Although a significant number of women recover their left ventricular (LV) function within 12 months, some remain with persistently reduced systolic function.Peripartum cardiomyopathy (PPCM) is an important cause of pregnancy-associated heart failure worldwideKnowledge gaps exist on predictors of myocardial recovery in PPCM. N-terminal pro-brain natriuretic peptide (NT-proBNP) is the only clinically established biomarker with diagnostic value in PPCM. We aimed to establish whether NT-proBNP could serve as a predictor of LV recovery in PPCM, as measured by LV end-diastolic volume (LVEDD) and LV ejection fraction (LVEF).P = 0.043) or LVEF  at follow-up.This study of 35 women with PPCM (mean age 30.0 ± 5.9 years) had a median NT-proBNP of 834.7 pg/ml (IQR 571.2–1840.5) at baseline. Within the first year of follow-up, 51.4% of the cohort recovered their LV dimensions (LVEDD < 55 mm) and systolic function (LVEF > 50%). Women without LV recovery presented with higher NT-proBNP at baseline. Multivariable regression analyses demonstrated that NT-proBNP of ≥ 900 pg/ml at the time of diagnosis was predictive of failure to recover LVEDD (OR 0.22, 95% CI 0.05–0.95, We have demonstrated that NT-proBNP has a prognostic value in predicting LV recovery of patients with PPCM. Patients with NT-proBNP of ≥ 900 pg/ml were less likely to show any improvement in LVEF or LVEDD. Our findings have implications for clinical practice as patients with higher NT-proBNP might require more aggressive therapy and more intensive follow-up. Point-of-care NT-proBNP for diagnosis and risk stratification warrants further investigation. Peripartum cardiomyopathy (PPCM) is an important cause of pregnancy-associated heart failure and occurs in women towards the end of pregnancy or within the first five months after delivery , 2. AlthDespite recent advances in the management of PPCM, predictors of myocardial recovery remain poorly understood. Previous baseline clinical factors that have been shown to influence LV recovery include LVEF, –6 LV dimB-type natriuretic peptide (BNP) and its prohormone, N-terminal B-type natriuretic peptide (NT-proBNP), are released in response to cardiac wall stress, , 13 and While elevated NT-proBNP levels have been shown to predict mortality and cardiovascular events in patients with heart failure, even amongst those who were asymptomatic,  little iWomen with PPCM, seen at the dedicated Cardiomyopathy Clinic at Groote Schuur Hospital, were recruited between 2013 and 2018. Patients were referred from primary or secondary care facilities or within the tertiary/quaternary hospital, and assessed by a team of cardiologists and heart failure specialists.Inclusion criteria included: (1) primary diagnosis of PPCM, i.e. documented clinical evidence of LV systolic dysfunction towards the end of pregnancy or during the first five months postpartum; (2) no other identifiable causes of heart failure; (3) LVEF ≤ 45% on presentation confirmed by transthoracic echocardiography. Exclusion criteria were: (1) patient unable to give informed consent; (2) other identifiable causes of heart failure; and (3) patients younger than 18 years.This study was approved by the University of Cape Town’s Faculty of Health Sciences Human Research Ethics Committee (HREC ref no R033/2013), and complied with the Declaration of Helsinki. All patients provided written informed consent prior to study entry.Eligible patients were enrolled at the baseline visit, at which time their medical and obstetric history, New York Heart Association (NYHA) functional class, clinical examination findings and prescribed medication were recorded. All patients had 12-lead electrocardiogram (ECG) and echocardiogram at the baseline visit. Blood was collected at the baseline visit for the measurement of full blood count, renal function and NT-proBNP.A resting 12-lead ECG was performed for all patients at baseline using a MAC 5500 HD  machine. The ECG was analysed for heart rate, rhythm, QRS duration, LV hypertrophy (LVH) by Sokolow–Lyon criteria , and a QEchocardiography was performed at the time of diagnosis and at follow-up. Two-dimensional and targeted M-mode echocardiography with Doppler colour flow mapping were performed using either a Philips CX50  or a VIVIDi  echocardiography machine. LV dimensions (i.e. LV end-diastolic diameter [LVEDD] and LV end-systolic diameter [LVESD]) and global systolic function (LV ejection fraction [LVEF]) were measured according to the guidelines endorsed by the American Society of Echocardiography .Blood samples were taken at the baseline visit. Full blood count and renal function were analysed by the National Health Laboratory Service (NHLS) at Groote Schuur Hospital. For NT-proBNP testing, plasma or serum was separated by centrifugation and aliquots were stored at − 80 °C. NT-proBNP was measured for each participant using the BNP Fragment EIA kit . NT-proBNP values were converted to pg/ml as recommended by current clinical practice guidelines.We considered two separate echocardiographic measures for LV recovery, i.e. LVEDD < 55 mm and LVEF ≥ 50% within the 12-month follow-up period. Patients who did not fulfil these echocardiographic criteria at follow-up echocardiogram, and those who died within the study period, were considered to have no LV recovery.p value of < 0.05 was considered to indicate statistical significance.Data were collected on Research Electronic Data Capture (REDCap Version 9.5.13), a secure electronic database hosted by the University of Cape Town , before This cohort of 35 women with PPCM had a mean age of 30.0 ± 5.9 years Table . Almost p = 0.025) and were less likely to have sinus tachycardia  at initial presentation. The baseline QTc interval was longer, however, in patients who failed to recover their LV dimensions . The baseline LVEF did not predict recovery of LV dimensions. The initial NT-proBNP was lower in those with recovery of LV dimensions within 12 months . As depicted in Fig. p = 0.380), though the gradient of decline was greater in those with NT-proBNP level measured < 900 pg/ml at baseline. Women with an NT-proBNP of ≥ 900 pg/ml had significantly higher LVEDD at follow-up . As shown in Table p = 0.043).Figure p = 0.041) and sinus tachycardia  at the time of first diagnosis. There was no significant difference in haemoglobin, creatinine or hs-CRP at baseline between women with LV recovery and LV non-recovery.Within the first year of follow-up, 51.4% of the cohort recovered their systolic function (LVEF > 50%). Women who did not recover systolic function by 12 months were more likely to present with a NYHA functional class III or IV . More than two-thirds of those who did not recover their LV function within one year presented initially with NT-proBNP levels of ≥ 900 pg/m . Patients with a baseline NT-proBNP < 900 pg/ml showed more consistent recovery of their systolic function at follow-up  .Although not statistically significant, there was a notable difference in the initial NT-proBNP values between those who recovered their LV function by 12 months and those who did not  and systolic function  within 12 months  – Fig. r = 0.344, p = 0.043) and LVEDD .There was no correlation between NT-proBNP and blood pressure (SBP p = 0.028), a tendency towards a larger left atrial (LA) diameter , and significantly increased LVEDD . Furthermore, these patients presented with a significantly lower LVEF  at the time of diagnosis. There was no difference in parameters that are known to influence NT-proBNP .Table In this study, we show that women with PPCM present with markedly increased NT-pro-BNP levels at the time of diagnosis. In this regard, a baseline NT-proBNP ≥ 900 pg/ml is predictive of failure to recover LV systolic function and dimensions at one-year follow-up. Importantly, NT-proBNP levels are usually not elevated during normal pregnancy or healthy postpartum period . NT-proB., a BNP cut-off value of < 111 pg/ml excluded heart failure in pregnant and postpartum women [Contemporary heart failure guidelines recommend natriuretic peptides as the biomarker of choice in diagnostic work-up of patients with heart failure . In thisum women . For PPCum women .Natriuretic peptides have also been studied for its prognostic value during pregnancy and the postpartum period. Normal BNP levels (< 100 pg/ml) have been shown to have a negative predictive value for adverse maternal events in pregnant women with heart disease . In wome. described increased mortality and rehospitalisation for heart failure amongst patients with an NT-proBNP above the median of the cohort [The predictive value of NT-proBNP in patients with mild to moderate heart failure was studied in a sub-study of the COPERNICUS trial  in which patients were stratified according to whether their NT-proBNP levels were above or below the median value of the cohort . Hartmane cohort . Conside. reported that NT-proBNP levels of > 1860 pg/ml were associated with a threefold increase in persistent LV systolic dysfunction at follow-up [. did not find BNP to be predictive of recovery of LV dimensions and systolic function in a cohort of 43 women with PPCM from Turkey [When interpreting NT-proBNP levels in heart failure, various clinical factors need to be considered. The level of natriuretic peptides increases with age, and therefore, higher cut-off values are suggested for the elderly. Whereas obesity lowers the concentration of natriuretic peptides, renal disease and atrial arrhythmias  in particular) are associated with higher NT-proBNP levels. None of the patients in this cohort had AF; this was not surprising, as AF has previously been described to be rare in PPCM . Furtherollow-up . In contm Turkey .. who reported that NT-proBNP levels were significantly higher in those women who did not show an improvement of at least 10 percentage units (e.g. 25–35%). In their study, NT-proBNP levels remained significantly higher in those who did not improve their LV function [Although our study showed that in most patients, there was an improvement in LV dimensions and systolic function, some remained with an LVEDD > 55 mm and LVEF < 50% at follow-up. We found that women with baseline NT-proBNP ≥ 900 pg/ml were more likely to show no improvement in their LV systolic function at one-year follow-up. This is supported by previous work by Forster et alfunction .Inflammation, increased levels of oxidative stress and systemic angiogenic imbalance appear to play a crucial role in the pathophysiology of PPCM. Through unknown mechanisms, increased levels of oxidative stress cause a cleavage of prolactin into a 16-kDa fragment, which causes endothelial dysfunction and induces cardiomyocyte apoptosis , 33. MorIncreased NT-proBNP levels are associated with LV remodeling . In thisAlthough not explored in this study, point-of-care (POC) NT-proBNP tests have previously been used in patients with heart failure. The benefit of POC testing is its ease of use, affordability and the immediate availability of the result . TherefoAs this is a single-centre study conducted at a tertiary hospital, where the most severe cases of PPCM are generally seen, there is a possibility of referral bias. Furthermore, considering that PPCM is a rare disease, we acknowledge that the small sample size of this study might have affected the precision of estimates, especially in the logistic regression analyses. We therefore encourage validation of our findings in a larger, multi-centred cohort.This study also lacks a control group and NT-proBNP measurements at follow-up. The slope of change in NT-proBNP levels in patients with PPCM might provide important information regarding the changes of LV recovery and selection of correct heart failure treatment in future studies.We acknowledge that RV function, which has previously been shown to have important prognostic value in PPCM,  was not We demonstrate the prognostic value of NT-pro-BNP for LV recovery in PPCM. We have shown that NT-proBNP may be useful in the risk stratification of patients with PPCM and may be used to implement more intensive treatment strategies of patients who have an NT-proBNP ≥ 900 pg/ml at diagnosis and individualise follow-up regimens. The application of POC NT-proBNP testing should be further studied for its use of diagnosis and risk stratification for patients with PPCM.


