Two radiologists independently assessed the image quality and RV volumes for both techniques, which were compared using the Wilcoxon test and paired Student’s t test, Bland–Altman, and linear regression analyses. The visualization of wall-motion disorders and tricuspid-regurgitation-related signal voids were also analyzed. Results: The mean acquisition time for CSrt was 22.4 ± 6.2 (SD) s (95% CI: 20.8–23.9 s) versus 442.2 ± 89.9 (SD) s (95% CI: 419.2–465.2 s) for SSFPref (p < 0.001). The image quality of CSrt was diagnostic in all examinations and was mostly rated as good . There was a high correlation between SSFPref and CSrt images regarding RV ejection fraction (49.8 ± 7.8 (SD)% (95% CI: 47.8–51.8%) versus 48.7 ± 8.6 (SD)% (95% CI: 46.5–50.9%), respectively; r = 0.94) and RV end-diastolic volume (192.9 ± 60.1 (SD) mL (95% CI: 177.5–208.3 mL) versus 194.9 ± 62.1 (SD) mL (95% CI: 179.0–210.8 mL), respectively; r = 0.98). In CSrt images, tricuspid-regurgitation and wall-motion disorder visualization was good (area under receiver operating characteristic curve (AUC) = 0.87) and excellent (AUC = 1), respectively. Conclusions: Compressed-sensing real-time cine imaging enables, in one breath hold, an accurate assessment of RV function and volumes in CHD patients in comparison with standard SSFPref, allowing a substantial improvement in time efficiency.Background and objective: To evaluate the reliability of compressed-sensing (CS) real-time single-breath-hold cine imaging for quantification of right ventricular (RV) function and volumes in congenital heart disease (CHD) patients in comparison with the standard multi-breath-hold technique. Methods: Sixty-one consecutive CHD patients (mean age = 22.2 ± 9.0 (SD) years) were prospectively evaluated during either the initial work-up or after repair. For each patient, two series of cine images were acquired: first, the reference segmented multi-breath-hold steady-state free-precession sequence (SSFP The advent of heart surgery and percutaneous cardiac procedures has considerably improved outcomes in patients born with congenital heart disease . It has Right ventricular (RV) function and volume assessment is of paramount importance in many of these patients, such as in post-repair tetralogy of the Fallot population, as treatment decisions and outcomes mainly rely on RV parameters according to the European Society of Cardiology guidelines for the management of adult congenital heart disease . Althougk-space subsampling, thus enabling a very high scan speed, and it uses non-linear iterative reconstructions to make the final image look as close as possible to that if the k-space had been fully sampled. The use of CS for CMR cine imaging theoretically enables real-time acquisition with whole-ventricle coverage in a single breath hold, and its reliability has been successfully tested in previous studies for left ventricular (LV) or sometimes right ventricular (RV) functional assessment in healthy volunteers and in patients with various extra-congenital pathologies [However, one major limitation of such extensive CMR examinations is currently the acquisition time, which can be difficult to tolerate in this population, as well as the iterative breath holds, which can be difficult to maintain, leading to poor-quality examinations because of breathing artifacts. To reduce this limitation, the development of acceleration techniques in MR imaging is crucial, and compressed sensing (CS) represents a promising technique in this category. Schematically, CS is a technique that combines a strong and random hologies ,9,10,11.We thus aimed at evaluating the reliability of real-time cine imaging using the CS technique for quantification of RV and LV function and volumes in congenital heart disease patients in comparison with conventional multi-breath-hold segmented steady-state free-precession cine imaging.From January to April 2019, 61 consecutive patients were prospectively included. All patients were clinically scheduled for CMR in the context of congenital heart disease for either the initial work-up or after repair. A single-ventricle anatomy was considered as an exclusion criterion. The protocol was approved by our institutional Ethics Committee, and the patients gave informed consent.ref) was considered as the reference technique, including a conventional short-axis stack, one LV and one RV two-chamber slice, and one four-chamber slice with an 8 mm slice thickness and a 2 mm gap; an additional prospectively triggered real-time CS sequence (CSrt) in a single breath hold. CSrt cine images were acquired with