been repeatedly shown to predict risk of future adverse cardiovascular events, however, the precise magnitude of change that should prompt action, the interventions that should be instituted, and the benefits of such monitoring have not been studied precluding a recommendation for use in routine practice. Similarly, whilst B-type natriuretic peptides should be used to guide heart failure therapy, we do not recommend their use in acute or chronic care settings to diagnose myocardial injury or damage in ESKD patients. In contrast to the use of NT-proBNP in the non-dialysis population, it is unlikely that a threshold value of NT-proBNP can be derived for either diagnosing or excluding structural cardiac pathology in dialysis population. This is due to the large between person variations of NT-proBNP in dialysis population. A clinically useful strategy requires precise guidance on a magnitude of relative change in serial NT-proBNP concentrations that can safely be ignored  versus that should prompt action, the associated time to event of such a change, the ideal monitoring interval, clear targets for intervention, and evidence that such intervention improves patient level outcomes. These parameters have yet to be established.5.Suppression of tumorigenicity 2 (ST2) and galectin-3 (GAL-3) are emerging biomarkers in the field of heart failure . They se5.1.ST2 is a member of Toll-like/IL-1 receptor superfamily with transmembrane (ST2L) and soluble isoforms (sST2). It was discovered in 1989 and its downstream effects include activation of T-helper type 2 (Th2) cells and production of Th2-associated cytokines. sST2 binds to IL-33 and functions as a ‘decoy’ receptor for IL-33, thereby attenuating the systemic effects of IL-33 The relationship of ST2 and renal function (measured by eGFR) was investigated in a Spanish study of 891 consecutive patients treated at a structured multidisciplinary heart failure unit 5.2.GAL-3 is a marker of tissue fibrosis, which is a hallmark of cardiac remodeling and heart failure. This can be reliably measured in the blood and studies have shown its prognostic value in heart failure 6.Growth differentiation factor-15 (GDF-15) is a 12-kDa secreted protein belonging to transforming growth factor-beta cytokine family. Hagstrom et al. in vitro. Measurement of the inactive, stable, mid-regional (MR) prohormone of this peptide (MR-proADM) is now possible. Maisel et al. Adrenomedullin (ADM) is released from a multitude of tissues and was first isolated from human pheochromocytoma cells. It has potent vasodilatory, hypotensive and natriuretic properties Copeptin, a glycoprotein, is a marker of neurohormonal activation and part of the prehormone molecule of the antidiuretic hormone or arginine vasopressin. There is evidence that copeptin might be useful as a diagnostic or prognostic biomarker and risk-stratifier in a range of cardiovascular disease conditions Osteoprotegerin (OPG) has emerged as independent biomarker of cardiovascular disease in patients with acute or chronic heart disease as well as in the healthy population. OPG is a mediator of vascular calcification Osteopontin is a glycoprotein that is expressed in various cell types, including cardiomyocytes and fibroblasts and has been shown to be significantly increased in patients with heart failure irrespective of the underlying cause and correlate with the severity of heart failure Adiponectin is a multifunctional adipocyte-derived protein with anti-inflammatory, antiatherogenic and insulin sensitizing activity Matrix metalloproteinase 9 (MMP-9) is a potential biomarker for cardiac remodeling. MMP-9 levels have been shown to correlate with LV enlargement, lower ventricular ejection fraction, and persistent adverse LV remodeling in chronic systolic heart failure patients Fetuin-A is predominantly made by the liver and is decreased in heart failure patients, indicating that anti-inflammatory activity is down regulated in these patients and that calcification may be associated with heart failure Although all of these very novel biomarkers have diagnostic and prognostic potential, their clinical utility remains unclear currently.7.Dialysis patients have up to 100-fold increased risk of cardiac death compared to the general population. This increased risk has remained unchanged over the last decade, whilst patient numbers on dialysis have grown exponentially. A key factor underpinning this mortality risk is fluid overload-induced cardiomyopathy. Progress in improving outcomes has been limited by our current inability to assess fluid state and cardiac risk status in an accurate and dynamic manner. NT-proBNP is a promising biomarker that has been shown in preliminary studies to predict mortality and correlate with cardiomyopathy and fluid state. The two cardiac troponins, cTnI and cTnT, represent potentially valuable biomarkers for the diagnosis and management of cardiovascular disease in dialysis patients. Future randomized studies should investigate if early intervention for minor, but significant, changes in cardiac troponin concentrations improves patient outcomes in the dialysis population as has been demonstrated in the non-dialysis population