Naja oxiana, on the isolatedrat heart.The cardiovascular system is one of the first systems to be affected by snaketoxins; but not many toxins exert a direct effect on the heart. Cobra venomcardiotoxins are among those few toxins that attack the heart. Although thetwo cardiotoxin types (S and P) differ in their central-loop structure, itis not known whether they differ in their effect on the mammalian heart. Wecompared the effects of S- and P-type cardiotoxins, CTХ-1 and CTХ-2,respectively, from the cobra  An isolated rat heart perfused according to the Langendorff technique wasused in this study to investigate the activity of cardiotoxins CTX-1 andCTX-2. The following parameters were registered: the left ventriculardeveloped pressure, calculated as the difference between systolic anddiastolic pressure in the left ventricle, the end-diastolic pressure, theheart rate, time to maximal end-diastolic pressure (heart contracture), andtime to depression of the heart contraction. Both cardiotoxins at the concentration of 5 μg/mL initially produce a slightincrease in systolic intraventricular pressure, followed by its rapiddecrease with a simultaneous increase in diastolic intraventricular pressureuntil reaching contracture. CTX-2 blocks cardiac contractions faster thanCTX-1; in its presence the maximum diastolic pressure is reached faster andthe magnitude of the developed contracture is higher. The P-type cardiotoxin CTX-2 more strongly impairs rat heart functionalactivity than the S-type cardiotoxin CTX-1, as expressed in its fasterblockage of cardiac contractions as well as in more rapid development andgreater magnitude of contracture in its presence.  Among the vast family of three-finger snake venom toxins, there is a group ofproteins called cardiotoxins (CaTXs) or cytotoxins that exert damaging effects onthe heart. In particular, CaTXs cause systolic heart arrest and induce a membraneleakage of cardiomyocytes. They are β-structured proteins consisting of 59 to 61amino-acid residues with the structure stabilized by four disulfide bonds. Thisgroup of toxins is characterized by direct interaction with the membrane, leading tomembrane depolarization and cell death (see reviews ). CaTXs are classified into two types, P and S: P-type includes CaTXs with a prolineresidue at position 30 of the amino-acid sequences and alanine at position 28 inmost sequences, while S-type toxins have a serine residue at position 28  and neveThe effects of various CaTXs on myocardial tissue develop quite typically: theinitial increase in contractility is followed by its suppression and by an increasein diastolic tension , 5. At tNaja oxiana belong to the S- and P-types, respectively [Cytotoxins (cardiotoxins) 1 (CTX-1) and 2 (CTX-2) from the venom of the Central Asiancobra ectively . In our ectively , we studectively . Howeverectively , 10-12, Najanaja atra cobra venom and some of its fractions, identified by theauthors as cardiotoxic to the rat heart, was studied previously [It was shown previously that CTX-2 at the concentration of 10 μg/mL produced adecrease in the amplitude of heart contractions, bradycardia and cardiac arrest insystole of an isolated frog heart, while CTX-1 caused arrhythmia, and atsignificantly higher concentrations also caused systolic cardiac arrest . The expeviously . HoweverNaja oxiana cobra venom as describedpreviously [Cardiotoxins were purified from eviously , 13, and2,1; CaCl2, 1.8; NaHCO3,14.5; NaH2PO4, 1.8; glucose, 11; pH 7.4. The perfusionsolution was aerated with 95% O2/5% CO2, while its temperaturewas held constant at 37 ± 0.1°C. Left ventricular pressure (LVP) was measuredisovolumetrically using a latex balloon introduced into the left ventricle throughan incision in the left atrium and inflated to a baseline diastolic pressure of 10mmHg. The balloon was connected to the pressure transducer, and the diastolic,systolic, and pulse LVP were recorded and processed using the software PhysExp. Adult male Wistar rats  were used for the experiments. Thestudy was conducted according to the guidelines of the Declaration of Helsinki,Directive 2010/63/EU of the European Parliament and of the Council on the protectionof animals used for scientific purposes (22 September 2010) and approved by theBiological Safety and Ethics Committee of the Institute of Cellular Biophysics. Hearts were perfused using the Langendorff techniqueessentially as previously described .Rats weAfter 30 minutes of equilibration, CTX-1 or CTX-2 was added to the solution and wasmaintained during the whole experiment at the concentration of 5 µg/mL. A group of 6rats was used for CTX-1 measurements and another of 5 rats for CTX-2. The followingparameters were registered: the left ventricular developed pressure (LVDP),calculated as the difference between systolic and diastolic pressure in the leftventricle; the end-diastolic pressure (LVEDP); the heart rate; time to maximum LVEDP(contracture of the heart) and time to depression of heart contractions (LVDP lowerthan 5 mmHg). In every experiment, the preparation was allowed to stabilize for 30minutes before the measurement; the parameters registered for 10 seconds before CaTxapplication were used as control values.t test. Data were presented asmeans ± SEM. Statistical data analysis was carried out using the software packagesMicrosoft Excel 2019 and GraphPad Prism 8.The data were checked for normal distribution using the Shapiro−Wilk test.Statistical significance of the obtained results at p < 0.05 was assessed usingthe paired and unpaired Student’s To compare the action of toxins, the concentration of 5 μg/mL was chosen since atlower concentrations the effect develops fairly slowly (during 30 to 60 minutes), which cCaTXs are the main components of cobra venom and manifest cytotoxicity againstdifferent types of cells . As discThe biological effects of CaTXs include tissue necrosis, cardiac arrest and severalothers . It shouNajaoxiana cobra venom. Our experiments showed that, in general, thedevelopment of the effects of both CaTXs on the whole rat heart proceeded asdescribed in the literature for preparations of various types of myocardial tissue -the initial increase in contraction is followed by suppression with a simultaneousincrease in the resting tension [2+ ions due to increase of theextracellular Ca2+ influx [2+ ions is probably higherin the presence of this toxin. However, it should be noted that due to the positiveforce-frequency correlation of the rat myocardium in the range of physiologicalfrequencies [To compare the effects of the S- and P-type CaTXs on the isolated rat heart, weapplied two individual toxins, CTX-1 and CTX-2, purified from  tension , 21. The tension , vascula tension , and in  tension . The obsquencies , an incr2+ and Na+ ions. These processes may include theactivation of ion channels [In our experiments, the heart rate does not increase in the presence of CaTXs  and, thechannels , formatichannels , and a cchannels , 29, ultchannels ,31. All2+ and Na+ ions as theincrease in LVEDP is much stronger and the time to fully develop the effects issignificantly shorter in the case of CTX-2. Overall, our results indicate that CTX-2possesses a higher potency than CTX-1 in relation to damaging effects on the wholerat heart. Thus, the higher activity of CTX-2 as compared to CTX-1 demonstrated inthe frog heart [Some differences between CTX-1 and CTX-2 in interaction with phospholipids wereobserved previously . While bog heart  and the og heart  is retaiinvitro leads to its greater toxicity ex vivo.Therefore, for the first time, we have compared the effects of two types of CaTXs onthe isolated mammalian heart. Both toxins showed a similar profile of action;however, the P-type toxin CTX-2 has a higher potency. Apparently, the previouslyshown greater ability of this toxin to disrupt the lipid bilayer CaTXs: cardiotoxins; CTX-1: cytotoxin (cardiotoxin) 1; CTX-2: cytotoxin(cardiotoxin) 2; LVDP: left ventricular developed pressure; LVEDP: leftventricle end-diastolic pressure; LVP: left ventricular pressure.


