Besides determining exercise capacity, right ventricular (RV) function has prognostic value in heart failure and after cardiac surgery. We therefore investigated the impact of PMVR on RV function in patients with severe MR.Percutaneous mitral valve edge-to-edge procedure (PMVR) using the MitraClipp < 0.01 vs. pre), 3 months 42.8%  (p < 0.01 vs. pre); 2D RV GLS (%): pre −12.9% , post −16.0%  (p < 0.01 vs. pre), 3 months −17.2%  (p < 0.01 vs. pre)]. Factors that attenuated RV improvement were larger ventricular volumes, lower LV function, secondary MR, and a higher STS score .Sixty-three patients undergoing PMVR at our department were prospectively enrolled. Transthoracic echocardiography was performed before, early (2–12d) after PMVR and after 3 months, including advanced echocardiographic analyses such as 3D imaging and strain analyses. At baseline, all patients presented with advanced heart failure symptoms. Etiology of MR was more often secondary and, if present, left ventricular (LV) dysfunction was predominantly caused by ischemic cardiomyopathy. PMVR substantially reduced MR to a grade ≤ 2 in most patients. Echocardiographic assessment revealed a largely unchanged LV systolic function early after PMVR, while in contrast RV function substantially improved after PMVR , post 40.0%  (By using advanced echocardiographic parameters, we discovered an early improvement of RV function after PMVR that is preserved for months, independent from changes in LV function. Improvement of RV function was less pronounced in patients presenting with an advanced stage of heart failure and a higher burden of comorbidities reflected by the STS score. Accoara, CA) . Parametara, CA) .® procedure (Right ventricular (RV) function was shown to determine exercise capacity and to possess prognostic value for heart failure and in cardiac surgery outcome –12. Due rocedure –26. Beyorocedure , 28. Howrocedure . Due to rocedure .We therefore sought to provide further insight on the influence of PMVR on ventricular function using more advanced echocardiographic methods such as 3D echocardiography and myocardial strain analysis in addition to standard 2D echocardiography in a real-world setting.® system at our department. In advance patients were assessed clinical, by transthoracic as well as transoesophageal echocardiography to evaluate MR severity along with mitral valve (MV) morphology. Coronary angiography was performed in all patients to exclude relevant coronary artery disease requiring revascularization. Patients were referred for PMVR by an interdisciplinary team of interventional cardiologists, cardiac imagine experts, cardiac surgeons, and cardiac anesthesiologists based on current guidelines and MV anatomy.The study protocol is in accordance with the ethical guidelines of the 1975 declaration of Helsinki and approved by the local ethic committee of Hannover Medical School (#3047-2016). All patients gave written informed consent to participate in this study. We prospectively studied consecutive patients suffering from severe MR undergoing elective PMVR using the MitraClipPatients' characteristics concerning general traits, comorbidities and laboratory values were obtained from medical records. PMVR was performed under general anesthesia and fluoroscopic as well as transoesophageal echocardiographic guidance, as described earlier . PreexisSixty-three patients were initially included in the study. One patient withdrew consent for the study and one for the PMVR procedure. Fourteen patients did not attend the follow-up visit in our outpatient clinic 3 months after PMVR. During the first year, five patients deceased, while one withdrew consent for the study. Five patients were lost to follow up after 1 year, but eight patients, who did not attend the outpatient clinic for their 3 months follow-up visit, could be interviewed by phone 1 year after PMVR.Transthoracic echocardiography using a PHILIPS EPIQ7 ultrasound machine equipped with a X5-1 transducer  was performed before and early after PMVR (2–12d) as well as 3 months after PMVR during routine follow-up in the outpatient clinic. Severity of MR was graded following the technique defined by Foster et al. . Images 2 test. Comparison of quantitative variables between groups were performed using the Mann-Whitney-U-Test. Changes of dependent variables over time were analyzed using a variance analysis by the Friedman method followed by Wilcoxon test in the case of significant results. P values were corrected for multiple testing by the Bonferroni method. Cochran's Q test was used for comparison of dependent dichotomous variables. Univariable logistic regression analysis was performed to assess predictors for RV improvement after PMVR. Multivariate analysis was not performed due to the limited number of patients in the subgroups. P values <0.05 were considered statistically significant. Statistical analyses were done using IBM SPSS Statistics 26 .All results are presented as median with interquartile range (IQR) or mean with standard deviation. Qualitative variables were compared using the chiMost patients presented with secondary etiology of MR . Median p = 0.457). Heart failure burden, evaluated by NYHA functional class, improved at 3 months, with more than one third still being NYHA I or NYHA II after 12 months (Three months after PMVR MR was reduced and most patients (58.5%) presented with a MR grade ≤ 2 . No sign2 months . During Echocardiographic assessment showed only a temporary trend for a decrease in LV function (3D LVEF) early after PMVR . There wIn contrast, various RV function parameters revealed a significant improvement in RV function early after PMVR that was sustained at 3 months follow-up . 3D RVEFWhen considering different subpopulations effects on RV function seem to be more pronounced in patients suffering from primary MR. Comparing other subgroups , retrieved no significant differences in short term changes of RV function .n = 36) were divided into tertiles depending on improvement of 3D RVEF. Being in the lowest tertile (change of <5.2% RVEF) was defined as lack of RV improvement. Patients without relevant improvement of RV function had higher Society of Thoracic Surgeons (STS) scores, more frequently secondary MR, lower LV function  and higher LV volumes, and higher RV diastolic volume with reduced longitudinal function (RV GLS). Neither pulmonary artery pressures and the pulmonary vascular resistance before PMVR nor the transmitral gradient after PMVR were shown to be different between the two groups. In summary, respective patients presented with a more advanced stage of disease  This improvement is independent from changes in LV function. (3) The improvement seems to be less pronounced in patients suffering from more advanced heart disease, i.e., higher RV and LV volumes and reduced LV function and secondary MR. (4) Advanced echocardiographic methods like 3D imaging and strain analyses are superior to the standard parameter TAPSE in detecting changes in RV function.The main findings of our study are: (1) RV function improves early after PMVR using the MitraClipLV function showed a transient marginal significant  decrease early after PMVR. This decline was more prominent in patients with preserved or mildly reduced LVEF (>40%) due to Frank-Starling-mechanism in a volume overload state before PMVR. By reducing MR pressure load is increased, followed by a decline in EF and stroke volume. However, due to reduced volume overload EF ameliorated within the first months after PMVR. Recently, another study found similar long-term results regarding the LV in a group of patients undergoing PMVR . RegardiThe occurrence or presence of reduced RV function has repeatedly been associated with a worsening of patients' prognosis –39. For In our study improved RV function could be detected using advanced echocardiographic methods, while TAPSE, in turn did not reveal any significant changes. This partly is in line with earlier reports indicating TAPSE to be a less reliable parameter of RV function compared with advanced echocardiographic methods like 3D EF, RV FAC, GLS and free wall strain. However, some reports state significant changes in RV function after PVMR even measured using TAPSE , 42, 43,The main limitation of the study is the small sample size that limits the explanatory power of subgroup analyses. Therefore, analyses of subpopulations need to be considered with precaution and require verification in a larger patient cohort. Moreover, a relevant number of patients was lost to follow up and did not attend their appointments in our outpatient clinics for the scheduled echocardiographic examination reflecting a real-world scenario. Furthermore, the follow up period was relatively short regarding ventricular remodeling. However, changes in RV parameters could be seen very early after PMVR, which suggests that long-term follow-up in this regard is neglectable. Finally, the data only derive from one center.However, we still believe that the presented data are of significant novelty especially concerning the very early change of RV parameters and the use of advanced echocardiographic methods in the evaluation of RV function.In summary, we could identify an improvement of RV function early after PMVR which is preserved or even pronounced at 3 months and independent from changes in LV function. Factors that reduce the potential of RV recovery after PMVR included higher LV volumes and lower LV systolic function, higher RV diastolic volume and more severely reduced RV GLS, secondary MR and a higher STS score. Our data reveal that advanced echocardiographic methods should be implemented in daily routine for evaluation of RV function since the widely used TAPSE seems to be less sensitive in reflecting RV dysfunction and its improvement and should be interpreted with caution. Further studies are needed to elucidate a threshold of LV and RV impairment beyond patients do not profit from PMVR.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by the local Ethics Committee of Hannover Medical School (#3047-2016). The patients/participants provided their written informed consent to participate in this study.JN, JB, JW, and DB: substantial contributions to the conception or design of the work. JN, HB, MO, J-TS, UB, and DB: the acquisition, analysis, and interpretation of data for the work. JN and DB: drafting the work. HB, MO, J-TS, UB, JB, and JW: revising it critically for important intellectual content. JN, HB, MO, J-TS, UB, JB, JW, and DB: provide approval for publication of the content and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All authors contributed to the article and approved the submitted version.JN received travel support for congresses from Orion Pharma, not related to this manuscript. J-TS received travel support for congresses from Abiomed. No conflict of Interest regarding this submission. JB received honoraria for lectures/consulting from Novartis, Vifor, Bayer, Servier, Abiomed, Pfizer, Boehringer Ingelheim, AstraZeneca, Cardior, Daichii Sankyo, CVRx, BMS, MSD, Amgen, Corvia, not related to this article, and research support for the department from Zoll, CVRx, Vifor, Abiomed, not related to this article. JW is a consultant for Biosensor/NVT and Medtronic and reports personal fees from Edwards, Daiichi Sankyo, Biotronik, Volcano/Philips all outside the submitted work. DB received honoraria or travel support from Abbott, Bayer, Biotronik, Boehringer Ingelheim, Daiichi Sankyo, Novartis, and Orion Pharma, and research support from CVRx, Novartis, and Zoll, all not related to this manuscript. The remaining 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.