the same slice number, position, and thickness as those used in the reference technique. An additional phase-contrast imaging sequence was acquired on the pulmonary trunk to assess the RV stroke volume and the severity of the encountered tricuspid regurgitation. The details of the imaging parameters are listed in All CMR examinations were performed on a 1.5 T magnetic resonance scanner . For each patient, two series of two-dimensional cine images were systematically acquired: prospectively triggered segmented multi-breath-hold steady-state free-precession sequence , end-diastolic volume (EDV), end-systolic volume (ESV), and stroke volume (SV). The same parameters were measured for the left ventricle, as well as the LV mass. For these quantitative measurements, endocardial and epicardial contours were segmented on the conventional short-axis stacks of cine images using a dedicated analysis software . According to our CMR practice, RV trabeculations were included in the RV volume. Four-chamber and long-axis slices were used as reference images to trace the atrio-ventricular valve planes to ensure an optimal delineation of the heart base for an accurate volume calculation.The quantitative assessment consisted of the evaluation of RV functional parameters with both the SSFPref and CSrt cine images was rated on the basis of a four-point Likert scale as follows: 4 = excellent, 3 = good, 2 = fair image quality, and 1 = non-diagnostic examination.The overall subjective image quality of the SSFPIn addition, the objective RV image quality was assessed using previously published criteria, which are mostly based on artifact rating, and they were adapted to the RV . SchematThe depictions of the regional RV wall-motion abnormalities  were also rated at 4 anatomical levels , and the depictions of tricuspid-regurgitation-related flow artifacts were assessed on the four-chamber slice.ref and CSrt cine images were independently analyzed offline by a CMR radiologist (HF) with 3 years of experience. After anonymization, the images from both sequences were randomized and mixed. The two types of cine sequences from one patient were not read in the same session. A radiologist (JP) with 10 years of experience performed the functional RV assessment on a 20-patient sample for the determination of interobserver agreement with the new CS cine technique [The acquired SSFPechnique .ref and CSrt were compared using paired Student’s t test, Bland–Altman, and linear regression analyses. The interobserver agreement of CSrt was determined by calculating the intra-class correlation coefficient. An analysis of variance was performed to compare the RV stroke volumes assessed with both cine sequences with the forward pulmonary volume assessed with PCI. Differences in quality scores between SSFPref and CSrt were assessed using the Wilcoxon test. Values of p < 0.05 were considered statistically significant. For the depictions of valvular regurgitations and wall-motion disorders, a receiver operating characteristic (ROC) curve was used. The statistical analysis was performed with dedicated software .Categorical data are represented as numbers (percentages). Continuous variables are represented as mean ± standard deviation (SD) ) in the case of normal distribution and median (range: minimum–maximum) in other cases. SSFPn = 33/61; 54.1%), pulmonary atresia with a ventricular septal defect , cardiac shunt , transposition of great arteries , aortic coarctation , congenital pulmonary stenosis , cor triatriatum sinister , congenitally corrected transposition of the great arteries , pulmonary atresia with intact ventricular septum after biventricular repair , and congenital aortic stenosis . The 61 patients  years; 95% CI: 19.9–24.5 years) underwent CMR for: tetralogy of Fallot (rt acquisition was 22.4 ± 6.2 (SD) s (95% CI: 20.8–23.9 s) versus 442.2 ± 89.9 (SD) s (95% CI: 419.2–465.2 s) for SSFPref (p < 0.001). The mean acceleration factor provided by CSrt was 20.8 ± 5.6 (95% CI: 19.3–22.2) as compared with SSFPref. A mean number of 13.3 ± 2.9 slices (95% CI: 12.5–14.1 slices) was acquired with each sequence.The mean duration for single-breath-hold CSref and CSrt segmentations for the RV and LV functional parameters are presented in ref and CSrt for RVEDV (192.9 ± 60.1 (SD) mL (95% CI: 177.5–208.3 mL) versus 194.9 ± 62.1 (SD) mL (95% CI: 179.0–210.8 mL), respectively; p = 0.169). The RVEF was slightly underestimated in the CSrt images (CSrt: 48.7 ± 8.6 (SD) % (95% CI: 46.5–50.9%); SSFPref: 49.8 ± 7.8 (SD) % (95% CI: 47.8–51.8%); p = 0.006) as a result of a statistically significant but