GWI (p < 0.001) and GCW (p < 0.001), but not GWW (p = 0.241) nor GWE (p = 0.854) were significantly reduced after TAVI. Patients with a low flow low gradient (LF-LG) AS had lower left ventricular ejection fraction (LVEF) (p < 0.001), worse global longitudinal strain (GLS) (p < 0.001), and lower baseline GWI (p < 0.001), GCW (p < 0.001) and GWE (p = 0.003). The improvement in GWI and GCW observed after TAVI in the general study population were abolished among LF-LG patients. In conclusion, non-invasive MW might be useful to further classify patients with AS and to predict non responders.Changes in cardiac mechanics after correction of severe Aortic Stenosis (AS) are under-investigated. Myocardial Work (MW) is emerging as a useful non-invasive correlate of invasively measured myocardial performance and oxygen consumption. The aim of this study was to assess the usefulness of MW in the clinical management of patients with AS undergoing transcatheter aortic valve implantation (TAVI). Consecutive patients referred for TAVI were included in this observational study. Echocardiograms were performed before and after TAVI to measure Global Work Index (GWI), Global Constructive Work (GCW), Global Wasted Work (GWW), and Global Work Efficiency (GWE). Mean transvalvular gradient was significantly improved ( Severe aortic stenosis (AS) is associated with variable degrees of compensatory left ventricular (LV) adaptation . These cAssessment of systolic LV performance in these patients represents a clinical conundrum. Left ventricular ejection fraction (LVEF) generally remains preserved despite initial deterioration of LV function. Global longitudinal strain (GLS) has been shown to be an earlier and more sensitive marker of LV dysfunction ,4. NeverNoninvasive myocardial work, a non-invasive correlate of myocardial performance and oxygen consumption, has been introduced, it uses segmental strain and non-invasive blood pressure to calculate LV pressure–strain loops ,7,8. In this context, the aim of the present study was to assess the feasibility of non-invasive myocardial work assessment in patients with severe AS, the impact of stenosis correction by means of transcatheter aortic valve implantation (TAVI), and to investigate its usefulness for pre-procedural assessment.2 or an aortic valve index ≤ 0.6 cm2 per square meter. Low flow low gradient (LF-LG) severe aortic stenosis is defined as an aortic valve AVA ≤ 1.0 cm2 or indexed ≤ 0.6 cm2/m2 and a mean transvalvular gradient < 40 mmHg. Surgical risk was assessed using the Euroscore II. Clinical management was guided through collegial discussion of the Heart Team, according to current guidelines. Exclusion criteria were: hemodynamically relevant aortic regurgitation (more than mild), presence of left bundle branch block at EKG, suboptimal quality of the echocardiographic images. The regional ethics committee approved the study, and all the patients provided written informed consent.In this single-centre study, consecutive patients with symptomatic severe AS scheduled for transcatheter aortic valve implantation (TAVI) at the Cardiology Department of the University Magna Graecia of Catanzaro  from January 2018 to August 2019 were included. Severe AS was defined by an aortic valve area below 1 cmClinical examination, anamnesis, a 12-lead ECG, and laboratory tests were performed at baseline. Echocardiography was undertaken before and after TAVI for all patients. Non-Invasive Blood Pressure (NIBP) was registered at every examination. For a subgroup of patients, Invasive Blood Pressure (IBP) was measured during TAVI. All clinical data were anonymized and collected in an electronic database.All patients underwent a standard Trans-Thoracic Echocardiography (TTE) using a Vivid E9 ultrasound system . For the quantification of the severity of aortic stenosis, we measured the left ventricular outflow tract (LVOT) diameter, LVOT flow by pulsed wave doppler (PW), AS jet by continuous wave doppler (CW), and the aortic valve area (AVA) calculated by continuity equation, as recommended. For the strain analysis, two-dimensional (2D) 4-chamber, 3-chamber, and 2-chambers apical views were acquired, with an optimized frame rate (≥60 frames/sec). All the recorded images were transferred to an imaging workstation , which allowed offline semi-automated analysis.The left ventricular (LV) Myocardial work (MW) is estimated as the area of the LV pressure–strain loop by a dedicated software , as previously described . Howeverp-value of 0.05 was considered significant. Corrections for multiple comparisons were applied to statistical analyses. Specifically, as GWI, GCW, GWW, and GWE present are not completely independent, adjustment with the Holm method was applied in this case. To account for comparison in multiple independent subgroups , adjustment with the Bonferroni method was applied [Continuous variables are presented as mean ± standard deviation, categorical as percentages. The Kolmogorov–Smirnov test was used to assess normality. Analysis of Variance (ANOVA) or Student T-Test was used for comparisons with continuous variables. The Chi squared test was used for dichotomous variables. Pearson’s R test was used to assess correlation between variables. Multiple logistic regression was used to test predictors of clinical adverse events , as previously described . Covaria applied ,14. As m applied .Based on the previous literature, we estimated a 15% reduction in mean Global Work Index after TAVI in the study population. Thus, we calculated that 70 patients would have been required to detect the estimated change in Global Work Index after TAVI with a 90% power and an alpha level of 0.05.The statistical analyses were performed using SPSS v.21 .During the enrolment period, 73 consecutive patients with symptomatic severe AS scheduled for TAVI fulfilled the inclusion and exclusion criteria and were included. As shown in p < 0.001). Similarly, the Bland–Altman plot showed good reproducibility . A modest, non-significant change of E/E’ was observed from 13.2 ± 3.0 to 12.7 ± 2.1 after TAVI (p = 0.205). Global longitudinal strain after TAVI (−18.8 ± 4.0) was not significantly improved compared to pre-procedural values  (Standard baseline echocardiographic parameters are reported in = 0.060) .GWI and GCW were significantly reduced after TAVI and this difference was maintained during the follow-up . On the p = 0.417) nor in GLS (p = 0.142) (p = 0.007) and GCW (p = 0.014) compared to men (p = 0.763) nor in GWE (p = 0.393) at baseline. The delta change of GCW after TAVI was larger in women, although it remained significant in both sex groups . A similar effect was found for GCW (p < 0.001 in both groups), while a significant delta change in GWE was measured in women (p = 0.014), but not in men (p = 0.656). No significant delta change was observed in either group for GWW (Despite no difference in mean LVEF (= 0.142) , women hd to men , with no for GWW . These rp < 0.001) and a worse GLS (p < 0.001) compared to high gradient (HG) AS (p < 0.001), GCW (p < 0.001) and GWE (p = 0.003) and no difference in GWW (p = 0.605)  (Patients with a low flow low gradient (LF-LG) severe aortic stenosis presented a lower LVEF ( (HG) AS . These p= 0.605) . The redfor GCW) . These rp = 0.018), cigarette smoke , chronic obstructive pulmonary disease (COPD) , or presence of mitral regurgitation . Predictors of HF-related rehospitalization included diabetes , hypercholesterolemia  and residual aortic regurgitation after TAVI , along with baseline GWI , baseline GCW , baseline GWE , delta change in GCW , or GWE .Patients were followed up for a total of 128 patient years at risk. During a median follow-up of 24 months, 11 patients (15%) died and 23 (32%) were re-hospitalized. Of these re-admissions, 7 (10%) were related to HF. Univariate predictors of cardiovascular death included endocarditis , along with powerful predictors such as hypercholesterolemia (p = 0.023), mitral regurgitation (p = 0.020), and COPD (p = 0.019). In addition, GWI was the only independent predictor of HF-related re-hospitalizations (p = 0.024).At multivariate analysis, baseline GWI remained an independent predictor of death , together with hypercholesterolemia (p = 0.028), mitral regurgitation (p = 0.021), and COPD (p = 0.021). In addition, GWI was an independent predictor of HF-related re-hospitalizations (p = 0.050) together with hypercholesterolemia (p = 0.046).Similarly, multivariate analysis showed that baseline GCW was an independent predictor of death  correction of severe AS by means of TAVI has a significant impact on non-invasive myocardial work parameters, which are maintained over time during the follow-up; (ii) non-invasive myocardial work indices are capable to further stratify patients with severe AS, as they were able to discriminate between LF-LG AO and the more common form of AS with HG; (iii) the improvement of myocardial work indices after TAVI is not equally present across patient subgroups, as women tended to experience a less pronounced delta change in myocardial work after TAVI. The delta change is apparently abolished in specific subgroups, such as in patients presenting with LF-LG severe AS; (iv) myocardial work indices are independent prognostic predictors of adverse clinical outcomes.The evidence that baseline myocardial work indices are able to independently predict adverse clinical events pairs well with recent results reporting a significant correlation between non-invasive myocardial work and clinical symptoms in AS patients . In addiOur results further confirm previous findings by other groups, that correction of peripheral blood pressure by the transvalvular pressure gradient to estimate LV pressure in patients with AS is feasible and effective. In fact, Jain et al. recently assessed LV mechanics after TAVI in 35 patients with severe aortic stenosis. They found a significant improvement in GLS with a parallel reduction in GWI . Since G


HTN, p = 0.01), septal E/e′ ratio , lateral E/e′ ratio , and NYHA functional class . Additionally, per one-year increase in age, the integrated score index increased 0.2 in the healthy elderly, 0.15 in the CAD, and 0.06 in the HTN patients . Conclusion: Under aggressive treatment, diastolic function was relatively preserved in HTN subjects with aging in comparison with elderly and CAD subjects.Background: This 12-year study aimed to compare the longitudinal change in left ventricular diastolic dysfunction (LVDD) between healthy elderly, coronary artery disease (CAD), and hypertension (HTN) patients. Methods: From 2008 to 2020, 1476 patients were included, and 3181 echocardiography examinations were conducted. Finally, 130 participants , 51 with CAD (68.31 ± 12.09 years old), and 43 with HTN (68.31 ± 12.09 years old)) with more than a 10-year follow-up period were included in the final analysis. Results: The change in diastolic function was different among these subjects according to the integrated score index (elderly vs. HTN,  Intrinsic cardiac aging is defined as age-related degeneration and decline in cardiac function, either left ventricular systolic or diastolic dysfunction (LVDD) . For patp ≤ 0.014) [In addition to cardiac aging, other diseases such as coronary artery disease (CAD), hypertension (HTN), and physical deconditioning, appear to be critical in the onset of LVDD and its progression towards HFpEF . Kuznets2, subjects with a poor acoustic window or with echocardiographic evidence of heavy mitral annulus calcification, hemoglobin of ≤13 g/dL, albumin of ≤3.2 g/dL, or serum creatinine of ≥1.4 mg/dL. All subjects underwent 2D echocardiography and tissue Doppler imaging (TDI) examinations. This study was approved by the Ethics Committee and Institutional Review Board (IRB) on Human Research of the Medical Research Department of the National Taiwan University Hospital, Taipei, Taiwan. All subjects provided written informed consent before participating in the study.In this single-center study, 1476 participants were enrolled initially for transthoracic echocardiography from January 2008 to September 2020. Recruitment of participants included healthy elderly, CAD, and HTN patients who volunteered for health examinations in Taipei City and the surrounding rural area in Taiwan. The exclusion criteria were rheumatic valvular disease, severe mitral or aortic regurgitation, significant aortic stenosis , a fasting plasma glucose level of >126 mg/dL (7.0 mmol/L) or casual plasma glucose of >200 mg/dL (11.1 mmol/L), HbA1c level of >7%, thyroid disease, cerebrovascular accidents, malignancy, body mass index (BMI) of >30 kg/mIn this study, we planned to investigate the sequential changes in LV diastolic function with a preserved left ventricular ejection fraction (LVEF) in healthy elderly individuals (>60 years) and patients with CAD and HTN. Therefore, a history of congestive heart failure or symptoms and/or abnormal LVEF of <50%, congenital heart disease, cardiomyopathy, arrhythmias, chronic obstructive pulmonary disease, and those with a follow-up period of less than 10 years were excluded. A total of 130 participants , 51 with CAD, and 43 with HTN) and 752 echocardiography examinations were included in the final analysis .An annual re-evaluation was arranged for each participant after the initial enrollment. Blood pressure (BP) measurements, medications, laboratory, and echocardiography examinations were checked annually during the follow-up period. In order to retain the maximal recruitment of this long-duration study, several strategies were performed to lower the attrition rates. First, the environment for the echocardiographic examination was user-friendly. In particular, for the elderly participants, there was a full-time assistant to