In repaired tetralogy of Fallot (rTOF), abnormal left ventricular (LV) rotational mechanics are associated with adverse clinical outcomes. We performed a comprehensive analysis of LV rotational mechanics in rTOF patients using cardiac magnetic resonance (CMR) prior to and following surgical pulmonary valve replacement (PVR).2 at CMR, and (4) had images suitable for feature tracking analysis. These subjects were matched to healthy age- and sex-matched control subjects. CMR feature tracking analysis was performed on a ventricular short-axis stack of balanced steady-state free precession images. Measurements included LV basal and apical rotation, twist, torsion, peak systolic rates of rotation and torsion, and timing of events. Associations with LV torsion were assessed.In this single center retrospective study, we identified rTOF patients who (1) had both a CMR ≤ 1 year before PVR and ≤ 5 years after PVR, (2) had no other intervening procedure between CMRs, (3) had a body surface area > 1.0 mA total of 60 rTOF patients  and 30 healthy control subjects  were included. Compared with healthy controls, rTOF patients had lower apical and basal rotation, twist, torsion, and systolic rotation rates, and these parameters peaked earlier in systole. The only parameters that were correlated with LV torsion were right ventricular (RV) end-systolic volume  and RV ejection fraction . At a median of 1.0 year (IQR 0.5–1.7) following PVR, there was no significant change in LV rotational parameters versus pre-PVR despite reductions in RV volumes, RV mass, pulmonary regurgitation, and RV outflow tract obstruction.In this comprehensive study of CMR-derived LV rotational mechanics in rTOF patients, rotation, twist, and torsion were diminished compared to controls and did not improve at a median of 1 year after PVR despite favorable RV remodeling.The online version contains supplementary material available at 10.1186/s12968-021-00750-3. Patients undergoing surgical repair of tetralogy of Fallot (rTOF) have excellent short-term survival –3; howevAbnormal left ventricular (LV) function, however, is also seen in rTOF patients and is associated with adverse events , 13–17. Therefore, we used cardiovascular magnetic resonance imaging (CMR) to perform a detailed analysis of LV rotational mechanics in rTOF patients before and after surgical PVR. A more thorough understanding of LV dysfunction and the effects of PVR on LV myocardial mechanics may lead to improved indications and outcomes for the procedure.2 at the time of the first CMR, and (5) had CMR images suitable for feature tracking (FT) analysis. Patients with TOF-PR physiology were defined as having a PR fraction > 40% and a right ventricular (RV) outflow tract (RVOT) peak gradient by echocardiography ≤ 25 mm Hg and patients with TOF-RVOTO physiology were defined as having a PR fraction ≤ 30% and a RVOT peak gradient or TR peak gradient ≥ 40 mm Hg by echocardiography. Similar grouping criteria for rTOF patients have been used in prior publications [2 to avoid including a large range of heart sizes which could produce a confounding effect on torsion metrics and to analyze a cohort of patients undergoing PVR at the most common time-in late childhood and adulthood. Age and sex matched controls were identified who had a CMR at Boston Children’s Hospital interpreted as normal, and who had no systemic or genetic disease with cardiovascular impact. A statistical power analysis was performed for sample size estimation based on preliminary data showing that the standard deviation of the change in torsion after PVR was 0.44 deg/cm. Using a two-sided, α = 0.05 level one-sample test of the null hypothesis that the mean absolute change in torsion was 0, the projected sample size required to detect a mean change in torsion as small as 0.22 deg/cm  with 80% power was 32 patients. Given that the standard deviation was based on preliminary data and in order to ensure adequate power, we aimed to have 60 rTOF subjects. These 60 subjects were randomly selected from patients meeting the inclusion criteria. We matched the rTOF subjects with 30 controls, a 2:1 matching strategy driven by the limited availability of age and sex matched control subjects who had undergone a CMR using the same technique as the rTOF subjects.In this single center study, rTOF subjects were retrospectively identified who met the following inclusion criteria: (1) had a CMR both ≤ 1 year before surgical PVR and ≤ 5 years after surgical PVR performed at Boston Children’s Hospital since January 1, 2002, (2) had no other intervening cardiac procedure between CMRs, (3) had predominantly volume loading (TOF-PR) or pressure loading (TOF-RVOTO) physiology at the time of PVR, (4) had a body surface area (BSA) > 1.0 mications –34. ThesFor the rTOF subjects, data were abstracted from the medical record and included age at initial TOF repair, type of TOF repair, total number of cardiac surgeries, age at PVR, total number of PVRs, age at CMR, electrocardiographic (ECG) QRS duration at the time of CMR, and the results of echocardiograms performed within 12 months of each CMR. The Committee for Clinical Investigation at Boston Children’s Hospital approved this study and waived the requirement for informed consent.The CMR protocol used for patients with rTOF has been previously published . BrieflyLV rotational mechanics were measured by performing FT analysis on the short-axis bSSFP cine images using commercially available software . FT is an image processing technology that quantifies myocardial tissue deformation . LV endoData are presented as mean ± standard deviation or median with interquartile range (IQR) as appropriate for continuous variables and as frequency (percentage) for categorical variables. A Student’s t-test was performed for mean comparisons between the rTOF and healthy control groups and between the rTOF patients with differing physiology. A Fisher exact test was performed for comparisons of categorical variables. Analysis of variance (ANOVA) was conducted for mean comparisons among 3 groups. If there was a significant 3-group difference, the p-value was adjusted for pairwise comparisons using the Tukey adjustment for multiple comparisons. The Benjamini–Hochberg false discovery rate method was applied to the total set of statistical tests performed for this study. A two-sided one sample t-test was used to assess whether the mean change in CMR and echocardiographic parameters between the first and second CMR was different from 0. The Pearson correlation coefficient was used to assess the correlation of clinical measures with peak torsion. Intra- and interobserver reproducibility were evaluated by estimation of the intraclass correlation coefficient (ICC). A p-value of ≤ 0.05 was considered statistically significant. Statistical analyses were performed using SAS  and R .There were 60 rTOF patients  and 30 controls . Their demographic and clinical information are presented in Table The conventional CMR and echocardiographic parameters for the rTOF patients and the healthy controls are presented in Table The rotational mechanics from the CMR FT analysis for the rTOF patients and healthy controls are presented in Table In the rTOF patients, nearly all of the LV rotational parameters had no significant change following PVR (Table Two subgroups of rTOF patients were compared: patients with predominantly volume-loaded physiology (TOF-PR) (n = 38) and patients with predominantly pressure-loaded physiology (TOF-RVOTO) (n = 22) at the time of PVR , between the 18 patients with a staged repair and the 42 patients with a primary complete repair , or between the 31 patients repaired before 1990 and the 29 patients repaired in or after 1990 .The intra- and interobserver reproducibility (n = 15) for peak systolic torsion as measured by the ICC were good  and moderate , respectively.Table In this comprehensive analysis of CMR-derived LV rotational mechanics in rTOF patients before and after surgical PVR, we found that compared to heathy control patients, rTOF patients had lower apical and basal rotation, twist, torsion, and systolic rotation rates. Nearly half of the rTOF patients demonstrated reversed basal and/or apical rotation. Among a variety of clinical, CMR, and echocardiographic parameters, torsion correlated only with RVESVI and with RVEF. At a median of 1 year after PVR, despite reductions in RV volumes, RV mass, PR, and RVOT obstruction, there was no improvement in peak apical or basal rotation, twist, torsion, or rotation rates. The overall finding of reduced torsion and twist pre-PVR with minimal change post-PVR was also seen in both the predominantly volume-loaded subgroup and the predominantly pressure-loaded subgroup. These findings provide detailed insight into the impaired LV rotation mechanics in rTOF patients.Impaired LV function has been shown to be an important predictor of adverse clinical outcome in rTOF , 14; howIt has been proposed that the LV rotational abnormalities in rTOF are related to unfavorable ventricular-ventricular interactions , 42–44. Our findings support and expand upon a small number of previously published works, mostly using speckle-tracking echocardiography –31, 47 aThere have also been a few studies that have similarly shown that various rotational parameters do not significantly change after PVR , 25, 50.Other CMR methods have been used to assess LV rotational mechanics in rTOF patients. A recent study using tissue phase mapping found altered twist function in 47 rTOF patients with preserved LVEF . SimilarOur study has several limitations. As no difference in torsion was found following PVR, an analysis of statistical power is of interest. Using the observed (rather than preliminary estimate) standard deviation of the mean change in torsion following PVR (0.84 deg/cm), with 60 patients, there was 80% power to detect a mean change of 0.3 deg/cm in torsion using a two-sided 0.05 level test. Differences less than 0.3 deg/cm seem unlikely to be clinically significant. Our study included only patients who had undergone surgical PVR; the impact of transcatheter PVR on rotational parameters was not assessed. Post-PVR assessment was performed at a median of 1 year. At this point, there were significant reductions in RV volumes, RV mass, PR, and RVOT obstruction. It is possible that with longer follow-up the remodeling process would continue and lead to beneficial changes in LV rotational parameters. However, with time, bioprosthetic pulmonary valve function will deteriorate leading to RV adverse remodeling . HallberLV rotation, twist, and torsion in rTOF patients are diminished compared to healthy controls and do not improve at a median of 1 year after PVR despite significant reductions in RV volumes, RV mass, PR, and RVOT obstruction. These findings suggest that factors other than pulmonary valve dysfunction and its sequelae may contribute to LV dysfunction. Additional research is needed to better understand the mechanism of LV rotational abnormalities in rTOF patients and to evaluate whether serial assessment of these parameters can impact prognosis and management decisions.Additional file 1: Table S1. Left ventricular rotational rates and timing of events. Table S2. Left ventricular rotational rates and timing of events in repaired tetralogy of Fallot subgroups.