not clinically relevant underestimation of the RVESV in CSrt. The analysis of variance did not demonstrate any significant differences with respect to the RV stroke volume, regardless of the measurement method (SSFPref: 93.6 ± 25.7 (SD) mL (95% CI: 87.0–100.2 mL); CSrt: 92.3 ± 26.0 (SD) mL (95% CI: 85.7–99.0 mL); PCI: 88.6 ± 27.1 (SD) mL (95% CI: 91.6–95.5 mL); p = 0.605). No statistically significant differences were visible between SSFPref and CSrt for LVEF and LVEDV. The LV mass was slightly overestimated in CSrt. The linear regression yielded good agreement between both acquisition techniques for all RV functional parameters  paired measurements out of the limits of agreement (LOA) depending on the RV parameter considered (LOA in RVEF bias: −13.7 to +9.3%).Detailed results regarding the SSFPrameters , and thert images in various clinical situations. The image quality of CSrt was diagnostic in all examinations (rt images (p = 0.0001) because most of the examinations were rated as excellent with SSFPref and good with CSrt. However, qualitative artifact presence was statistically lower in the CSrt images than in SSFPref (p = 0.0016). Considering SSFPref as the gold standard, there were no diagnostic losses for regional RV wall-motion abnormalities in CSrt images, demonstrating a 100% sensitivity and specificity (normokinetic: n = 157/244 (64.3%); hypokinetic: n = 39/244 (16.0%); akinetic: n = 1/244 (0.4%); dyskinetic: n = 47/244 (19.3%)). The tricuspid-regurgitation-flow void depictions in CSrt images had a sensitivity and specificity of 74.2% and 100%, respectively . Using SSFPref, 23/61 (37.7%) tricuspid regurgitations were depicted (mild: 20/23 (87.0%); moderate: 3/23 (13.0%)). Of the 8/61 (13.1%) tricuspid regurgitations that were not depicted with the CSrt cine, all were quantified as mild with the reference technique (the difference between RVSV and anterograde pulmonary volume was measured with the phase-contrast sequence) [inations . There wequence) .rt and for the standard SSFPref cine techniques, while the former allows a drastically shorter acquisition time. The agreement between CSrt and SSFPref regarding the RV volume assessment is in line with the findings of previous studies performed on smaller cohorts of healthy volunteers and non-CHD patients [t test comparisons performed in our study demonstrated a statistically significant trend towards a 1.07% RVEF underestimation (relative mean difference = −2.14%), a 3.51 mL RVESV overestimation (relative mean difference = 3.54%), and a 1.28 mL RVSV underestimation (relative mean difference = −1.36%) with CSrt. The segmented steady-state free precession cine is currently considered the gold-standard technique for the measurement of ventricular volumes, including in CHD patients [rt-evaluated RV functional parameters. Additionally, our findings demonstrate a strong agreement between both SSFPref and CSrt for functional LV parameters, despite the slight LV mass overestimation with CSrt, as previously reported [Our prospective monocentric study based on a cohort of 61 pediatric and grown-up CHD patients, including 33 tetralogies of Fallot, demonstrated that the quantification of RV function and volumes yields similar results for CSpatients ,10. The patients ,16,17. Hpatients ,19. A moref and CSrt on Bland–Altman plots when the RVEF or RVESV increase . These rt sequence consisted of a single-breath-hold cine acquisition; however, some patients could not fully achieve the required apnea due to their clinical condition. They were not excluded from the study, as our aim was to be as representative as possible of our CHD population that we encounter in daily practice. Despite these free-breathing ends of acquisition, no major artifacts  were noticed in the CSrt images, which all had diagnostic quality. These findings strongly suggest the possibility of the free-breathing acquisition of CSrt cine, which is particularly relevant for pediatric or end-stage CHD patients. Although the aim of this study was not to evaluate free-breathing imaging protocol, free-breathing CSrt has been demonstrated to be a reliable alternative that allows faster acquisition than sequences based on registration of multiple acquisitions and motion-correction algorithms [rt may allow one to either (a) shorten breath-holding duration by splitting the stacks of cine slices to reduce the number of cine loops acquired per breath hold, especially for patients with shortness of breath, or (b) to shorten the overall examination duration, as suggested in the present study (average: 22 s (CSrt) versus 7 min and 22 s (SSFPref) for 13 cine slices) to improve the clinical workflow and tolerance in children or to spare examination time in order to acquire additional sequences. Indeed, a comprehensive study of hemodynamic patterns is a key point in the initial work-up of CHD or in repair follow-up. Four-dimensional (4D) flow is a promising but time-consuming technique that may take advantage of the thusly spared time [The CSgorithms ,26. The red time ,28. Depered time . As extered time ,31,32.rt . Even trt rates .ref, as 2 min were necessary in order to visualize the whole cine stack in spite of a graphics processing unit upgrade.The minimum age in our population was 7 years, and further studies would be needed for validation in younger children. We also have to report that despite the drastic decrease in acquisition time, the data reconstruction process was more time consuming than with SSFPrt sequence was designed in order to reduce the acquisition time as much as possible. In a different way, some authors have successfully tested CS cine to improve the spatial or temporal resolution with quite similar or even moderately shorter acquisition times than those for reference SSFPref, or even to achieve three-dimensional cine acquisitions [ref, which can be very useful for patient comfort and workflow.Regarding the blurry aspect of images that we observed with CS, it must be said that the CSisitions ,35,36. Ort as compared to SSFPref [Although it is in line with the current literature, the bias observed between the two sequences in RVEF measurement (∼10%) is clinically relevant and must be taken into consideration in CHD follow-up ,38. The  SSFPref . Indeed, SSFPref .Compressed-sensing real-time cine imaging enables the assessment RV function and volumes in patients with CHD while providing a significant reduction in examination duration and allowing an improvement in time efficiency and patient care.


In heart failure, metaboreflex activation caused exaggerated increases in Ea and in this setting, SAD significantly increased the rise in Ea elicited by muscle metaboreflex activation (1.3 ± 0.3 mmHg/mL to 2.3 ± 0.3 mmHg/mL). Thus, we conclude that the arterial baroreflex does buffer muscle metaboreflex induced increases in Ea and this buffering likely has effects on the ventricular-vascular coupling.The ventricular-vascular relationship assesses the efficacy of energy transferred from the left ventricle to the systemic circulation and is quantified as the ratio of effective arterial elastance to maximal left ventricular elastance. This relationship is maintained during exercise via reflex increases in cardiovascular performance raising both arterial and ventricular elastance in parallel. These changes are, in part, due to reflexes engendered by activation of metabosensitive skeletal muscle afferents—termed the muscle metaboreflex. However, in heart failure, ventricular-vascular uncoupling is apparent and muscle metaboreflex activation worsens this relationship through enhanced systemic vasoconstriction markedly increasing effective arterial elastance which is unaccompanied by substantial increases in ventricular function. This enhanced arterial vasoconstriction is, in part, due to significant reductions in cardiac performance induced by heart failure causing over—stimulation of the metaboreflex due to under perfusion of active skeletal muscle, but also as a result of reduced baroreflex buffering of the muscle metaboreflex-induced peripheral sympatho-activation. To what extent the arterial baroreflex modifies the metaboreflex-induced changes in effective arterial elastance is unknown. We investigated in chronically instrumented conscious canines if removal of baroreflex input via sino-aortic baroreceptor denervation (SAD) would significantly enhance effective arterial elastance in normal animals and whether this would be amplified after induction of heart failure. We observed that effective arterial elastance (E The lata) . Most nooke work , 2021b.  stifled .a observed during sympathetic activation during exercise in normal and heart failure subjects are a result of large increases in heart rate but also though significant increases in peripheral vasoconstriction  and maintained using isoflurane gas (1.5–2.5%). Analgesia was maintained by application of a fentanyl patch (TD 125–150 μg/h) preoperatively and left for 3 days. To prevent infection prophylactic antibiotics Cephazolin (500 mg IV) was administered during the procedure and Cephalexin (30 mg/kg) was administered after twice daily by mouth. Additional analgesic management was provided during the recovery