accompany them during the course of the echocardiographic measurements. Second, the appointment times were flexible during the course of follow-up. Third, participants were oriented to their roles, the study demands, and research responsibility. Finally, the results of the examinations were clearly explained to the participants as incentives and feedback for their participation.The key goal of this study was to evaluate the evolutional change in LV diastolic function between the subjects with CAD and HTN. Therefore, the aging-related decrease in LV diastolic function should be considered. First, healthy elderly participants without any systemic diseases were enrolled. They were categorized as the control group in comparison with the CAD and HTN groups.The CAD subjects were screened according to their clinical symptoms, physical examinations, resting electrocardiography, exercise stress electrocardiography, myocardial perfusion imaging, or electron-beam computed tomography (CT). They all accepted coronary angiography for the final diagnosis of CAD, and the results were evaluated by two cardiologists. In addition to lifestyle modifications , the CAD patients were all under regular pharmacotherapy for ischemic heart diseases ,6,7.2) and physical activity) during this period [For the HTN subjects, the definition of HTN was BP of >140/90 mmHg or those taking HTN medication. The on-treatment target BP was less than 130/80 mm Hg . The lons period .Comprehensive echocardiographic measurements using 2D echocardiography and TDI were performed with Vivid S5  equipped with a 1.7/3.4 MHz imaging transducer, with standardized imaging acquisition from key cardiac views, as recommended for appropriate cardiac chamber size and dimensions for M-mode and 2D or Doppler quantification according to the American Society of Echocardiography guidelines ,13,14. TThe transmitral Doppler flow velocity was measured using a 5 mm sample volume placed at the tips of the mitral leaflets in passive end expiration. A standardized loop of 10 cardiac cycles was downloaded to a computer for offline analysis of the early filling (E-wave) and late filling (A-wave) phases ,13,14. TThe diastolic score was calculated to evaluate the association of LV diastolic function with cardiac aging, CAD, and HTN. This score index was based on the results of the echocardiography with a score of 1 for an E/A ratio of <1, a score of 1 for a septal e′/a′ ratio of ≤0.8, a score of 2 for a lateral e′/a′ ratio of ≤1, a score of 2 for a septal E/e′ ratio of ≥10–15, a score of 3 for a lateral E/e′ ratio of ≥8–15, and a score of 1 for a deceleration time of >240 ms. The sum of each score was considered as the final value for the score index. Either a septal or a lateral E/e′ ratio of >15 was given a total score of 10, regardless of the other measurements [p-value of <0.05 was considered statistically significant. Statistical analysis was performed by SPSS software version 24.0 .Continuous data are expressed as the mean ± standard deviation (SD). Differences between the continuous data of groups were determined by performing one-way analysis of variance (ANOVA) followed by the Fisher’s Least Significant Difference (LSD) post hoc test for multiple paired comparisons. Even though the next scheduled appointment was arranged after each examination, some participants missed the annual evaluations unexpectedly. Hence, we chose linear mixed models (LMM) to analyze the longitudinal data of each group . There wThis study was conducted from January 2008 to September 2020. The total follow-up time was 5751 person-years; the mean follow-up time was 7.68 person-years. The time of follow-up examination was arranged annually after the first echocardiographic examination. From 2008 to 2020, 1476 patients were enrolled in the study, and 3181 follow-up echocardiographies were collected. However, some participants were lost to regular follow-up, and data with less than a 10-year follow-up period were excluded. At the end of the study, a total of 130 participants , 51 with CAD, and 43 with HTN) and 752 echocardiography examinations remained for final analysis .Generally, the thickness of the left ventricular wall, such as the interventricular septum (IVS) and left ventricular posterior wall (LVPW), was almost the same between the groups at enrollment . These dCardiac function was further evaluated by the integrated score index and the New York Heart Association (NYHA) class ,18. Eithp < 0.001) , calcium-channel blockers (CCB), angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEI/ARB), and Spironolactone were categorized and analyzed. Compared with the elderly and CAD subjects, the HTN subjects had a higher usage of CCB and ACEI/ARB medication upon enrollment (< 0.001) .p < 0.001) (p < 0.05) (p < 0.001) (p = 0.07) and Lat E/e′ (p = 0.28) did not change with aging for the HTN subjects (p < 0.001) (p = 0.03) in the HTN subjects  was individually analyzed by the linear mixed model (LMM) method. The results for each group are summarized in < 0.001) . The LVE < 0.05) . Diastol< 0.001) . Interessubjects . For the< 0.001) . Howeversubjects . Comparep < 0.05) and LV diastolic parameters  were different both within the elderly and HTN comparison and the CAD and HTN comparison (p = 0.01) and the functional NYHA class   . TherefoThe lab data and mediation were also analyzed by the GEE method to investigate the possible factors contributing to these results. However, there were no obvious differences in lab data  or type of medication used in these groups  after the two-group comparisons .This was a very long-term real-world observational study; therefore, participants lost-to-follow-up and selection bias were inevitable during such a long period of time (more than one decade). Additionally, a relevant proportion of patients in the CAD group may also have suffered HTN after enrollment. Therefore, we hypothesized that the observed difference would tend toward the null in this intention-to-treat study. If there was any evolutional change in diastolic function between these groups at the end of the study, the real difference between them would be larger than our expectation.There were three main findings from our study, providing new evidence for possible clinical application. First, diastolic function was preserved in the HTN subjects with aggressive treatment in comparison with the elderly and CAD participants. Second, specific parameters such as the Lat E/e′ and the integrated score index seemed to be able to detect the difference in aging effects on the LV diastolic function among these groups. Finally, aggressive BP control appeared to be an effective method of reducing the risk of HFpEF during this longitudinal study.In a previous study, the integrated score index was shown to discriminate healthy subjects from patients with LV diastolic dysfunction  . Comparep < 0.001) (p = 0.05) and Lat E/e′ (p = 0.23) detected that LV diastolic function was preserved in the HTN subjects during this period (p < 0.001) (p = 0.02) (p < 0.05)  decreased with aging in each group (< 0.001) . Only ths period . The sam< 0.001) . In cont = 0.02) . These e < 0.05) .In previous studies, the correlation of the E/e′ ratio with pulmonary capillary wedge pressure was well established in patients with LV systolic dysfunction . HoweverIn this study, we compared the change in LV diastolic function with aging among three groups . As discussed above, both CAD and HTN subjects were prescribed lifestyle modifications and pharmacological therapy while enrolled in this study. However, the diastolic function was preserved in the HTN group during this period. It seems that the aging effects on diastolic function in the subjects with preserved LVEF were different between diseases.Previously, Kuznetsova et al. reported a longitudinal follow-up of left ventricular diastolic function in the general population . From thp = 0.18 and <0.001, respectively) (p < 0.001)  . This mi< 0.001) . From thThe previous Aspirin in Reducing Events in the Elderly (ASPREE) trial also provided similar insights to the present study . In the p < 0.001) (p = 0.18)   rather t = 0.18) . This mi = 0.18) . In a prThis was a one-center observational study with more than one decade of follow-up. There were some inevitable limitations. In this study, initially, the treatments for HTN were according to JNC 7. The target value of BP control was adjusted and updated by the clinicians according to the patient’s clinical condition during this period, which might have influenced the results. The selection bias and the small study patient group were the main negative parameters that could have affected our results. The limited sample size for this type of longitudinal analysis and the large number of covariables compared should be taken into consideration. Specific parameters for special populations such as HTN and CAD patients could provide more information about this issue. Finally, this study began more than 10 years ago, so the recommendations for the evaluation of left ventricular diastolic function by echocardiography were from 2009.In this more than 12-year study, LV diastolic function decreased gradually with increasing age among all groups. There was no significant difference between the elderly and CAD groups in both systolic and diastolic function during this period. In contrast, the LV diastolic function was preserved in the HTN group in comparison with the elderly and CAD participants. We suggest that aggressive BP control could slow the LV diastolic function deterioration that commonly occurs with the aging process.


Introduction: Pulmonary stenosis with an intact ventricular septum (PS-IVS) is one of the common causes of cyanotic heart disease in neonates with diverse morphologies as well as management and treatment protocols. The aim of this study was to evaluate short and midterm results of balloon pulmonary valvuloplasty (BPV) for this disorder.Methods: Between 2012 and 2016, Totally 45 neonates and infants under 6 months old were evaluated.The patients had a minimum right-to-left ventricular pressure ratio of 1, right-to-left shunting at the patent foramen ovale or atrial septal defect level, and tricuspid valve Z-scores higher than -4. Results: Immediately after the procedure, the right ventricular pressure dropped to the normal values in 8 (20%) patients. The immediate procedural success rate was seen in 42 (93.3%) cases: the right-to-left ventricular pressure ratio dropped to below 50% or the level of O2 saturation rose above 75%. Of three cases unresponsive to BPV, two of them underwent patent ductus arteriosus (PDA) stenting and one procedural death occurred. At 6 months’ follow-up, of 42 patients, this pressure was still with in the normal range in 36 (80%) infants, while it had returned to high values in 9 (20%) patients and necessitated repeat valvuloplasty. After BPV, severe pulmonary valve regurgitation was observed in14.2% patients; the condition was more common when high-profile noncompliant balloons were used. Conclusion: Balloon pulmonary valvuloplasty in infants with PS-IVS confers acceptable results insofar as it improves echocardiographic parameters and hemodynamic changes at short- and midterm followups.Balloon selection with sizes more than 1.2 of the diameter of the pulmonary valve annulus and the use of noncompliant high-pressure balloons results in higher degrees of pulmonary regurgitation. Also, it is not a unique term because the diverse morphologies of this disorder call for different management approaches and its exact diagnosis requires the evaluation of clinical information, echocardiographic findings, and catheterization data.2Pulmonary stenosis with intact ventricular septum (PS-IVS) is one of the frequent causes of cyanotic heart disease in neonates and infants,The size of the right ventricular (RV) cavity, size of the infundibulum of the right ventricular outflow tract (RVOT), and diameter of the tricuspid valve (TV) are important landmarks. Other variables with major roles in this regard include the right-to-left ventricular (RV/LV) pressure ratio, ductal prostaglandin dependency, severity of the clinical manifestations, and associated anomalies.4Until recently, surgical pulmonary valvotomy aimed at increasing the pulmonary blood flow was the treatment of choice; nevertheless, transcatheter balloon pulmonary valvuloplasty (BPV) is now the standard therapy for this disorder.7 Accordingly, we sought to evaluate both the short- and midterm results of Balloon pulmonary valvuloplasty in 45 neonates and infants with PS-IVS and the effects of our interventional procedures on the patients’ outcome.The decompression of the RV with BPV with or without ductal stenting has been accompanied by various short- and long-term prognoses in different studies.This study was a prospective review that 45 patients less than 6 months old admitted to our Center with a diagnosis of PS-IVS between May 2012 and July 2016 were evaluated. This study was approved by university ethical committee according to the Helsinki Declaration of the World Medical Association (Ethic code number:IR.RHC.REC.1391.70). Informed consent was obtained from the parents. Prostaglandin E1 (PGE1) was initiated if the level of O2 saturation was below 75%.The inclusion criteria comprised age under six 6 months old, severe PS, RV/LV pressure ratio equal to or higher than 1, right-to-left shunting at the patent foramen ovale (PFO) or atrial septal defect level (ASD), and tricuspid valve Z-score greater than -4. The exclusion criteria consisted of stenosis of the supra-pulmonary valve and the peripheral pulmonary branches, association with other structural heart diseases, tricuspid valve Z-score less than -4, hypoplastic