Arteriovenous fistula (AVF) is the preferred type of vascular access for maintenance haemodialysis but it may contribute to maladaptive cardiovascular remodelling. We studied the effect of AVF creation on cardiac structure and function in patients with chronic kidney disease (CKD). In this prospective cohort study patients with CKD listed for first AVF creation underwent cardiac magnetic resonance (CMR) imaging at baseline and at 6 weeks. All participants had ultrasound measurements of fistula blood flow at 6 weeks. The primary outcome was the change in left ventricular (LV) mass. Secondary outcomes included changes in LV volumes, LV ejection fraction, cardiac output, LV global longitudinal strain and N-terminal-pro B-type natriuretic peptide (NT-proBNP). A total of 55 participants were enrolled, of whom 40 (mean age 59 years) had AVF creation and completed both scans. On the second CMR scan, a mean increase of 7.4 g  was observed in LV mass. Significant increases in LV end-diastolic volumes (p = 0.04) and cardiac output (p = 0.02) were also seen after AVF creation. No significant changes were observed in LV end-systolic volumes, LV ejection fraction, NT-proBNP and LV global longitudinal strain. In participants with fistula blood flows ≥ 600 mL/min (n = 22) the mean increase in LV mass was 15.5 g (95% CI 7.3–23.8) compared with a small decrease of 2.5 g (95% CI − 10.6 to 5.6) in participants with blood flows < 600 mL/min (n = 18). Creation of AVF for haemodialysis resulted in a significant increase of LV myocardial mass within weeks after surgery, which was proportional to the fistula flow. Creation of an AVF establishes a shunt from the arterial to the venous circulation, and exposes the low pressure, high capacitance venous system to the high pressure, low capacitance arterial system. Immediately following creation, there is an associated increase in cardiac output and a decrease in subendocardial perfusion as a consequence of reduced systemic vascular resistance, increased myocardial contractility, and an increase in stroke volume and heart rate4. Over the following weeks, circulating blood volume increases in conjunction with increases in atrial and brain natriuretic peptides5. As the fistula increases in size and blood flow, there are further increases in left ventricular (LV) filling pressure and subsequent changes on atrial and ventricular chamber dimensions and function6. The physiological consequences may even progress till there is myocardial decompensation, left ventricle dilatation, and a decline in ejection fraction, eventually leading to LV hypertrophy (LVH) or heart failure7. All these changes are additive to underlying pre-existing LVH, dilatation, and dysfunction caused by progressive uraemic cardiomyopathy and may be associated with adverse outcomes in dialysis patients6.Establishment of a functioning arteriovenous fistula (AVF) has been the mainstay of haemodialysis (HD) treatment due to its durability, delivery of adequate solute clearance and low risk of infection. However, creation of an AVF is not benign and may have deleterious effects on cardiac structure and function8. In the haemodialysis population, a study of adults with no history of congestive heart failure found that each 1 g/m2 increment in LV mass index was associated with a 62% increased risk of fatal and non-fatal cardiovascular events9. Despite its detrimental effects when present, the impact of LVH regression on mortality remains uncertain. An elegant multifactorial interventional study by London et al. has demonstrated that a 10% decrease in LV mass translated into a 28% decrease in cardiovascular mortality over a 5-year period10. Foley et al. found that improvements in LV mass over a 1-year period after the initiation of dialysis were associated with a reduced likelihood of cardiac failure but notably not with mortality risk11. Patients particularly susceptible to these effects are the ones with pre-existing heart disease and high flow fistulas. Fistulas with flows exceeding 2 L/min and upper arm fistulas are traditionally at increased risk for the development of heart failure14.Maladaptive cardiac remodelling and, in particular, increased LV mass is an independent predictor of adverse cardiovascular events in CKD and has been used as a surrogate end point.15 showed a mean increase of 13% in LV mass, 21% in LV end-systolic volumes, and 25% in cardiac output 6 months after AVF creation.The effects of AVF creation on functional and structural cardiac parameters have been previously studied. Using cardiac magnetic resonance (CMR) imaging in 24 patients with CKD stage 5 undergoing fistula creation, Dundon et al16. Parallel to the vascular remodelling in the fistula arm, creation of a non-physiologic shunt initiates the cascade of haemodynamic changes in the heart muscle, thus, perhaps structural changes and LVH develop quickly despite the widely held belief that changes evolve gradually. Data show that the mean brachial artery flow increases from 56 mL/min before to 365 mL/min 1 day after and to 720 mL/min 28 days after AVF creation17 and cardiac output increases by 15% in 14 days1.Typically, arteriovenous fistulas attain 40–60% of maximum blood flow within 1 day of creation, and reach their maximum flow as early as 6 weeks after creationThe aims of this study were two-fold: (i) to investigate myocardial changes early after AVF creation and (ii) to determine whether myocardial changes are proportional to the AVF blood flow. To address these questions, a prospective study using CMR imaging to evaluate changes on cardiac structure and function 6 weeks after AVF surgery in patients with advanced CKD was performed.From December 2, 2016, to August 20, 2018, 252 participants were screened and 55 were enrolled Fig. . Of the The baseline characteristics of the study participants are shown in Table 2  was found.The primary end point showed a mean increase of 7.4 g  in LV mass. To adjust for body surface area, change in LV mass index was also calculated. An increase of 5.1 g/m2 (95% CI 5.2–14.0) in the higher flow group compared with a small decrease of 0.3 g/m2 (95% CI − 5.2 to 4.6) in the lower flow group  compared with a small decrease of 2.5 g (95% CI − 10.6 to 5.6) in the lower flow group . There was a substantial increase in LV mass observed on the second CMR scan after an average time of 6.3 weeks from AVF surgery. The effect was proportional to the brachial artery flow rate, with a 10.2% increase in LV mass in participants with flows exceeding 600 mL/min compared with a small decrease in those with lower blood flows. To the best of our knowledge this is the first study demonstrating such early changes in LV mass, and linking the early AVF flow to the change in LV mass.18. In another prospective echocardiographic study of 47 patients, LV mass increased by 12.2 ± 32% one year post-AV access creation19. With AVF creation, we observed a 4.8% increase in LV mass, 6.1% increase in LV end-diastolic volume, 8.7% increase in LA volume and 8.7% increase in cardiac output. In patients with fistula flows ≥ 600 mL/min, the increases were 10.2%, 8.7%, 14.7% and 13.9%, respectively, and there was also an increase in NT-proBNP levels. Linear regression analysis showed that increase in the LV mass and LV mass index was more pronounced in subjects with lower LV mass at baseline, and in the higher flow group, increase in LV mass was demonstrated in all except 2 subjects. There are no previous studies examining the cardiac changes shortly after AVF creation for comparisons of our findings.Arteriovenous fistula surgery is associated with adaptive cardiac remodelling necessary to accommodate the increase in cardiac output sufficient to service the fistula, whilst maintaining systemic blood supply. In a prospective study of 43 pre-dialysis patients, AVF formation resulted in a sustained reduction in arterial stiffness and blood pressure as well as an increase in cardiac output and LV ejection fraction using echocardiography17. Upper arm fistulas tend to have the highest blood flow rates and in fact, access flow has been shown to be up to twice as high in upper compared with forearm fistulas16. Consequently, the incidence of heart failure has been shown to be much higher in patients with a brachiocephalic compared to those with a radiocephalic AVF (40 vs 8%)12. In this study, 67% of the upper arm fistulas had flow rates exceeding 600 mL/min compared with 38% of the forearm fistulas and regression analysis showed that increases in the LV mass expectedly were proportional to the brachial artery flow.The typical blood flow in the brachial artery is approximately 50 mL/min, which rapidly increases 10- to 20-folds after the fistula is created21. They are thought to be secreted in greater quantities in response to increases in myocardial wall stretch22. Population-based studies suggest that plasma levels of brain natriuretic peptide and NT-proBNP are useful screening tests for heart failure and asymptomatic LV dysfunction23. In a short-term prospective study of 16 CKD patients both atrial natriuretic peptide (ANP) and BNP levels were maximally increased  10 days after AVF creation1. In another prospective study of 47 patients, plasma NT-proBNP levels increased by 170 ± 465% one year post-AV access creation19. The cardiac structural changes coupled with a rise in validated biomarkers of cardiac remodelling, such as NT-proBNP, suggest that observed changes could translate into clinical outcomes. To this end, the significant increases in LV and LA volumes in keeping with a rise in NT-proBNP in the higher flow AVF group may add important prognostic information. In addition, the minimal changes in LV mass, chamber volumes and NT-proBNP in the lower flow group are physiologically plausible and further strengthen our findings.Brain natriuretic peptide and its inactive N-terminal fragment have been studied extensively in patients with advanced CKD, and both markers have been shown to be strong predictors of cardiovascular morbidity and mortality24, with a preferential reduction in diastolic blood pressure25. It is assumed that the reduction in diastolic blood pressure may have been related to changes in arterial compliance and drop in systemic vascular resistance resulting from the complex effects of the fistula-related haemodynamic changes. A decrease in diastolic but no significant change in systolic blood pressure was seen in this study cohort. However, this study was powered to observe the change in CMR-derived LV mass and was not specifically powered to study the changes in blood pressure.A recent meta-analysis of 14 studies showed that creation of AVF leads to modest but significant decreases in blood pressure in patients with advanced CKD26 or systolic dysfunction and if so over what time period. Or whether they normalise with dialysis.We have demonstrated that AVF creation may increase CMR-derived LV mass in patients with advanced CKD, particularly if ‘high flow’. Because of the short interval between the scans (median 8.3 weeks), the increase in LV mass observed is unlikely to be resulting from worsening of uraemia, plasma volume overload or changes in haematocrit and in fact serum creatinine, body weight and haematocrit did not change significantly between the scans. These results demonstrate that AVF creation, which is the cornerstone of haemodialysis treatment, has the potential to confer substantial cardiovascular risks in CKD patients, especially the ones with underlying cardiovascular disease. However, alternative vascular access choices have their own limitations. First, grafts are likely to induce similar haemodynamic changes and so may not reduce cardiovascular maladaptation. Second, catheters may have other risks, such as infection, that may result in adverse outcomes. Many unknowns remain, and several of those key questions were beyond the scope of this study. For example, baseline NT-proBNP levels, LV mass and LV mass index were higher in participants with blood flows < 600 mL/min, which is indicative of reduced LV compliance or “diastolic dysfunction”. A plausible alternative explanation of our findings is that cardiac stiffening and poor cardiac remodelling in this group resulted in lower AVF blood flows. Appropriately designed experimental studies are needed to infer causality. Also the long-term implications of the demonstrated changes in LV end-diastolic and LA volumes