from each procedure by administration of buprenorphine (0.015 mg/kg IV) and acepromazine (0.1 mg/kg IM) on an as needed basis. All anesthetic, analgesic and surgical procedures performed in this study have been used previously .The first surgical procedure was a left thoracotomy in which a 20PAU flow probe  was placed on the ascending aorta for measures of cardiac output and 3 stainless steel pacing electrodes were sutured to the apex of the left ventricle for induction of heart failure via rapid ventricular pacing at 225–245 bpm for 25–30 days. In this procedure unrelated to the current study two sonomicrometry crystals  were implanted into the myocardium, a 3PSB flow probe  was placed on the circumflex artery. The pericardium was reapproximated and the chest was closed in layers. All cables and leads were exteriorized dorsally between the scapulae. Animals were given a minimum of 14 days to recover prior to the next procedure.The second surgical procedure utilized a left retroperitoneal approach for placement of a 10PAU blood flow probe  on the terminal aorta to measure hindlimb blood flow. Caudally to the flow probe a vascular occluder  was placed to induce progressive reductions in hindlimb blood flow to elicit the muscle metaboreflex during exercise. Cranially to the flow probe a 19-gauge polyvinyl catheter  was placed for measures of mean arterial pressure. Unrelated to the current study a 4PSB flow probe  was placed on the renal artery. Additionally, 7 animals in this study during this procedure were instrumented with a 19-gauge polyvinyl catheter  in the jugular vein for measures unrelated to the current study. The surgical site was closed in layers and all cables, catheters and occluder lines were tunneled subcutaneously and exteriorized dorsally between the scapulae. Animals were given 14 days minimally to recover prior to any experimental protocols.Sino-Aortic Baroreceptor Denervation (SAD) consisted of two additional anesthetic events in five animals after completion of control experimental protocols utilizing the same anesthetic and analgesic methods described above. Removal of sino-aortic baroreceptor input was achieved through bilateral transection of the aortic depressor and carotid sinus nerves as previously described by Placement of a Central Venous Catheter was performed during the second procedure in animals which did not undergo SAD by placing a catheter in the jugular vein and advancing it to the atrial caval junction. In subjects that underwent SAD the CVP catheter was placed during the SAD procedure in the same manner as the control animals. The central venous catheter was used to assess central venous pressure.group). The second group also contained 5 animals which after completion of control experiments underwent SAD and then repeated all the control experiments prior to induction of heart failure (SADgroup). For each experiment animals were brought to the laboratory space and acclimated to the environment and personnel for 15–30 min prior to the beginning of the experiment. Once the experiment began the animals flow probes were connected to bench top flow meters  and catheters were connected to pressure transducers . The pressure transducers were connected to a Gould recording system model RS3800 . All data was acquired in Windaq  acquisition software. Heart rate was determined using a cardiotachometer that was triggered by the peak cardiac output signal. One-minute steady state values were taken during rest, exercise (3.2 km/h with 0% grade), and during exercise (3.2 km/h with 0% grade) with sequential reductions in hindlimb blood flow to elicit the muscle metaboreflex in a controlled repeatable fashion using the hindlimb vascular occluder. These experiments were repeated after induction of heart failure via rapid ventricular pacing at a rate of 225–245 bpm for 25–30 days in the Controlgroup animals. In the SADgroup animals, experiments were repeated after SAD prior to heart failure induction and then repeated after.All experiments were performed minimally 14 days after the second surgical procedure or minimally 7 days after the second SAD procedure. All animals served as their own control within their separate experimental groups. These groups were divided as follows: 5 animals performed control experiments prior to immediate induction of heart failure via rapid ventricular pacing —an assessment of the resistance of the entire vascular system that subtracts the contribution of the ischemic hindlimb.NIVR = mean arterial pressure/(cardiac output – hindlimb blood flow)a) = NIVR × heart rateEffective Arterial