right ventricle, and right ventricle- dependent coronary perfusion.8The echocardiographic examinations were performed by a single operator using a Vivid 7 system . The pulmonary valve was considered dysplastic when the valve was thick and had low motion with a small annulus size without post-stenotic dilation in the main pulmonary artery (PA). The size of the RV and the normality of the 3 segments of the right ventricle chamber  were assessed. In addition, the diameter of the tricuspid valve annulus was measured in the 4-chamber view and the tricuspid valve Z-score was calculated according to the patients’ body surface area and appropriate tables.10Six months after pulmonary valvuloplasty, RV/LV pressure ratio was calculated by echocardiography. The pressure gradient across the pulmonary valve was measured by considering the pulmonary artery pressure normal in this group of patients, and the RV pressure was determined. In the presence of tricuspid valve regurgitation, the RV pressure was measured based on Bernoulli equation. Furthermore, the systolic aortic pressure was measured for the assessment of the left ventricle systolic pressure with an appropriate pressure cuff based on age and RV/LV pressure ratio was estimated.Contrast echocardiography was performed for a better evaluation of intra cardiac shunts, especially in the ASD level. The width of the regurgitation jet determined the severity of the tricuspid regurgitation as mild, moderate, or severe.The right ventricle size and function, severity of tricuspid and pulmonary regurgitation (PR), and intra-atrial shunts in the ASD and patent ductus arteriosus (PDA) levels were evaluated post BPV and subsequently 1 and 6 months afterward in the outpatient follow-up.2 level, and blood pressure were continuously monitored during the procedure. The intracardiac pressure was measured with a fluid-filled catheter system. Before and after BPV, the RV/LV pressure ratio and the right ventricle to pulmonary artery gradient were measured. A 4-F or 5-F Judkins coronary catheter was placed in the RVOT, and a 0.014-in guide wire was passed through the pulmonary valve into the ductus arteriosus and the descending aorta, if accessible, or the pulmonary branches.Anesthesia was induced in under the observation of a cardiac anesthesiologist. The drug protocol consisted of intravenous midazolam and ketamine. Tracheal intubation was performed according to the patient’s condition. Oxygen saturation, arterial blood OBased on the severity of pulmonary stenosis, the balloon-to-pulmonary valve annulus diameter was calculated and a proper balloon valvuloplasty catheter was selected. In some patients, balloon dilation was done with smaller balloon sizes and gradually larger balloons were selected until the maximal diameter was used.The BPV procedure was considered successful if the guide wire and the intended pulmonary balloon were successfully passed through the pulmonary valve and an appropriate waist was formed .The selection of the appropriate balloon size was based on the echocardiography and catheterization measurements. The diameter of the pulmonary valve annulus was measured in the short-axis view via echocardiography. During the cardiac catheterization, the diameter of the pulmonary annulus was calculated in the anteroposterior and lateral views after the injection of the contrast medium into the RV.Also, we select the balloon type based on several factors including: the age and weight, ability of passing venous introducer sheaths, pulmonary valve cusp thickness, and limitation of pulmonary valves motion.If the RV pressure after balloon pulmonary valvuloplasty dropped to less than 36 mm Hg, it was considered a normal RV pressure.2 saturation was increased to above 75% and Prostaglandin E1 was discontinued.The procedure was deemed successful if the RV/LV pressure gradient was decreased to below 50% of the left ventricle pressure or if the level of O2 test, and Friedman test were applied for the statistical analyses. SPSS  was used for all the analyses.The continuous data with normal and non-normal distributions were reported with means and standard deviations, respectively, and the categorical data were reported with frequencies. The Kruskal–Wallis test, Pearson χForty-five patients, consisting of 23 (51.1%) males and 22 (48.9%) females, at a mean body weight of 4.8, right frontal axis deviation was observed. Eight (17.7%) patients had normal axes and only 2 (4.4%) had superior axes. Patterns of right ventricle hypertrophy were observed in the ECG of the majority of the study population (93.3%), and 3 patients had left ventricle hypertrophy.Echocardiography findingsP = 0.034).All the 45 patients had ASD or PFO. The tricuspid valve regurgitation was severe in 31.1% and moderate in 12.3% of the study patients, with the rest having mild TR. The RV size was normal  in 28 (62.2%) patients, small  in 9 (20%), and larger than normal in 8 (17.8%). After the procedure, 32 (71.1%) patients had trivial-to-mild tricuspid valve regurgitation and only 1 patient had severe tricuspid valve regurgitation. The change in the severity of tricuspid valve regurgitation was significant after BPV  infants, moderate in 7 (15.5%), and mild in 32 (71.1%).2 saturation was increased to above 75% in 42 patients.The pulmonary balloon size was between 100% and- 120% of the diameter of the pulmonary valve annulus in 36 (80%) patients and between 120% and 150% in 8 (17.7%). In 1 (2.2%) infant, the balloon size was smaller than the diameter of the pulmonary valve annulus because a larger balloon failed to pass through the pulmonary valve following coronary balloon predilation. Predilation of the balloon for the pulmonary valve was not required in 32 (71.1%) cases, while predilation was done in 13 (28.8%) with smaller to larger balloons sequentially in 2 to 3 steps with 0.014-in coronary guide wires. This procedure was repeated once more due to significant residual pulmonary stenosis after the first pulmonary valvuloplasty in 8 cases.BPV procedure was performed successfully in all the 45 cases. The level of O2 saturation was increased, and the infants were extubated. During follow up, in first patient stent of PDA was occluded spontaneously and PTPC repeat again 1 year later and second patient refer to One and half repair surgery and PDA stent was occluded during surgery.Of three cases that did not respond to initiate BPV, PDA stenting was done in 2 infants with Genesis Blue 4.5 Xorms stents. After PDA stenting, O2 saturation increased to > 75%). At 6 months’ follow-up, the right-to-left ventricular pressure ratio was still within the normal range in 36 (80%) infants, but it had returned to high values in 9 (20%) and required repeat valvuloplasty. Of these 9 patients, three infants did not respond to repeat BPV and were, therefore, subjected to surgical valvotomy but six patients respond to BPV appropriately. During the follow-up, the change in the pressure was significant after 6 months (P = 0.009). Thirteen (28.8%) patients were treated with beta-blockers post procedurally and after 6 months, the RV pressure was normal in this group.The RV was equal with the LV pressure in 23 (48.8%) cases and suprasystemic in 23 (51.1%). The RV dropped to less than 36 mm Hg immediately after the procedure in the catheterization laboratory in 8 (20%) infants. The immediate success rate was seen in 42 (93.3%) patients  infants.Trauma to the vascular access was observed in 7 patients, all of whom were under 3 months old. In the presence of lower-limb pallor, coldness, and pulselessness, intravenous heparin was infused and 3 patients needed thrombolytic therapy.There was 1 death in a neonate less than 1 month old due to procedural complications. This patient suffered the rupture of the RVOT during catheterization resulting in tamponade and underwent pericardiocentesis and urgent surgical pericardiotomy but expired 5 days later. The hospitalization period was less than 3 days in 3 (6.6%) patients, 3 to 5 days in 20 (44.4%), 5 to 7 days in 14 (31.1%), and more than 7 days in 8 (17.7%).Although in older studies the number of pulmonary balloon dilations and the immediate success rate were important, recent studies attach more significance to the mid- and long-term outcomes of the procedure and focus on several factors that may affect the outcome. In the present study, we comprehensively evaluated the outcome of the Balloon pulmonary valvuloplasty procedure in infants less than 6 months old with a 6-month follow-up.13 Coronary balloon pre-dilation required in 29% of patients which was in line with Hassan et al (30%) but in Yucel et al study this rate was 18%. 14Immediate procedural success rate was 93% in our study. The overall success rate in different studies varies between 85% to 87%. 17 Nonetheless, at 6 months’ follow-up, the RV had returned to the normal values in most of our patients (80%).After BPV by immediate procedural success rate, we observed a significant reduction in the RV pressure (<36 mm Hg) in a small number of our patients (20%), which is consistent with other studies.17 reported that after BPV on 30 patients, the mean RV was 42 mm Hg in 9 patients and 61 mm Hg in the remainder, who needed intervention.Humpl et al,14 observed moderate and severe TR in significant percentage of total 55 neonate respectively. The authors reported that the need for the augmentation of the blood flow after BPV was more in the patients with severe TR. Elsewhere, Saad et al,11 studied 76 infants with severe PS and reported a reduction in the incidence of TR from 56% to 20% at 6 months’ follow-up following BPV.In our study, about one-third of cases has severe TR before procedure, nevertheless, at six month follow up, most (71%) had mild TR and only one patients had severe TR. Yucel et al,On echocardiography, larger RV is often accompanied by RV systolic dysfunction and severe TR. In cases with small right ventricle sizes (Z-score = -2 to -4) on echocardiography, the right ventricle cavity is severely hypertrophied but the systolic function is nearly normal. In this group of patients, right-to-left shunting via the interatrial communication and cyanosis are frequent.In the current study, the majority of the patients with persistently high RV pressures at 6 months’ follow-up (20%) needed repeat valvuloplasty. Three cases failed to respond to valvuloplasty and underwent surgery. This condition occurred in a group with small, dysplastic, and thick pulmonary valves and severely hypertrophied high right ventricle chambers.18 on 15 neonates.In our study, most patients were hospitalized for between 3 and 7 days, but there was no significant correlation between age and the mean weight and the length of hospitalization. The median length of hospital stay was 11.6 days in a study by Odemis et al,15 and Humpl et al,17. In study of Hoetama et al, BPV was done on 8 neonates with transjugular approach and they mentioned that using BPV with transjugular access is safe in neonate with critical PS.19In our study, we observed trauma to the vascular access in 7 patients, all of whom were under 3 months old. This rate chimes in with those reported by Chubb et al,15 on 39 neonates with Critical pulmonary stenosis or atresia with intact ventricular septum, the 30-day mortality after BPV was 6 patients, 2 of them died whom expired due to tamponade. Humpl et al 17 reported 5 postprocedural deaths (3 early and 2 late).We had 1 death (in 45 patients) due to RVOT rupture and tamponade. In the study by Chubb et al,In our study, the use of low-profile semicompliant balloons in most of the patients was correlated with mild post-procedural pulmonary regurgitation, whereas the use of high-profile noncompliant balloons was correlated with a higher incidence rate of moderate and severe PR. Moreover, when the balloon size was between 120% and 150% of the diameter of the pulmonary valve annulus, there was a high degree of PR in comparison with when balloon sizes less than 120% were selected. Therefore, in our study, the factors with an impact on pulmonary regurgitation were balloon selection with sizes more than 1.2 the diameter of the pulmonary valve annulus, use of noncompliant high-pressure balloons, and larger right ventricle chambers and annuli. It seems that the prevention of severe PR requires not only the previous balloon-selection methods such as the diameter of the pulmonary valve annulus but also more accurate methods such as balloon selection based on the patient’s body surface area.factors that increase the probability of repeat BPV or surgery—including dysplastic pulmonary valves, pulmonary valve diameter, TV diameter, RV size , balloon size, and type and profile of the balloon.The BPV procedure is now deemed conventional therapy for neonates and infants with PS-IVS. The treatment protocol, however, should be on a patient-by-patient basis because there are a number of factors—including the RV morphology, patient’s general condition, and issues related to the interventional procedure. In our study, the right ventricle indices were abnormal immediately after BPV, but our midterm follow-up demonstrated that the indices had returned to the normal values. Another salient point is that favorable results are dependent on the selection of proper balloons. Undoubtedly, further studies with longer follow-up durations are required to shed sufficient light on the other aspects of the management protocol.we thank the staff and participants in Rajaie Cardiovascular, Medical, and Research Center in pediatric field.None.The study protocol was approved by the Ethics Committee and the Review Board of Iran University of Medical Sciences (IR.RHC.REC.1391.70)we have not any financial support from person, industry and organs.