and BNP are unclear. Further work needs to be done to investigate whether they translate into adverse LV remodellingThe strengths of this study include a prospective consecutive design, use of CMR as cardiac imaging modality, and standardised scanning protocols to limit variability. The study limitations included use of the modified Simpson’s method rather than the short axis stack of cines for estimation of LV parameters. We lack power and follow-up duration to detect clinically significant outcomes, such as cardiovascular events and patient survival. Although the cohort was a single-center experience with relatively small number of participants, our study group is representative of the typical CKD population referred for AVF creation. The right heart was not assessed, but the study was adequately powered to examine LV mass, which was our primary outcome.We have shown that AVF creation is associated with a significant increase in LV myocardial mass, cardiac chamber dimensions and NT-proBNP levels. The changes are more pronounced in higher blood flow arteriovenous fistulas. Although these surrogate markers are strongly associated with cardiovascular outcomes, the impact of AVF creation on clinical and mortality outcomes remains to be proved.http://dx.doi.org/10.36399/gla.pubs.215112) was approved by the institutional review board  and registered with ClinicalTrials.gov (NCT02997046). Written informed consent was obtained from all participants, and the studies were performed according to hospital guidelines for diagnostic procedures.A prospective observational single-centre study was conducted between December 2, 2016, and August 20, 2018. The study protocol  listed for creation of an autogenous forearm or upper arm AVF were eligible for enrollment. Dialysis patients were only included if they were dialysing via a tunnelled catheter and had no prior permanent access. Consecutive patients with CKD who attended the outpatient renal clinics were screened for eligibility. Exclusion criteria were (a) standard contraindications to MRI, (b) frail, elderly or participants with multiple or serious comorbidities, and (c) previous arteriovenous access creation (autogenous or synthetic graft) in either or both arms. All participants had CMR imaging followed by MR angiography with relevance to research questions out with the present studyBaseline CMR imaging was performed  before undergoing AVF creation. Repeat CMR and duplex ultrasound (US) of the fistula arm was conducted 6 weeks after the creation of AVF.28. Brachial artery flows were assessed independently from the other cardiac parameters to ensure blinding. Serum N-terminal-pro B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac Troponin I (hs-cTnI) were measured by immunoassays . Estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation29. Information on the history of diabetes mellitus, hypertension, ischaemic heart disease, and peripheral vascular disease was obtained from the electronic patient records.All scans were performed following a standardised protocol  volume, LV ejection fraction, cardiac output, cardiac index, LV global longitudinal strain, septal thickness, NT-proBNP, and hs-cTnI. Primary and secondary outcomes were also assessed for the blood flow subgroups.15. Based on the increase in LV mass as the primary end point, power calculations (including accounting for a dropout rate of 15%) indicated that 49 subjects would provide a 7% difference in the LV mass from baseline to 6-week CMR with a power of > 80% and a 2-sided α level of 0.05 (online Data Supplement).The sample size was calculated using data from a single-arm pilot study involving CMR imaging prior to and 6 months following fistula creation that demonstrated increases in LV mass with AVF creationDescriptive statistics are expressed as means and standard deviations or medians and interquartile ranges for continuous measures as appropriate, and percentages are reported for categorical variables. We used independent sample t-tests and Pearson’s chi-squared tests to explore differences in baseline characteristics.Independent t-tests were also used to compare the change in LV mass between the first and second scans for the total population and between the 2 groups. Two-sided tests were performed for all analyses, and the level of significance was set at p < 0.05. To estimate pre- versus post-AVF creation differences, the change between initial and subsequent measurements was calculated for each person. The mean change was compared between the 2 groups with an unpaired t-test. For comparisons of non-normally distributed data, Wilcoxon rank-sum and Wilcoxon signed rank tests were used. All statistical analyses were conducted with Stata/SE Statistical Software, version 15.0 .Supplementary Information.


A previously healthy octogenarian presented with new onset heart failure symptoms. Comprehensive multimodality imaging including complete echocardiography with longitudinal strain analysis, cardiac magnetic resonance imaging (cMRI), nuclear medicine pyrophosphate (99-mcTcPYP) scan along with biomarker, monoclonal protein analysis, and fat pad biopsy confirmed diagnosis of transthyretin cardiac amyloidosis. Patient was admitted to cardiology service for further evaluation.An 81-year-old female of Jamaican descent with no prior past medical history or hospitalizations presented to the hospital with complaints of four-week history of dizziness, dyspnea on exertion, and lower extremity edema. She denied angina, productive cough, and neurologic symptoms. She was hypertensive with blood pressure of 147/101 mm Hg, regular heart rate of 94 beats/minute, afebrile with 100% oxygen saturation on room air. The electrocardiogram showed sinus rhythm without acute changes. Chest radiograph revealed cardiomegaly and pulmonary congestion. Chemistry panel was unremarkable with normal renal and hepatic function, with no electrolyte abnormalities. NT-Pro-B-type natriuretic peptide was elevated at 6,000 pg/mL. Troponin T was mildly elevated at (0.07 A 12-lead electrocardiogram (ECG) obtained on presentation revealed normal sinus rhythm, low QRS voltage, poor R-wave progression, and Q waves in anteroseptal leads . TransthRight ventricle was moderately enlarged, and right ventricular systolic function was severely impaired. The PA systolic pressure was estimated to be 40 mmHg based on complete tricuspid regurgitation spectral doppler signal. Diastolic profile was suggestive of restrictive LV filling pattern. There was abnormal global longitudinal (GL) strain with apical longitudinal strain preservation, a pattern suggestive of cardiac amyloidosis (CA) Figures  and 3.To rule out obstructive coronary artery disease, a left heart cardiac catheterization with coronary angiography was performed. This showed angiographically normal coronaries  and an LCardiac MRI was then pursued, which revealed areas of subendocardial delayed gadolinium enhancement within the left ventricle not conforming to a vascular territory. This was also noted throughout the left atrium and along the septal subendocardial surface of the right ventricle . These fIn the setting of monoclonal gammopathy of undetermined significance (MGUS) a nuclear medicine pyrophosphate scan (99mTc-PYP) was performed to distinguish between light chain (AL) amyloidosis and transthyretin (TTR) amyloidosis. 99mTc-PYP scan showed grade 2/3 myocardial radiotracer uptake suggestive of TTR amyloidosis . The heaThe patient presented in New York Heart Association (NYHA) functional Class III. Her heart failure symptoms were managed primarily with intravenous loop diuretics to achieve euvolemia. An attempt was made to start standard guideline directed therapy with beta-blockers and angiotensin converting enzyme inhibitors (ACEI), when diagnosis was in question, but she was unable to tolerate them due to hypotension.With the use of diuretics, her functional status markedly improved, and she was able to return to performing her usual daily activities. Her symptoms improved to NYHA Class II.Amyloidosis is a commonly underdiagnosed cause of cardiomyopathy . The twoATTR results from deposition of misfolded TTR, a protein tetramer that is produced in the liver and deposits as insoluble amyloid in extracellular spaces causing damage to the heart and or peripheral nerves. ATTR CA can be wild-type  or variant  . ATTR-wtATTRv-CA is an autosomal-dominant disease in which gene mutations lead to changes in the protein TTR . The preTo avoid misdiagnosis, genetic testing for the Val122Ile mutation can play a role in identification and treatment for patients as well as their family members. Novel treatments are being developed for amyloidosis (ATTR) subtypes that can slow the progression of cardiomyopathy by working as transthyretin silencers and stabilizers [Clinically significant cardiac involvement in both types of TTR typically presents as a syndrome of heart failure with preserved ejection fraction , abnormaCardiac MRI is another useful imaging modality showing various patterns of late gadolinium enhancement. However, it is unable to distinguish between the AL and TTR subtype .99mTc-DPD) and 99mTc-PYP. 99mTc-DPD scintigraphy is currently the most studied isotope in ATTR-CA and has widespread use among amyloid centers in Europe [99mTc-PYP scanning is more commonly utilized. There has yet to be a direct comparison of the different radiotracers to determine if one has greater specificity in diagnosing ATTR-CA [Nuclear imaging technique with bone-seeking radiotracers have become a diagnostic method for ATTR-CA and is able to distinguish it from AL-CA with high specificity . Differen Europe . It is n ATTR-CA . The exaOur patient was an elderly African American female, presenting de novo with significantly increased ventricular wall thickness and heart failure of uncertain etiology. While keeping more prevalent pathologies in the differential; it is important to consider amyloidosis as a potential etiology in this demographic despite her age, sex, and race. While it is true that ATTR-wt CA appears to be more common in older white men, it has also been shown to be present in up to 50% of elderly women admitted with heart failure in at least one prospective study where 99mTc-PYP imaging was used with high accuracy of detection of ATTR-wt cases . SimilarRegardless of patient's age, TTR genetic testing should be performed in all patients with ATTR-CA since the results have significant implications for family members at risk as mentioned earlier.Our case illustrates the occurrence of advanced biventricular systolic heart failure in an elderly woman with ATTR-CA. Her course had been rather indolent, but this condition can be in fact undiagnosed or underdiagnosed for years as many “subtle” signs can be attributed to the aging process.Her case is unique as this condition typically present with heart failure with preserved ejection fraction (HFpEF). The right ventricle (RV) is usually normal or thickened, especially in the anterior wall, and if the RV is involved, signs of pulmonary hypertension may be observed. In the advanced phases of the disease, biventricular systolic function deteriorates. This has substantial clinical implications, as treatment strategies may become even more limited.Usual guideline directed medical therapy with angiotensin-converting enzyme inhibitors (ACE-I), and beta-blockers for heart failure with reduced EF (HFreF) have not been shown to offer clinical benefit. In fact, most medications have potential to cause harm as they may exacerbate hypotension when amyloid-associated autonomic dysfunction is present or further limits cardiac output due to relatively fixed stroke volumes secondary to restrictive filling . AccuratThis case highlights the different imaging modalities that can be used to diagnose cardiac amyloidosis. Echocardiogram and electrocardiogram findings in conjunction with cardiac MRI can assist with the initial diagnosis when amyloidosis is suspected. Nuclear imaging with 99mTc-PYP can further distinguish between different types of amyloidosis (AL vs. ATTR).Although endomyocardial biopsy is the gold standard diagnostic test, hematology testing, fat pad, genetic testing, and bone marrow biopsies can aid in confirming the diagnosis without putting patients at risk for complications with endomyocardial biopsy. Early detection can lead to an increased number of patients being referred for treatment.


Background: Greater red and processed meat consumption has been linked to adverse cardiovascular outcomes. However, the impact of these exposures on cardiovascular magnetic resonance (CMR) phenotypes has not been adequately studied.Objective: We describe novel associations of meat intake with cardiovascular phenotypes and investigate underlying mechanisms through consideration of a range of covariates.Design: We studied 19,408 UK Biobank participants with CMR data available. Average daily red and processed meat consumption was determined through food frequency questionnaires and expressed as a continuous variable. Oily fish was studied as a comparator, previously associated with favourable cardiac outcomes. We considered associations with conventional CMR indices , novel CMR radiomics features , and arterial compliance measures . We used multivariable linear regression to investigate relationships between meat intake and cardiovascular phenotypes, adjusting for confounders  and potential covariates on the causal pathway .Results: Greater red and processed meat consumption was associated with an unhealthy pattern of biventricular remodelling, worse cardiac function, and poorer arterial compliance. In contrast, greater oily fish consumption was associated with a healthier cardiovascular phenotype and better arterial compliance. There was partial attenuation of associations between red meat and conventional CMR indices with addition of covariates potentially on the causal pathway, indicating a possible mechanistic role for these cardiometabolic morbidities. However, other associations were not altered with inclusion of these covariates, suggesting importance of alternative biological mechanisms underlying these relationships. Radiomics analysis provided deeper phenotyping, demonstrating association of the different dietary habits with distinct ventricular geometry and left ventricular myocardial texture patterns.Conclusions: Greater red and processed meat consumption is associated with impaired cardiovascular health, both in terms of markers of arterial disease and of cardiac structure and function. Cardiometabolic morbidities appeared to have a mechanistic role in the associations of red meat with ventricular phenotypes, but less so for other associations suggesting importance of alternative mechanism for these relationships. Multiple epidemiological studies have demonstrated associations between greater meat consumption and worse cardiovascular outcomes –4. In paIt has been proposed, that these relationships may be mediated through adverse cardiometabolic alterations , 10. MorWe studied novel associations between red and processed meat consumption and measures of cardiovascular structure and function in the UK Biobank, including conventional cardiovascular magnetic resonance (CMR) metrics, novel CMR radiomics features, and measures of arterial compliance. We considered associations between oily fish intake as a comparator previously linked with favourable cardiovascular endpoints . We consThe UK Biobank is a cohort study of over 500,000 participants. Recruitment was between 2006 and 2010 through postal invite of UK residents aged 40–69 years identified through National Health Service (NHS) registers. Individuals who were unable to consent or complete baseline assessment due to illness or discomfort were not recruited. Baseline assessment of participants comprised characterisation of socio-demographics, lifestyle, environmental factors, medical history, and a range of physical measures . The proThis study complies with the Declaration of Helsinki; the work was covered by the ethical approval for UK Biobank studies from the NHS National Research Ethics Service on 17th June 2011 (Ref 11/NW/0382) and extended on 10th May 2016 (Ref 16/NW/0274) with written informed consent obtained from all participants.Dietary intake was assessed using a self-report food frequency questionnaire at the baseline UK Biobank visit. Participants were asked to estimate their weekly intake of a range of food items over the preceding year. We considered beef, pork, lamb/mutton, processed meat, and oily fish consumption . We cons42 post-processing software . Briefly, LV endocardial and epicardial borders were manually contoured in end-diastole and end-systole in the short axis view. The first phase of acquisition was selected as end-diastole. End-systole was defined as the phase with the smallest mid-ventricular LV intra-cavity blood pool as determined by visual inspection. The most basal slice for the LV was selected when at least half of the LV blood pool was surrounded by myocardium. LV papillary muscles were excluded from LV mass. RV endocardial borders were traced in end-diastole and end-systole with volumes below the pulmonary valve plane considered as part of the RV. This ground truth manual analysis dataset was used to develop a fully automated image analysis pipeline with inbuilt quality control, which has been applied to the first 20,000 UK Biobank CMR studies  according to a pre-defined acquisition protocol, which is detailed in a separate publication . Assessm studies . Details studies , 19. ForCMR radiomics is a novel image analysis technique permitting computation of multiple indices of shape and texture . RadiomiAortic distensibility is a measure of local aortic compliance. Lower aortic distensibility indicates poorer vascular health and is a marker of arterial disease . Aortic Arterial stiffness index (ASI) provides an estimate of large artery stiffness derived from a pulse waveform contour . Higher p-values. For ASI, we assessed associations with measures taken at both baseline and imaging visits. We identified significant interval change in ASI from baseline to imaging. Therefore, we also considered “change in ASI” as a separate outcome, expressed using standardised residuals derived from regression of ASI at imaging on ASI at baseline. The average time interval between baseline and imaging assessment was 7.5 years in the CMR set and 8.2 years in the ASI set.Statistical analysis was performed using R Version 3.6.2  and RStun = 144), we performed cluster analysis  were of White ethnic background; Black, Asian, and Other ethnicities made up 0.5%, 1.0%, and 1.5% of the analysis sample, respectively. The cohort was predominantly healthy, with only 5.5%  having a history of pre-existing cardiovascular disease . The rates of cardiometabolic morbidities were also lower than the general population, in line with previous analyses of the UK Biobank  years, 52.1% were women . The maj Biobank , 34. TheGreater consumption of red and processed meat was associated with smaller LV volumes in end-diastole and end-systole, higher LV mass, and lower LV stroke volume . Greater13 radiomics shape features were extracted from each ventricle (LV and RV) in end-diastole and end-systole. Greater oily fish consumption was associated with significantly larger LV volumes, larger cavity dimensions in both the short and long axis, and greater surface area of the LV cavity , 6. InteConsidering these relationships as well as association with lower LV stroke volume, the overall picture suggests that greater red and processed meat intake is associated with of an unhealthy LV phenotype with impaired myocardial contractility. The pattern of associations of cardiac structure and function metrics with greater oily fish intake is distinctly different to that of the meat exposures and, overall, suggestive of a healthy phenotype.The same pattern of associations was observed across the different red meat types in end-diastole and end-systole  and consFirst-order features are histogram-based statistics describing the global distribution of signal intensity values in the defined region and may signify global tissue-level myocardial changes . EighteeRadiomics texture features allow quantification of the pattern of inter-voxel signal intensities. Applied to the LV myocardium, radiomics texture features may provide biologically informative quantifiers about underlying tissue properties. We extracted 72 texture features from the LV myocardium in end-diastole and end-systole . Cluster analysis identified seven inter-correlated groups of features , to whicThere was record of ASI at the baseline, imaging, and at both time points for 167,432 , and poorer arterial compliance . By comparison, greater oily fish consumption was associated with larger LV and RV volumes, better myocardial function (higher LV/RV stroke volume), and better arterial health . There was evidence that cardiometabolic morbidities may have a mechanistic role in the associations of unprocessed red meat with ventricular phenotypes, but less so for other associations suggesting importance of alternative mechanisms for these relationships. Radiomics analysis provided complementary and incremental information demonstrating association of the different dietary habits with distinct overall shape of the ventricles and LV myocardial texture. Greater oily fish consumption was associated with a less elongated LV , whilst greater red and processed meat intake was associated with a more elongated LV. The different dietary habits were also associated with different patterns of associations with signal intensity based radiomics features . Overall, greater red and processed meat intake was associated with lower average global signal intensity and a more homogenous signal intensity pattern both globally and when considering inter-pixel relationships. In contrast, greater oily fish consumption was associated with, on average, a brighter myocardium , with greater range and variation in signal intensities, and greater randomness in the pattern of intensity levels. These findings indicate that meat and fish consumption are associated with different signal intensity patterns at the LV myocardium, suggesting possible differences at the tissue level associated with the different exposures.To the best of our knowledge, the specific impact of red or processed meat intake on CMR imaging phenotypes has not been previously studied. The association between a number of dietary patterns and CMR indices of cardiac structure and function have previously been addressed in two studies of the Multi-Ethnic Study of Atherosclerosis (MESA) cohort. These evaluated long-term effect on CMR measures of LV structure and function of two specific dietary patterns: Mediterranean  and the Existing literature suggests a number of possible explanations for the association between higher red meat consumption and cardiovascular disease. Firstly, these observed effects may be mediated through alterations of the cardiometabolic profile. Greater red and processed meat intake is linked to adverse lipid profiles , higher The large sample and detailed characterisation of participants including CMR scanning and objective measures of arterial health permitted a uniquely comprehensive assessment of the relationship between the various meat exposures and cardiovascular phenotypes with consideration of a range of confounders and mediators. The uniform scanning and analysis procedures presented a high-quality standardised dataset. Common to all nutritional epidemiology research, the measurement and tracking of dietary behaviours is extremely difficult. Our exposures are defined on the basis of a self-report food frequency questionnaire from a single time point, and thus do not account for potential changes in dietary behaviour over time. However, a formal evaluation of the performance of the UKB dietary questionnaire demonstrated good repeatability for the main food groups . FurtherGreater consumption of red and processed meat is associated with poorer cardiovascular health characterised in terms of CMR cardiac structure and function, novel radiomics features, and measures of arterial compliance from CMR and plethysmography. Our findings support previous clinical associations and provide greater insight into potential mechanisms of dietary impact on cardiovascular health.http://www.ukbiobank.ac.uk/register-apply/.The data analysed in this study is subject to the following licences/restrictions: This research was conducted using the UKB resource under access application 2964. UK Biobank will make the data available to all bona fide researchers for all types of health-related research that is in the public interest, without preferential or exclusive access for any persons. All researchers will be subject to the same application process and approval criteria as specified by UK Biobank. For more details on the access procedure, see the UK Biobank website. Requests to access these datasets should be directed to The studies involving human participants were reviewed and approved by NHS National Research Ethics Service (Ref 11/NW/0382). The patients/participants provided their written informed consent to participate in this study.ZR-E, SEP, and NCH conceived the idea and designed the study. CM performed statistical analysis. JC cross-checked and advised on statistical analysis. PG led the