Background: A novel, fully automated right ventricular (RV) software for three-dimensional quantification of RV volumes and function was developed. The direct comparison of the software performance with cardiac magnetic resonance (CMR) was limited. Therefore, the aim of this study was to test the feasibility, accuracy, and reproducibility of a fully automated RV quantification software against CMR imaging as a reference.Methods: A total of 170 patients who underwent both CMR and three-dimensional echocardiography were enrolled. RV end-diastolic volume (RVEDV), RV end-systolic volume (RVESV), and RV ejection fraction (RVEF) were obtained using fully automated three-dimensional RV quantification software and compared with a CMR reference. For inter-technical agreement, Spearman correlation and Bland–Altman analysis were used.Results: The fully automated RV quantification software was feasible in 149 patients. RVEDV and RVESV were underestimated, and RVEF was overestimated compared with CMR values. RV measurements obtained from the manual editing method correlated better with CMR values than that without manual editing  with less bias and narrower limit of agreement (LOA). The bias and LOA for RV volumes and EF using the automated software without and with manual editing were greater in patients with severely impaired RV function or low frame rate than those with normal and mild impaired RV function, or high frame rate. The fully automated RV three-dimensional measurements were highly reproducible.Conclusion: The novel fully automated RV software shows good feasibility and reproducibility, and the measurements had a high correlation with CMR values. These findings support the routine application of the novel 3D automated RV software in clinical practice. Right ventricular (RV) function has been demonstrated to be independently associated with poor clinical outcomes in patients with a variety of cardiac and pulmonary pathologies , 2. AlthRecently, a new fully automated 3D RV quantification software using machine learning algorithms (MLA) was introduced. Limited studies had validated its accuracy against CMR imaging , 15. HowTherefore, the purposes of this study were (i) to validate the feasibility, accuracy, and reproducibility of the fully automated 3D software for RV volumes and function quantification against CMR imaging in a large population with a wide range of RV function; (ii) to determine the impact of severity of RVEF and FR on the accuracy of the fully automated 3D RV measurements.A total of 170 patients who had undergone both CMR and 3DE examinations with a median of 1 day ) frames/s, for four cardiac cycles with short breath hold. The acquisition quality would be considered inappropriate if endocardial boundary in one segment was not clear in the A4C view. 2D and 3D images were stored for offline study. The stored data set were transferred to a workstation where they were studied and analyzed for RV quantification with the fully automated software. The RV-focused A4C views with clear endocardial border were selected. Five landmarks were ensured in the apical, coronal, and basal short-axis views.The acquisition of a 3DE data set was subjectively assessed to ensure the complete visualization of the endocardial border in 3DE acquisition in three views  . The imaWhen the requested contour adjustment was performed on 2D images in both long- and short-axis views at end diastole, a new speckle tracking dataset was obtained. If the software made an erroneous 3D RV cast, a revision analysis would be performed. The subject would be discarded if the new 3D cast was still erroneous.Results  with manual editing were also obtained through manual adjustment in the end-diastolic frame and end-systolic frame at both long- and short-axis views. These data  were compared with those from CMR for accuracy validation.CMR imaging was performed using a 1.5T scanner  with a phased array of cardiovascular coil. For the identification of the long axis of the heart, retrospective ECG-gated localizing echo spine sequences were used. Steady-state free precession (SSFP) dynamic gradient-echo cine loop was acquired using retrospective ECG gating and parallel imaging technique with 6-mm slice thickness of the imaging plane. The parameters were set as 340 × 255-mm field of view, 256 × 205 scan matrix, and 80° flip angle. The median FR was 32 [IQR (28 to 36)] frames/s with 10- to 15-s breath holds.* 100%).CMR imaging was analyzed with conventional CMR software  by a sophisticated technician who was blinded to echocardiographic findings. Disc summation method of multiple short-axis views was used for the calculation of RVEDV and RVESV. RVEF was calculated through the standard formula , quantified as the absolute differences between the repeated two measurements in percentages of their mean, and intraclass correlation coefficient (ICC).The analysis time for the software in both modes  was measured in 20 patients. For fully automated mode, the time was measured from clicking the analysis button to displaying the results. While for manual editing mode, the analysis time also included tracking revision and endocardial border adjustment in both end-diastolic and end-systolic frames.p < 0.05 was considered to be statistically significant.Continuous variables are presented as mean ± standard deviation (SD), or median and IQR, while categorical variables are presented as frequency (percentage). Shapiro–Wilk test was used to determine whether the data conforms to the normal distribution. Since these data were not normally distributed, the Friedman's analysis with Wilcoxon comparison was used to compare the results among the three groups. Spearman correlation analysis was used to assess the correlation of between variables. Bland–Altman analysis was used for the determination of bias and limit of agreement (LOA). For the agreement of categorization between 3DE with fully automated analysis and CMR, and between 3DE auto edit analysis and CMR, the weighted Kappa statistical analysis was used. Correlation coefficient was compared using MedCalc version 19.0.4  for the RV measurements obtained from the automated software without or with manual editing against CMR imaging as a reference. Data were analyzed using SPSS version 22  and GraphPad prism 8.0 . A two-sided n = 27), good in 50.3% (n = 75), fair in 23.5 % (n = 35), and poor in 8.1% (n = 12). The mean age of the subjects was 46 ± 15 years, and 115 (77.18%) were men. The entire population consisted of 12 (8.05%) healthy subjects and 137 (91.95%) patients. Among the 137 patients, 19 patients were diagnosed with ischemic heart disease, 53 with dilated cardiomyopathy, 18 with heart transplantation recipients, 15 with valvular heart disease, 16 with hypertrophic cardiomyopathy, eight with hypertensive heart disease, three with multiple myeloma, two with perinatal cardiomyopathy and one with uremic cardiomyopathy, one with rheumatic heart disease, and one with viral myocarditis. Forty-eight percent of the patients [dilated cardiomyopathy (n = 52) and ischemic heart disease (n=19)] with end-stage heart failure were included in the waiting list of heart transplantation.The fully automated RV quantification software was feasible in 149 (87.6%) subjects. Clinical characteristics of study subjects are shown in p < 0.0001]. The results were improved with the manual editing method and successfully approximated the RV volumes and RVEF against CMR [RVEF: 35.6 (22.9–45.6)% vs. 34.0 (17.5–44.5)%; RVEDV: 116.9 (88.6–148.9) ml vs. 119.8 (91.1–175.8) ml; RVESV: 73.6 (48.1–113.7) ml vs. 78.1 (51.7–147.7), all p < 0.0001). Strong correlations were observed between RV measurements obtained from 3D Auto RV and CMR . The correlations further improved when we performed manual editing method  in comparison with CMR. RV measurements obtained from the manual editing method correlated better with CMR values than that without manual editing . In addition, RVEF using 3D auto RV software with manual editing had smaller biases and narrower LOAs against CMR values than that of 3D auto RV quantification . A similar trend was also observed in RVEDV and RVESV.The correlation and Bland–Altman analysis for RV volumes and EF using 3D auto RV software with/without manual editing against CMR as a reference are presented in The effects of RV function on RV volumes and EF using 3D auto RV software with/without manual editing compared with CMR measurements are summarized in p < 0.0001).The agreement of categorization  between 3DE with fully automated analysis and CMR, and 3DE with manual edit method and CMR, are presented in When the effect of FR was evaluated, there was no significant impact on the RVEF. However, the biases and LOA for RV volumes were larger in patients with FR ≤ 23 frame/s regardless of whether the manual editing was performed. Additionally, the biases and LOA for RV volumes and RVEF derived from the manual editing method was smaller than those without manual editing irrespective of FR .The intraobserver, interobserver, and test–retest variability of the 3D Auto RV software with and without manual editing method are shown in The median time of analysis for 3D fully automated RV quantification software was 12s (IQR 9–14 s), which is much shorter than that of the manual editing method .The main findings of the present study can be summarized as (i) RV volumes and function using fully automated RV quantification software were strongly correlated with CMR values. (ii) The manual editing method improved measurement accuracy. (iii) The bias and LOAs for the RV volumes and EF using the 3D auto RV software were smaller in patients with normal or mild impaired RV function or FR >23 frame/s than those with severely impaired RV function or FR ≤ 23 frame/s regardless of whether the manual editing was performed. (iv) The fully automated software showed excellent reproducibility and reduced the duration of analysis.3D assessment is required for accurate analysis of the right ventricle due to its irregular shape and complex contract mode . NowadayIn order to overcome the variability caused by manual input, a novel, fully automated RV quantification software using MLA has been developed and validated against CMR. It is reported that the fully automated software showed excellent accuracy and reproducibility compared with CMR. This new software without manual editing worked in one-third of the population. However, manual editing was still required in the rest of the study population . A recenHowever, these two studies were limited by the relatively small number of study subjects , 15; theThe prior results regarding the accuracy of novel 3D automated RV quantification software for RVEF measurement in comparison with CMR are discordant. Genovese et al. demonstrated that RVEF by the 3D automated software was underestimated against CMR imaging , whereasThe degree of RVEF has a great impact on 3D auto RV measurements and is the major factor contributing to the difference in RV quantification against CMR. Our study demonstrated that the biases for RV volumes and EF using the 3D auto method were larger in patients with severely impaired RV function. The biases improved when manual editing was performed. These results are in keeping with the study of Tsang et al. which showed that the biases and LOA for LV volumes using the 3D auto LV quantification software were larger in patients with reduced LVEF . PreviouOur study demonstrated that the 3D auto RV software performed worse in subjects with severely impaired RV function, as evidenced by larger bias and wider LOA. The accuracy become higher when we performed manual editing. Although the 3D auto RV software worked worse in patients with severely decreased RVEF, the 3DE with fully automated analysis also diagnosed that the patient had severely impaired RVEF regardless of whether the values were different.The FR plays an important role in the accuracy of 3D auto RV measurements. Our study revealed that novel 3D auto analysis for RV