radiomics analysis. AJ contributed to the radiomics analysis. KL supervised radiomics analysis. LB provided aortic distensibility measures from automated analysis pipeline. NA provided cardiac measures from automated analysis pipeline. ZR-E wrote the manuscript. All authors read and provided critical appraisal of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The most upregulated were extracellular matrix , cell adhesion  and cytoskeletal proteins  and enzymes of carbohydrate (PKM) or norepinephrine (MAOA) metabolism. Downregulated were MYH6 and FAO enzymes. Therefore, when exposed to identical VO, both ventricles display similar upregulation of stress and metabolic markers. Relatively larger response of ACF RV compared to the LV may be caused by concomitant pulmonary hypertension. No evidence supports RV chamber-specific regulation of protein expression in response to VO.Mechanisms of right ventricular (RV) dysfunction in heart failure (HF) are poorly understood. RV response to volume overload (VO), a common contributing factor to HF, is rarely studied. The goal was to identify interventricular differences in response to chronic VO. Rats underwent aorto-caval fistula (ACF)/sham operation to induce VO. After 24 weeks, RV and left ventricular (LV) functions, gene expression and proteomics were studied. ACF led to biventricular dilatation, systolic dysfunction and hypertrophy affecting relatively more RV. Increased RV afterload contributed to larger RV stroke work increment compared to LV. Both ACF ventricles displayed upregulation of genes of myocardial stress and metabolism. Most proteins reacted to VO in a similar direction in both ventricles, yet the expression changes were more pronounced in RV (p Until recently, right ventricle (RV) received little attention and the mechanisms responsible for RV dysfunction are poorly understood3. RV differs in many aspects from the LV, having different embryonic origin, geometry, wall thickness and operating pressures6. Whether these differences translate into a “RV-specific” response to increased hemodynamic stress is unknown. Such interventricular differences may theoretically represent a target for chamber-specific therapies.Due to current scope of heart failure (HF) epidemics, exploration of new approaches to prevent or stabilize HF is a priority for research. One of important milestones of HF progression is the onset of right ventricular failure due to transition of initially left ventricular disease into biventricular HF with dismal prognosis7. However, the response of RV to chronic volume overload (VO), a common contributing factor to HF, is studied much less8. The most frequent cause of VO of RV is severe tricuspid regurgitation that accompanies all forms of advanced HF9. Chronic VO of RV also occurs in patients with congenital heart disease10 or after implantation of left-ventricular assist device12. Therefore, chronic VO of RV is common, yet understudied condition.RV dysfunction can develop due to pressure overload resulting from pulmonary hypertension and this scenario is often investigated17. It is unclear whether RV response fundamentally differs from LV response to excessive VO. Function of ventricles exposed to VO is influenced by altered loading and geometry, so only load-independent assessment by simultaneous invasive pressure–volume analysis can provide insight into chamber-specific responses to VO. Advantageous model to study interventricular differences in stress response is chronic infrarenal aorto-caval fistula (ACF), a condition that imposes identical VO both on the left and the right heart, leading to biventricular cardiac hypertrophy, dilatation, dysfunction and symptomatic heart failure19.Few studies examined molecular mechanisms of volume-induced RV dysfunction14.The goal of this study was to characterize the functional and molecular response of RV and LV to chronic VO and to identify hemodynamic factors that drive VO chamber remodeling using pressure–volume analysis, echocardiography, quantitative proteomics, and gene expression of selected genes previously implicated in development of RV failurep < 0.0001), increased atrial weight and increased lung weight due to congestion , was increased in ACF by 25% compared to controls. Ventricular stroke work was markedly increased in both ventricles, but the increase was relatively larger in the right ventricle . Load-independent measure of chamber contractility—preload-recruitable stroke work (PRSW), was indeed significantly reduced both in ACF RV  and LV , confirming depressed systolic chamber function. LV diastolic function was impaired  but RV diastolic function was not influenced by ACF.Invasive hemodynamics and pressure–volume analysis Table , Fig. 1d90) that was similarly prolonged in both VO-exposed ventricles compared to controls.The RV and LV exposed to volume overload (VO) could possibly differ in action potential duration or trabecular contraction force, therefore we measured these parameters and presented the results in Fig. Nppa, more upregulated in LV than in RV) and increased myosin heavy chain isotype ratios (Myh7/6), mostly due to downregulated Myh6 gene. Monoamine oxidase-A (Maoa) and transglutaminase-2 (Tgm2), genes previously associated with ACF20, were similarly upregulated in RV and LV, apelin7 (Apln) was similarly downregulated in both ACF ventricles, with no effect of VO on apelin receptor (Aplnr)  of selected genes  showed that ACF led to upregulation of myocardial stress genes Fig. a: natriu) Figure .Figure 2Hk1) to Medium chain Acyl CoA dehydrogenase (Acadm) reflected enhanced glycolysis over the fatty acid oxidation in both ventricles. Increased ratio of glucose transporters Glut1/Glut4 was consistent with increased non-insulin dependent glucose uptake in ACF ventricles, more pronounced in RV. In both ventricles, VO had no effect on genes related to tissue hypoxia and angiogenesis , only Angiopoetin 2/Angiopoetin 1 ratio was significantly increased in both ACF ventricles, more in the LV. Expression of genes of cGMP-dependent signaling pathway , was not consistently affected by VO 15 and myocardial substrate metabolism (Glut1/4 ratio)21 21 Fig. c. In thep-value < 0.05 vs. controls), 25 additional proteins met the same differential expression criteria only in the RV  and 3 proteins were differentially expressed in the LV only  (Table slope: < 0.001). The individual list of the most differentially regulated proteins (> twofold change up or down compared to controls) is presented in Table Triplicate iTRAQ-based LC–MS/MS proteomic analysis of pooled samples of RVs and LVs of ACF and control animals identified over 3000 cardiac proteins. 1487 proteins were detected in all three replicates and provided quantitative expression data with adjusted p-value calculations. Only the proteins identified with at least 2 unique peptides  were further considered (full list of identified proteins is provided as a supplementary dataset). 19 proteins were differentially expressed in both ACF ventricles  and expression changes in substrate metabolic genes consistent with enhanced glycolysis and reduced fatty acid oxidation. By proteomic analysis, we identified several novel cardiac proteins differentially regulated by ACF with qualitatively concordant changes in both ventricles. The principal finding is that in response to identical surplus volume load, the pattern of proteome alterations is almost identical between ventricles, but the magnitude of changes is relatively more pronounced in the RV than in the LV. More pronounced changes on the right side can be explained by relatively larger increase in stroke work by RV compared to LV. Therefore, quantitative differences in protein expression between ventricles are explainable by hemodynamics, rather than by an existence of a “chamber-specific” regulation10. Study suggests that one possible way how to preserve RV function and to prevent adverse RV remodeling in HF could be to lower excessive hemodynamic loading.The study describes biventricular changes in myocardial function and protein composition induced by chronic VO due to ACF. In response to ACF, both ventricles displayed eccentric hypertrophy, reduced contractility, prolonged duration of action potential, upregulation of genes associated with myocardial stress  were paradoxically increased in ACF, likely due to confounding influence of chamber geometry, grossly changed by ACF. Therefore, TAPSE or strain deformation analysis overestimate RV contractility in volume overloaded ventricles. Limited utility of regional RV function indexes is also supported by low correlation of TAPSE, RV global strain and strain rate with gene expression of markers of myocardial remodeling Table , in contmax showed a trend toward reduction in ACF compared to control22, RV dP/dtmax was increased in ACF19, reflecting either afterload-dependence of this parameter or heterometric (Frank-Starling) adaptation to increased load. Load-independent measure of chamber contractility—preload-recruitable stroke work (PRSW) was reduced in both ventricles, confirming indeed depressed systolic function15. Diastolic function (dP/dtmin and tau) was impaired in ACF LV, which might contribute to the development of pulmonary hypertension23.Hemodynamic results are consistent with previous reports, although no study utilized pressure–volume analysis of both ventricles simultaneously in this model. While LV dP/dt24. The explanation could be in a different stress response compensation, or due to difference in regulation of cardiac growth between ventricles25, or it can be explained hemodynamically. Our data support the latter mechanism. Pressure–volume data showed that ACF RV has to bear relatively higher increment of hemodynamic burden than LV. RV stroke work is increased 6.4-fold while LV stroke work is increased 3.5-fold in ACF compared to normal. Larger loading of the RV can be explained by pulmonary hypertension that adds to VO of the right heart, likely due to latent pulmonary vascular disease26 that is reflected by increased surrogate of transpulmonary pressure gradient . Pulmonary vascular disease in ACF develops due to chronic elevation of pulmonary venous pressure23 and due to excessive pulmonary blood flow26.Despite both ventricles handle the same increase in cardiac output in ACF, the increase in myocardial mass was relatively larger in the RV compared to LV . Larger impact of ACF on RV compared to LV was noticed previously27 but not all29 previous studies demonstrated reduced contractility of isolated cardiomyocytes22 or isolated papillary muscle preparations29 from rats with VO due to ACF. Further and more detailed analyses of RV and LV myofilament sensitivity are mandated. Both RV and LV from ACF group showed profound electrophysiological remodeling with almost doubling of action potential duration (APD) compared to controls. Prolongation of APD may be a compensatory mechanism how to maintain contraction strength in VO. APD prolongation is pro-arrhythmogenic and together with other mechanisms can contribute to increased risk of arrhythmic sudden death in volume-overloaded hearts30.The response to volume overload (VO) could possibly change action potential duration or trabecular contraction force in RV or LV. Isolated ventricular trabeculae showed no impact of ACF in developed force or force-frequency relationship supporting minimal interventricular differences in response to VO. SomeNppa) in both ventricles31. ACF-induced upregulation of ANP mRNA was massive and it was more pronounced in LV than in RV. In most HF animal models, including ACF32, as well as in humans with cardiac overload, the progression of cardiac hypertrophy into HF is associated with reduced expression of Myh6 gene, coding α-myosin heavy chain, either absolutely or in relation to Myh7, gene of β-myosin heavy chain33. Change of Nppa gene expression and Myh7/6 ratio are therefore the most consistent molecular markers of HF and were upregulated in both VO-exposed ventricles. At a given surplus of mass, expression of Nppa or Myh7/6 were more pronounced in RV than in LV . These changes were demonstrated in both ventricles. Similar pattern of metabolic gene transcription program was observed previously in pressure-overloaded ventricles, including RV21. In summary, metabolic response to stress resembles a reactivation of fetal gene expression program and is uniform in terms of chamber (RV vs LV) or overload etiology21.Volume overload led to change in genes of myocardial substrate metabolism and bioenergetics, such as increased Vegfa and Hif1a in failing ventricles, but we observed increased ratio of Angpt2/Angpt1 mRNA (coding antiangiogenic angiopoietin-1 and angiopoietin-2), mostly in ACF LV, indicative of altered angiogenic signaling, similar to the response to myocardial infarction34. There were no consistent differences in genes of cGMP-dependent signaling pathway, speaking against relevance of this pathway in response to VO. Yet myocardial cGMP concentration was increased in ACF ventricles, probably reflecting stimulation of NP receptor-associated (particulate) guanylate cyclase by elevated natriuretic peptides.We did not find altered expression of genes coding Aplnr)35. Downregulation of myocardial apelin was previously described in failing pressure-overloaded LV or RV35, but this is the first study that links apelin to volume overload–induced remodeling.VO in both ventricles led to downregulation of apelin, a small peptide with cardioprotective, inotropic and angiogenic properties that has contra-regulatory effects to renin-angiotensin system and acts via apelin receptor  in both ventricles, or significantly altered only in one ventricle with concordant and/or not significant change of expression in the second ventricle. The data thus provide no support for chamber-specific protein expression patterns in response to similar hemodynamic stress, as proposed previously on basis of interventricular differences in physiology and embryonic origin RV Fig. d. IntereMost proteins emerged as differentially and correspondingly regulated in both ACF ventricles, compared to sham-operated ventricles, some of them for the first time associated with response to VO. The analysis of these proteins helps to understand VO-induced myocardial remodeling shared by both ventricles and they will be discussed by functional groups.periostin (POSTN)—a non-structural component of ECM, marker of myofibroblasts, cells necessary for cardiac adaptive healing and fibrosis36. Periostin assists in deposition of fibronectin-rich ECM and collagen crosslinking37, cardiomyocyte dedifferentiation38 and is extensively upregulated by TGFβ1, angiotensin II, infarction or hemodynamic overload, including VO40. VO-driven upregulation is almost twice in RV than in LV. Another TGFβ1-regulated protein upregulated in ACF hearts is cytoskeleton associated protein 4 (CKAP4), known to positively correlate with activated myofibroblast markers in both mouse and human cardiac tissue and to be negative modulator of fibroblast activation in injured heart41. We report again strong upregulation of tissue-type transglutaminase 2 (TGM2) in both ACF ventricles20, both on protein or mRNA level. TGM2 is responsible for crosslinking and stiffening of ECM and it was implicated in development of HF42. Another upregulated ECM protein is fibrillin 1, a constituent of ECM microfibrils that is enhanced in ANGII-induced cardiac fibrosis43.The most upregulated protein in ACF ventricles was XIRP1 and XIRP2. These proteins with almost cardiac-specific expression are associated with intercalated disks and play a role in myofibril assembly and repair44. XIRP2 modulates the effects of ANG-II on cardiac hypertrophy, fibrosis and myosin isotype switch45, regulates voltage-gated K changes (KV1.5)46, and was found to be upregulated in RV by experimental volume-overload47. XIRPs may therefore represent potential markers of cardiac injury. Mutations of both XIRPs were associated with arrhythmic sudden cardiac death and prolonged action potential46, a feature present also in VO-ACF hearts , consistently with our targeted mRNA analysis and previous studies33. Across species and types of overload, the downregulation of MYH6 gene is one of the hallmarks of HF48. ACF ventricles displayed also two-fold upregulation of non-muscle myosin 10 and downregulation of tropomodulin 4. Upregulated cytoskeletal signaling protein four and-a-half LIM domains 1 (FHL-1) which binds to and regulates titin stiffness was already linked to VO-induced cardiac LV remodeling in rats31. Another sarcomeric stress-sensing element upregulated in ACF is cardiac cysteine and glycine-rich protein 3 (CSRP3 aka MLP)49. Mutations in FHL150 and CSRP3 are known to cause cardiomyopathies. VO-ventricles showed an upregulation of annexin 5, intracellular protein that participates in Ca2+ handling, apoptosis and sarcolemma repair and is upregulated in failing human myocardium51.From other sarcomeric proteins, we found downregulated gene for neural cell adhesion molecule 1 , a plasma membrane protein relevant for cardiomyocyte cell–cell interactions. NCAM1 is, similarly to identified ECM proteins, regulated by TGFβ52 and overexpressed in cardiomyocytes of other HF models and failing human hearts, proportionally to severity of HF53. Another VO-upregulated protein involved in cell–cell interactions is nebulin-related anchoring protein (NRAP), an actin-associated protein localized in intercalated disc, implicated in sarcomere assembly and force transduction. NRAP overexpression in the mouse leads to right ventricular cardiomyopathy54. Intermediate filament protein synemin (SYNM) that stabilizes intercalated disc and participates in protein kinase A signaling was also upregulated; its absence leads to severe cardiac abnormalities55. ACF ventricles showed an upregulation of microtubule-associated protein 1A (MAP1A), not previously associated with HF, and upregulation of major vault protein—a member of ribonucleoprotein complex relevant for nucleo-cytoplasmatic transport56.One of the most upregulated proteins in ACF ventricles was Metabolic genes, ROS and chaperones: Proteomic analysis confirmed upregulation of glycolytic enzymes and downregulation of FA oxidation seen in targeted PCR analysis. Specifically, ACF ventricles showed upregulation of pyruvate kinase (PKM), the final enzyme of glycolysis. Upregulation of fetal isoform (PKM2) was previously observed in failing RV due to PH57. In parallel, we observed downregulation of α and β subunits of trifunctional enzyme of β-oxidation of fatty acids , more pronounced in volume-overloaded RV than in LV, consistent with switch in myocardial metabolic preference typical to fetal or failing heart39. Downregulation of mitochondrial 2,4-dienoyl-CoA reductase, an enzyme of β-oxidation of unsaturated fatty acids, was also observed in both VO ventricles. We observed an upregulation of B  isoform of creatine kinase (CK-B) that is typical for failing heart58 and a downregulation of its mitochondrial sarcomeric isoform (CKMT2), suggesting abnormalities in creatine shuttle and energy transfer.(MAOA), an enzyme that is responsible for degradation of catecholamines20. Upregulation of MAOA in ACF ventricles verifies our previous observation and is confirmed also on mRNA level , an enzyme that degrades asymmetric dimethyl arginine (ADMA), an endogenous inhibitor of nitric synthase. DDAH1-deficient rats have more severe PH and RV failure if exposed to monocrotaline62. In contrast, end-stage HF patients without PH have upregulated myocardial DDAH suggesting a contraregulatory response to putative ADMA elevation and ensuing NO deficit 63.Failing ACF ventricles (more RV than LV) showed upregulated dimethylarginine dimethylhydrolase1 64. Hemodynamics was tested only in resting state, without provocation maneuvers that could discern more subtle changes in cardiac function. Preload changing maneuvers  were not performed due to technical reasons, i.e. we cannot report arterial or ventricular elastance values. Proteomic analysis did not detect some proteins that are known to be differentially regulated in HF and were even detected at mRNA level, such as collagens, apelin or apelin receptor. Such discrepancy can be explained by very low expression, insufficient solubility or low molecular weight of the protein with insufficient number of peptides generated by trypsin. To confirm the hypothesis that concomitant PH is responsible for relatively larger RV proteome response to VO, it would be necessary to demonstrate the effect of PH-lowering on RV protein composition, and such experiment was not performed. Changes in pulmonary artery pressure hemodynamics, pulmonary arterioles/venules histology and RV myocardial metabolome in ACF-exposed rats should be further studied to better understand RV-PA coupling in conditions of volume overload.The study has several limitations. To reduce variance, only male rats were studied. Cardiac tolerance to volume overload is worse in males than in females, i.e. changes were more pronouncedIn conclusion, the study showed that ACF led to changes of molecular markers of heart failure, increased cardiac stress and altered substrate metabolism in both ventricles. RV reacted to ACF relatively more than LV, likely due to larger incremental stroke work due to pulmonary hypertension. Proteomic analysis identified high interventricular concordance of ACF-induced changes, indicating that the RV vs LV differences are explainable hemodynamically, rather than by a presence of “RV-specific” regulatory pathways. Reduction of PA pressure and RV load could therefore be a way how to preserve RV function and prevent adverse remodeling.65. After 24 weeks, RV and LV function , target gene expression (qPCR) and proteomics (LC–MS/MS) were studied. The study was performed in accordance with relevant guidelines and regulations and was approved by the Animal Ethic Committee of IKEM (#16600/2014-OVZ-30.0-14.3.14). The study was carried out in compliance with the ARRIVE guidelines, if not explicitly stated otherwise.Eight-week male Sprague Dawley rats underwent needle ACF/sham operation as described previously66. Subsequently, ventricular function was invasively assessed by 2F Pressure–Volume micromanometer-tip catheters  simultaneously introduced into the LV via the right carotid artery and into the RV via the internal jugular vein. Data were analysed by LABCHART PRO software .Echocardiography was performed under general anesthesia with 10 MHz transducer . RV fractional area change (FAC) was defined as difference of end-diastolic and end-systolic RV area, divided by end-diastolic area. RV volumes were calculated using monoplane ellipsoid approximation method67. Action potential duration (APD) was measured at 50% and 90% levels of repolarization .The papillary muscles were dissected from both ventricles. Contraction force and membrane potential was measured as described elsewhere70. The transcriptional data were normalized to control RV as a chamber with the generally lowest gene expression levels.Samples were taken from RV and LV free wall and placed into RNA later. Total RNA was isolated and genomic DNA removed. RNA quantity and integrity were measured. The RNA was reverse transcribed and qPCR was done using RealTime ready Custom Panel 384–32 . The analysis was performed on a LightCycler LC480 (Roche) according to manufacturer’s protocol. Resulting data were analyzed by the ∆Cp method using the R/Bioconductor statistical environment71 (for details see Supplement). The samples were labeled as follows: tags as follows: 114: right ventricle/control, 115: right ventricle/ACF, 116: left ventricle/control, 117: left ventricle/ACF. To remove unbound tags and to pre-fractionate the peptides into four fractions SCX OPTI-TRAP™ Cartridge  was used. Labeled peptide fractions were desalted and dried before LC–MS/MS analysis. 50 cm EASY-Spray column  with EASY-Spray™ Source with PepMap100 Pre-column was used for on-line peptide fractionation. A linear gradient was applied for 240 min using Ultimate 3000 Nano LC (Dionex). Data were collected on Thermo Orbitrap Fusion™ in MS3 reporter ion quantification mode. The top 10 most intensive peaks from MS2 fragmentation were simultaneously selected and fragmented in HCD, MS3 masses were acquired in the Orbitrap. In total, three independent iTRAQ analyses using the same pooled myocardial samples were performed. The raw data from all three analyses (each comprising of 4 SCX fractions) were merged and analyzed in Proteome Discoverer 2.2. Data were searched against Rat SwissProt and TrEMBL databases using Sequest HT. FDR 0.01 limit for peptides and proteins was set. Quantitative data were normalized on total peptide amount. Unique and razor peptides were used for quantification.All chemicals were from Sigma-Aldrich, unless stated otherwise. Pooled pulverized myocardial samples  were lysed, digested with trypsin using and labeled with four iTRAQ tags according to the manufacturer´s instructionsPulverized pooled heart samples were lysed, denatured and separated by SDS-PAGE. Proteins were transferred to PVDF membranes, which were than blocked and probed first with primary and then with HRP-conjugated secondary antibodies. The signal was detected using ECL detection system.Data were assembled and statistically analyzed using JMP 14 software package . Groups were compared using Student’s t test and Pearson’s correlation coefficient was used for assessment of correlation between continuous variables. The difference of linear regression slope from line of equality (x = y) or between two datasets was tested using GraphPad 6.0. Results are expressed as means ± SD, if not stated otherwise. P-value less than 0.05 was considered significant. Blinding during the data analysis was not considered.Expanded Materials and Methods section together with additional figures and supplementary proteomic dataset are provided in the supplementary material.Supplementary Information 1.Supplementary Information 2.