volumes performed better in high FR (>23 frame/s) than those of low FR ( ≤ 23 frame/s) regardless of whether the manual editing was performed. These findings are similar to those in previous study, which demonstrated that the biases and LOA for LV volumes using the 3D auto LV quantification software were larger in patients with low volume rates . HoweverIn this study, we tested the performance of 3DE auto RV software against CMR for RV quantification. The impressive feature of this software is the more rapid analysis and excellent reproducibly. Nevertheless, our study revealed that 3D auto RV software performed worse in subjects with RV dilation. Moreover, the severe outlier may occur in patients with extremely dilated right ventricle. Therefore, the novel software is needed to learn a large amount of RV contour information with the diverse pathology-related geometric changes to enhance the accuracy in a pathology-dependent way. With future technological improvements and machine learning algorithmic refinements with additional training on larger data sets, the percentage of subjects with accurate fully automated RV measurements without manual edit will rise over time.Although our study population consisted of a large number of patients with a wide range of RV sizes and function, it was still a single-center study with relatively limited sample size, which cannot be generalized to the whole community. Future multicenter studies with larger sample sizes are required to confirm our results. Forty-eight percent of the patients were included in the waiting list of heart transplantation; therefore, our study population cannot reflect the general population. Since both CMR and 3DE investigations were done at different times, there may be real volume discrepancies that limit agreement and trend. In addition, 3DE has lower temporal and spatial resolution than 2DE, which may have effects on RV measurements. Another important limitation is that the evaluated technology may depend on vendors regarding format and availability of images. Therefore, our findings might not be extrapolated to other vendors and software packages. The fully automated RV software may not be appropriate for patients with poor image quality. Hence, the accuracy of this software in individuals with poor image quality cannot be determined. Moreover, 3D full volume technique is strongly dependent on heart rate, so it is challenging in patients with arrhythmia such as atrial fibrillation. Thus, our results are not applicable to patients with irregular rhythms.The novel fully automated 3D software for RV volumes and EF quantification is highly feasible and reproducible. The values measured by novel fully automated RV software were strongly correlated with the CMR measurements in a large number of population with a diverse range of RV sizes and function. These findings support the routine use of the novel 3D auto RV software in daily clinical practice.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Institutional Ethics Board of Union Hospital, Tongji Medical College, Huazhong University of Science and Technology. The patients/participants provided their written informed consent to participate in this study.AA, YML, HL, XJW, and MXX: conception and design of the study. YTZ, YG, MZQ, and YXL: acquisition of data. YTZ, JJL, LXY, and LZ: analysis and interpretation of data. AA, YXL, and HL: drafting the article. AA, YML, HL, and MXX: revising the article. AA, YML, LZ, YG, and MXX: final approval of the article. All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.This work was supported by the National Natural Science Foundation of China (Grant Nos. 81922033 and 81727805), the Fundamental Research Funds for the Central Universities (Grant No. 5003530082), the Key Research and Development Program of Hubei (Grant No. 2020DCD015), and the Shenzhen Science and Technology under Grant (SGDX20190917094601717).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


P < 0.01) with exercise. With exercise, the time constant of LV relaxation shortened in 2, was unchanged in 3, and increased in the remaining patients . LV chamber stiffness constant was abnormally increased in all but 2 patients. Indices of LV systolic properties were normal at rest but failed to augment with exercise. In 15 who agreed to blood draw, inflammation and fibrosis markers were obtained. A significant association was observed between LV EDP and Pro-Col III N-terminal  and IL-1-soluble receptor  levels. HTX have diastolic dysfunction and can develop HFpEF several years after cardiac transplantation. The abnormally increased LV chamber stiffness and the prolongation or lack of shortening of the time constant of LV relaxation with exercise are the underlying reasons behind the observed changes in LV diastolic pressures with exercise.Heart transplant recipients (HTX) have several risk factors for heart failure which can trigger pro-inflammatory and fibrosis factors and set into motion pathophysiologic changes leading to diastolic dysfunction and HFpEF. The objective of the study was to determine if HTX recipients with dyspnea have diastolic dysfunction and HFpEF. Twenty-five HTX were included. LV systolic and diastolic functions were evaluated using conductance catheters to obtain pressure volume loops. LV function was assessed at rest and during moderate intensity exercise of the upper extremities. A significant increase occurred in LV minimal pressure (3.7 ± 3.3 to 6.5 ± 3.5 mmHg) and end diastolic pressure or EDP (11.5 ± 4 to 18 ± 3.8 mmHg, both  Data on long term results are more limited being based on mitral inflow by Doppler echocardiography which has major limitations as an index of left ventricular (LV) diastolic function in HTX recipients4. We hypothesized that HTX recipients can develop diastolic dysfunction and HFpEF. We thus sought to prospectively assess LV systolic and diastolic properties using the invasive gold standard of pressure volume loops in HTX.Heart transplant (HTX) recipients have limited exercise tolerance years after transplantation, despite normal left ventricular (LV) ejection fraction (EF) and normal LV filling pressures at rest. There are few studies early after transplantation including few patients, reporting abnormal LV diastolic pressuresAll HTX recipients ≥ 5 years after surgery  undergoing routine surveillance catheterization were prospectively evaluated over the past 18 months as per the standard practice at our institution. Patients with heparin allergy , history of percutaneous coronary intervention or myocardial infarction after transplantation, significant coronary artery disease at the time of LHC, active bleeding problems, any graft dysfunction defined by LV EF < 50% since transplantation, valvular heart disease (≥ moderate regurgitation), non-sinus rhythm, ESRD on hemodialysis (as arterio-venous communication can cause high output heart failure), and inability or refusal to give informed consent were excluded. None of the patients had mitral or aortic stenosis. Excluded were 5 patients who refused to consent, one with heparin allergy, 5 on hemodialysis, and 5 with CAD. While including patients with CAD and those with previous PCI or graft dysfunction could have resulted in a more representative sample, these are patients who a priori are known to have myocardial disease. The study was approved by The Methodist Hospital Research Institute IRB, and all patients provided informed consent. All methods were performed in accordance with the relevant guidelines and regulations.Access for LHC was obtained from the femoral artery. After calibration, a 7 French 12-electrode conductance catheter  was advanced into the LV by crossing the aortic valve using a stiff 0.18 platinum plus™ wire. The catheter was connected to a dedicated system  that continuously acquired and displayed pressure, volume, first derivative of LV pressure versus time, and ECG signals. Proper positioning of the conductance catheter was guided by fluoroscopy, echocardiography, and confirmed by the segmental volume signals. The catheter was placed along the long axis of the LV with its tip in the apex , preload recruitable stroke work (PRSW), and Starling Contractile Index (SCI) were derived as preload independent indices of LV systolic function. LV passive chamber stiffness (P = AeβV) was evaluated based on the stiffness constant (β), where a value exceeding 0.015 indicates abnormally increased chamber stiffness6. In addition to single beat derived parameters, patient performed Valsalva maneuver and data obtained during preload decrease were used to obtain pressure volume relationship. This approach has been previously validated against balloon occlusion of inferior vena cava7. In addition, stiffness constant was derived by the method of Klotz et al. using single point EDV and EDP8. The upper limits of normal for the latter variable is 6.08 based on normal controls without cardiovascular disease and without cardiovascular risk factors9. Stroke work from the PV loop along with end systolic pressure and ESPVR was used to obtain PV area (PVA) as a reflection of the total mechanical energy with the expression: PVA = stroke work + 0.5 × (end systolic pressure)2/ESPVR10.LV pressures and volumes were analyzed at end-expiration. LV minimal, end diastolic (EDP), and systolic pressures were measured Figs. , 3, 4. L11. The response to this specific exercise in patients without cardiac dyspnea is no change in mean wedge pressure , along with a significant 26% increase in stroke volume11. In comparison patients with HFpEF, develop a significant increase in mean wedge pressure from 11 to 28 mmHg for a similar increase in stroke volume11.Moderate intensity exercise  of upper extremities  was performed with simultaneous recording of LV pressures and volumes by the conductance catheter until patient exhaustion for duration of 5–10 min12. Definitions using exercise data included end expiratory LV EDP > 23 mmHg, based on upper limits of normal LV EDP with exercise being 23 mmHg, given value of mean EDP with exercise in normal subjects at 13 ± 5 mmHg13. The third definition was exercise LVEDP/CO slope > 2 mmHg/Liter per minute14. LVEDP was used in place of mean wedge pressure and mean PA pressure since PA pressures were not obtained during exercise. In addition, the noninvasive score H2FPEFF score was obtained15. This score takes into account age (1 point for age > 60 years), hypertension on ≥ 2 medications (1 point), presence of paroxysmal or persistent atrial fibrillation (3 points), BMI > 30 kg/m2 (2 points), pulmonary artery systolic pressure by Doppler echocardiography > 35 mmHg (1 point), and E/e′ ratio by echocardiography > 9 (1 point).Three definitions of HFpEF based on invasive date were evaluated. These included measurements at rest of LV EDP > 16 mmHg or τ > 48 ms16. Duration of diastole was obtained from echocardiographic Doppler recordings as the time interval between aortic valve closure and mitral valve closure. Isovolumetric relaxation time (IVRT), an index of LV relaxation, was measured as the time interval between aortic valve closure and mitral valve opening17. In addition, mitral annulus early diastolic velocity (e′) by tissue Doppler (TD), and LA reservoir strain by speckle tracking were measured as indices of diastolic function and LV filling pressures. LV long axis function was assessed using LV global longitudinal strain (GLS) from the three apical views16.Patients were imaged simultaneously with ultrasound systems equipped with a multifrequency transducer. Parasternal and apical views were acquired and used to measure LV dimensions, wall thickness, and mass, as well as biplane left atrial (LA) volumesThe levels of biomarkers reflecting inflammation, and collagen turnover were measured including: interleukin 1 (IL 1), interleukin 6 (IL 6), tumor necrosis factor alpha (TNF α), C reactive protein (CRP), interleukin 1 receptor type 1 (IL1 R1), growth differentiation factor 15 (GDF-15), procollagen type I N-terminal propeptide , procollagen type I C-terminal propeptide , procollagen type III N-terminal propeptide , matrix metalloproteinase 1 (MMP 1), and tissue inhibitor of metalloproteinase 1 (TIMP-1). Blood samples were obtained at the time of cardiac catheterization from the patients who consented to drawing blood.13, α = 0.05, and power = 0.9. Statistical significance was defined by P < 0.05.Data are shown as mean ± SD or median with interquartile range (IQR) based on whether they had normal distribution. Categorical data are shown in numbers and percentages. Comparisons between rest and exercise were performed with a 2-tailed paired student t-test or Wilcoxon signed-rank test. Linear regression was used to study relation between biomarkers and diastolic function. Sample size was based on a projected 5 mmHg EDP increment with exercise, SD = 5 mmHgA total of 25 patients were included in the study with a median of 8 years since cardiac transplantation and more than 3 years since the last rejection episode. The reasons for cardiac transplantation were amyloidosis in 1 patient, peripartum cardiomyopathy in 1 patient, post infarction severe LV dysfunction leading to HFrEF in 7 patients, and non-ischemic cardiomyopathy in the remaining patients. Data acquisition was possible in all patients recruited. Table LV mass index was normal in all patients, and none had LV hypertrophy, but 22 patients had concentric remodeling . LA maximum volume index was increased in all patients Table , which iNo significant relation was present between the change in e’ velocity and the change in the time constant of LV relaxation with exercise. LA reservoir strain was not significantly associated with LV pre-A pressure or LV EDP.P = 0.04]. Expectedly, both stroke work and PVA increased significantly with exercise , but not between τ and duration of diastole. LV chamber stiffness was abnormally increased and exceeded 0.015 in all but 2 patients. Similar findings were noted using multiple beats to obtain β (0.07 ± 0.02). There was no significant change in LV early diastolic peak filling rate with exercise  and IL-1-soluble receptor  levels.In this exploratory analysis, IL-6 was abnormally elevated in most patients. Pro-Col1 N-terminal was abnormally elevated in all, and TIMP 1 in 10 of 15 patients Table . Baselin12, 7 patients (28%) met the diagnostic criteria of HFpEF. Three of the seven patients had LVEDP > 16 mmHg and τ  > 48 ms, whereas 4 patients met the definition based on τ  > 48 ms. All off these 7 patients also had HFpEF based on exercise LVEDP/CO slope > 2 mmHg/Liter per minute14. In addition, 10 additional patients met the definition based only on exercise LVEDP/CO slope > 2 mmHg/Liter per minute. Therefore, a total of 17 of the 25 patients (68%) met HFpEF definition based on exercise LVEDP/CO > 2 mmHg/ Liter per minute. Patients who met this definition of heart failure were older, had a higher prevalence of diabetes mellitus, and a longer time since cardiac transplantation but these trends did not reach statistical significance level (P > 0.05). The severity and number of rejection episodes, and donor age were not significantly related to hemodynamic measurements. For LV EDP > 23 mmHg with exercise, 8 patients (32%) met the definition of HFpEF.Based on hemodynamic measurements at rest of LV EDP and/or τBNP was < 100 pg/mL in all 7 patients who met HFpEF definition based on hemodynamics measured at rest. It was elevated in only 3 of the 17 patients (18%) with exercise LVEDP/CO slope > 2 mmHg/Liter per minute, and 3 of the 8 patients (38%) with exercise LV EDP > 23 mmHg.2FPEF score, the mean was 2 and the median score was 2 (range 0 to 6). There were 3 patients with a score of 3, and 3 patients with score of 4 which denote approximately 50–70% probability of having HFpEF. Only one patient had a score of 6 which denotes a 90% probability of having HFpEF. The remaining patients had 0–2 score indicating low probability for HFpEF.For H19. In contrast, patients in this study developed a significant increase in LV diastolic pressures with dyspnea despite low workload and very modest rise in heart rate that led to exercise termination. The lack of increase in LV early diastolic filling rate reflects the opposing effects of LV relaxation and filing pressures on filling rate. In addition to abnormal diastolic function, cardiac contractile reserve appears compromised which along with the lack of an increment in peak filling rate precluded the increase in stroke volume with exercise. In this regard, in comparison to non-transplant patients with HFpEF who develop an increase in both wedge pressure and stroke volume with the exercise protocol used in this study11, the transplant population has two disadvantages: the abnormal diastolic function response to exercise and the lack of an increase in LV stroke volume. Interestingly, the exploratory analysis with biomarkers showed abnormal levels of interleukin-6 and TIMP-1 in several patients, suggesting they could serve as potential markers of the disease.The normal response to exercise is τ shortening and increase in LV filling rate to maintain adequate LV filling and to increase exercise stroke volume, as diastole duration is shortened with exercise. Importantly, LA pressure does not exceed the upper limits of normal rest pressure in healthy subjects, except at very high cardiac output, allowing normal subjects to exercise without increased filling pressure20. Despite transplantation, many patients have symptoms several years after surgery including exertional dyspnea and fatigue21. Some of these patients have reduced LV EF, but there is a paucity of data on their LV diastolic function and whether they have HFpEF. In fact, there are studies attributing the symptomatic status to anemia, chronic kidney disease, pulmonary pathology, and psychiatric reasons22. Aside from activation of inflammation and increased fibrosis, the incomplete sympathetic re-innervation many years after surgery can contribute to the absence of the normal shortening of τ with exercise23. Instead, lengthening of τ with exercise occurred in the majority of patients in this cohort.Heart transplantation is live saving in patients with end stage heart failure24, which supports relying on the stiffness constant (β) cutoff value of 0.0156 to identify patients with increased chamber stiffness. In comparison with invasive measurements, echocardiographic indices of diastolic function did not detect the presence of abnormal LV relaxation or the increased LV chamber stiffness constant. This highlights the need for invasive data to diagnose the presence of diastolic dysfunction and HFpEF in several patients from this population.To our knowledge, this is the first study to comprehensively evaluate LV systolic and diastolic properties in heart transplant recipients using the invasive gold standard of acquiring pressure volume loops with a conductance catheter to study cardiac function. LV stiffness was assessed by several analytic approaches and all methods led to consistent conclusions. Interestingly, the curve fitting constant (A) in this group of patients at 1.3 was very similar to that reported in non-transplant patients with HFpEF at 1.2Heart transplant recipients have several reasons that can lead to HFpEF. These include obesity, hypertension, diabetes, older age of donor heart, chronic allograft vasculopathy, and recurrent rejection episodes causing replacement and interstitial fibrosis. In addition, cytomegalovirus infection is associated with upregulation of MHC on endothelial cells with increased lipid content. The patients in this study had many of the above noted reasons for HFpEF which could serve as potential targets in a treatment regimen as well as in identifying high risk patients with intervention to be carried out before the development of HFpEF.25. Of note, all patients in this study had a CRP level that exceeded the above threshold with a mean increase of 177.5%. In addition to CRP, IL-6 was abnormally elevated in the majority of patients. Likewise, GDF-15 level at 1.6 ng/mL in this series of heart transplant recipients is similar to levels reported in HFpEF patients where the median level was 1.08 ng/mL and exceeded the 0.6 ng/mL level in normal controls26. Further understanding of the mechanisms involved linking these two processes can result in effective therapy not only for longer graft survival but also for prevention of HFpEF.The study draws attention to the potential role of inflammation and fibrosis in the development of HFpEF in this patient population. CRP is a pentameric protein with an established role in systemic inflammation. Previous work showed worse graft survival in patients with CRP > 1.06 mg/L19. In that regard, patients with cardiac transplantation within 5 years would not be suitable controls since they can have myocardial abnormalities related to rejection per se, and our objective was to look at graft function in the absence of rejection at a stage when other factors that influence cardiac function play a role. Adding multivariable regression analysis could have provided additional insights into the main determinants of the hemodynamic findings. This could not be pursued due to the small sample size and collinearity. The wide range of time (6–21 years) between transplantation and inclusion in the study is another limitation.Data were limited to 25 patients due to the invasive approach to generate pressure volume loops and the exclusion criteria, in addition to several patients declining to participate. There was some heterogeneity in the medications used in the study sample which could affect cardiac function. Nevertheless, the hemodynamic findings at baseline and with exercise were not different between patients who were on beta-blockers/calcium channel blockers and those who were not. Exercise testing during cardiac catheterization was not accompanied by measurements of peak oxygen consumption, and thus we could not link the abnormal LV systolic and diastolic function to exercise limitations. We did not evaluate for microvascular disease which is known to affect cardiac function in patients with HFpEF. Myocardial samples could have provided additional insights. However, patients received their transplants ≥ 5 years without concerns for rejection. We could not justify to IRB obtaining cardiac biopsies at time of cardiac catheterization. No control group was included as normal hemodynamic response to exercise is well establishedWhile patients exercised to exhaustion, the increment in heart rate and blood pressure were modest. This may have accounted for the lack of an increase in measurements of LV systolic properties with exercise. Notwithstanding, the question of LV systolic function contribution to exercise limitations, LV diastolic function abnormalities were consistently demonstrated in this group of patients by several analytic methods using data acquired invasively.This study draws attention to the diagnosis of HFpEF in heart transplant recipients. Many of the HFpEF patients in the study would not have been diagnosed without exercise assessment of LV diastolic pressures or invasive indices of LV diastolic function. Accordingly, it is reasonable to consider the invasive measurement of mean wedge pressure and cardiac output or LVEDP with exercise in symptomatic heart transplant recipients with normal LV filling pressures at rest. This could be achieved in a similar approach to what is used in patients with HFpEF using right heart catheterization for measurement of wedge pressure and cardiac output at rest and with graded exercise. Aside from trying to achieve a more satisfactory control of blood pressure, diuretics can be prescribed, and their doses escalated based on the cardiac catheterization results.In addition to the above clinical implications, the findings add to the growing body of evidence linking inflammation and fibrosis to the abnormal cardiac structure and function in HFpEF in a clinical model where the immune system is activated.