Transcatheter atrial septal defect (ASD) and patent foramen ovale (PFO) closure might have opposite short- and long-term haemodynamic consequences compared with restricted interatrial shunt creation, which recently emerged as a potential treatment modality for patients with heart failure with preserved ejection fraction (HFpEF). Given the opposing approaches of ASD and PFO closure versus shunt creation, we investigated the early and sustained cardiac structural and functional changes following transcatheter ASD or PFO closure.In this retrospective study, adult secundum-type ASD and PFO patients with complete echocardiography examinations at baseline and at 1‑day and 1‑year follow-up who also underwent transcatheter closure between 2013 and 2017 at the University Medical Centre Groningen, the Netherlands were included.p = 0.009) and atrial fibrillation  were associated with a sustained increase in LVFP after transcatheter ASD/PFO closure estimated by mean E/e’ ratio . In subgroup analysis, this was similar for ASD and PFO closure.Thirty-nine patients  were included. Transcatheter ASD/PFO closure resulted in an early and persistent decrease in right ventricular systolic and diastolic function. Additionally, transcatheter ASD/PFO closure resulted in an early and sustained favourable response of left ventricular (LV) systolic function, but also in deterioration of LV diastolic function with an increase in LV filling pressure (LVFP), as assessed by echocardiography. Age  contains supplementary material, which is available to authorized users. Atrial septal defect (ASD) is one of the most common adult congenital heart diseases, and the chronic left-to-right atrial shunt might eventually lead to the development of pulmonary arterial hypertension, arrhythmia and heart failure . ASD cloRecently, the artificial creation of a restricted interatrial shunt with a transcatheter device has emerged as a potential treatment modality for patients with heart failure with preserved ejection fraction (HFpEF) by means of reducing left atrial (LA) pressure . Given tn = 19), surgical approach transition (n = 7) or technical reasons (n = 3). The study flow chart is presented in Fig. This retrospective study recruited adult patients age > 18 years) who underwent transcatheter ASD/PFO closure with comprehensive echocardiographic datasets between 2013 and 2017 at the University Medical Centre Groningen, the Netherlands. Transcatheter ASD/PFO closure was indicated following the guidelines of the European Society of Cardiology (ESC) and the Netherlands Society of Cardiology . Among t8 years wTranscatheter ASD closure was performed using the Amplatzer Septal Occluder or PFO occluder  or the Figulla ASD Occluder or PFO occluder , under general anaesthesia and guidance of intraprocedural transoesophageal echocardiography. Before closure, mean right atrial (RA) pressure, mean LA pressure, mean pulmonary arterial pressure, pulmonary capillary wedge pressure and ratio of total pulmonary blood flow to total systemic blood flow (Qp/Qs ratio) were obtained using a Swan-Ganz catheter, and all measurements were recorded at end expiration based on average of five cardiac cycles.Comprehensive transthoracic echocardiography  and all offline measurements including two-dimensional speckle-tracking echocardiography analysis were performed following the ESC guideline , at basePulmonary artery systolic pressure was estimated using Bernoulli’s equation of peak tricuspid regurgitant velocity and RA pressure estimation, based on the size and collapsibility of the inferior vena cava . LV systt-test.Continuous variables are presented as mean ± standard deviation (SD) or as median with range. Categorical variables are expressed as frequency and percentage. Differences in echocardiographic characteristics between baseline versus 1‑day or 1‑year follow-up were compared using a paired P values ≤ 0.05 were considered statistically significant.A linear regression model was used to evaluate the association between clinical risk factors of HFpEF and cardiac functional changes assessed by echocardiography. A multivariable model was created by including all variables in the univariable analysis. Stratified analysis was performed for the significant echocardiographic changes at 1‑day and 1‑year follow-up after transcatheter closure by ASD versus PFO. All data analyses were performed using SPSS, version 22.0 .n = 39) was 48 ± 16 years, and 61.5% were women. Among all patients, 28 (72%) had a large ASD with RV volume overload, 12 (30.7%) had a history of hypertension, 9 (23.7%) had a history of AF and 2 (5.1%) had a history of diabetes mellitus.The mean age of patients included (Tab. Tab. p = 0.01), a change that persisted at 1‑year follow-up . Additionally, RA volume index showed a significant reduction at 1‑day follow-up  and at 1‑year follow-up .Following transcatheter ASD/PFO closure, RV basal diameter was significantly reduced at 1‑day follow-up , and this trend remained at 1‑year follow-up . Systolic tissue velocity of the lateral tricuspid annulus also showed a significant and sustained decrease at 1‑year follow-up compared with baseline . RA reservoir GLS (as a measurement of RV diastolic function) was significantly decreased at 1‑day follow-up  and remained significantly lowered at 1‑year follow-up . Moreover, RV isovolumic relaxation time also showed a significant increase within 1 year after transcatheter ASD/PFO closure compared with baseline, in all suggesting a sustained decline in RV diastolic function after closure.Irrespective of reduction in RV or RA dimension due to shunt closure, transcatheter ASD/PFO closure resulted in an early and continuous decrease in RV systolic and diastolic function. As for RV systolic functional assessments, RVGLS showed a significant decrease in the absolute value at 1‑day follow-up . We also found a stepwise increase between baseline and at 1 year in LV internal diameter in diastole  and in LV mass index .LV systolic function showed early improvement , and LA volume index significantly increased from 29.6 ± 12.4 mL/m2 at baseline to 34.5 ± 13.9 mL/m2 at 1 year (p = 0.04). LA reservoir GLS significantly decreased from 32.8 ± 13.9% at baseline to 26.7 ± 9.9% at 1 day (p = 0.006) and to 26.7 ± 10.7% at 1 year (p = 0.01).LVFP showed an early and sustained increase. Mean E/e’ ratio significantly increased from 6.3 ±2.0 cm/s at baseline to 7.3 ± 3.2 at 1 day  and LA reservoir GLS  in univariable analysis. Notably, age  and AF  remained significantly associated with sustained changes of E/e’ ratio in multivariable models after adjusting for baseline mean E/e’ ratio, sex, hypertension and ASD size .Furthermore, the presence of AF at enrolment and ASD size were significantly associated with sustained changes of LA volume index , the restricted size of the iatrogenic PFO and the limited follow-up of patients receiving this relatively new treatment , 15–20.With regard to left-sided filling pressures, our findings regarding changes in LV diastolic function following ASD closure are consistent with those of prior studies. Ewert et al. found that transcatheter ASD closure in the elderly is associated with an increase in LVFP and subsequent congestive heart failure due to masked underlying LV diastolic dysfunction , 22. We Likewise, LA reservoir GLS, as an additional reflection of LA myocardial compliance, emerged as a promising noninvasive surrogate for LVFP estimation . Prior sThe major limitation of our study is the relatively small sample size, although we included consecutive patients with ASD and PFO undergoing transcatheter ASD closure with full echocardiographic datasets of diastolic function up to 1 year. The age difference between the current population and much elderly HFpEF patients is also a limitation to be speculated about. The current study results might underestimate iatrogenic ASD creation in much elderly HFpEF patients. We acknowledge that absolute changes were small and of uncertain clinical significance. Nonetheless, this is one of the first studies to comprehensively assess patients with strain echocardiography before and after ASD closure, and our findings may carry implications for the propensity to develop HFpEF after ASD or PFO closure or, conversely, the propensity to benefit from iatrogenic ASD creation in HFpEF.Older patients and AF patients are predisposed to sustained increases in left-sided filling pressures following ASD or PFO closure. These findings support the concept that elderly HFpEF patients with AF in particular might benefit from the artificial creation of an atrial left-to-right shunt.In this study, transcatheter closure of an atrial septal defect (ASD) or a patent foramen ovale (PFO) resulted in an early and sustained increase in left ventricular (LV) filling pressure, as assessed by echocardiography.Older patients with ASD or PFO and patients with atrial fibrillation were predisposed to sustained increases in LV filling pressure resembling heart failure with preserved ejection fraction (HFpEF) following interatrial shunt closure.The findings of the present study support the current concept that creating a restricted interatrial shunt in patients with HFpEF might result in acute and sustained improvement in LV diastolic dysfunction and a decrease in LV filling pressures.Supplementary Table 3: Echocardiographic characteristics at baseline, day 1 and 1 year after following ASD closureSupplementary Table 4: Echocardiographic characteristics at baseline, day 1 and 1 year after following PFO closureSupplementary Table 5: Independent predictors of sustained changes in echocardiographic estimations of left ventricular filling pressures. after T‑ASD/PFO closure