Elastance  × mean arterial pressuregroup, SADgroup) where each animal in each group served as its own control. No direct assessments were performed across groups comparing Controlgroup to SADgroup except for assessing the relative change between normal heart failure and heart failure with SAD. When a significant interaction was observed, individual means were compared using a C matrix test for simple effects and a modified Bonferroni was used as a post-hoc test. The relative change in one variable between two states within the same group was assessed using a Students Paired t-test after determining the variables normality using a Shapiro-Wilks test. For the assessment of relative change between normal heart failure and heart failure with SAD a Welches t-test was used after determining the variables normality using a Shapiro-Wilks test. All data are reported as means ± standard error of the mean. Statistical significance was determined by an α level of P < 0.05.Systat Software (Systat 13.0) was used for statistical analyses. Data were analyzed using a Two-way ANOVA for repeated measures within each group  before and after induction of heart failure. In healthy subjects during the transition from rest to exercise significant increases in heart rate, stroke volume, cardiac output, and hindlimb blood flow occurred. No significant change in mean arterial pressure occurred during the transition from rest to exercise. Non-ischemic vascular resistance was significantly reduced with exercise. In response to muscle metaboreflex activation, heart rate, stroke volume, cardiac output, and mean arterial pressure all significantly increased whereas, no significant change in non-ischemic vascular resistance occurred. Hindlimb blood flow was significantly reduced with muscle metaboreflex activation as a result of inflation of the hindlimb vascular occluders. At rest after induction of heart failure, stroke volume, cardiac output, mean arterial pressure and hindlimb blood flow were all significantly lower than the control values. During steady state mild exercise after the induction of heart failure, heart rate, stroke volume, cardiac output, mean arterial pressure and hindlimb blood flow all increased vs. the values observed at rest. Non ischemic vascular resistance was significantly reduced in the transition from rest to exercise. Although, significant increases in stroke volume, cardiac output, mean arterial pressure and hindlimb blood flow occurred with exercise in heart failure, all of these values were significantly reduced vs. control. No significant changes as a result of heart failure induction were observed in heart rate, and non-ischemic vascular resistance during exercise. Hindlimb blood flow was significantly reduced in heart failure during muscle metaboreflex activation when compared to control. Muscle metaboreflex activation after induction of heart failure caused significant increases in heart rate and mean arterial pressure whereas stroke volume was significantly reduced. Non-Ischemic vascular resistance increased significantly with Muscle metaboreflex activation in heart failure and was significantly greater when compared to control. After induction of heart failure, muscle metaboreflex activation failed to induce any significant increase in cardiac output which remained significantly lower than the corresponding value in control. Furthermore, during muscle metaboreflex activation in heart mean arterial pressure and stroke volume were reduced relative to control.group during rest, exercise, and muscle metaboreflex activation. All of the control hemodynamics of the SADgroup from rest to exercise and exercise to muscle metaboreflex activation show the same significant changes as from the Controlgroup  induction induced significant reductions in stroke volume, cardiac output, mean arterial pressure, and hindlimb blood flow, in the SADgroup baseline resting values. Conversely significant increases in heart rate, and non-ischemic vascular resistance were observed at rest after induction of heart failure relative to SAD (orange). In response to exercise after induction of heart failure in the SADgroup, significant increases in stroke work, cardiac output, and hindlimb blood flow occurred. No significant change was observed in heart rate, and significant reductions in non-ischemic vascular resistance were observed. Heart failure induced significant reductions in stroke volume, cardiac output, mean arterial pressure, and hindlimb blood flow relative to control. Non-ischemic vascular resistance was significantly increased during exercise after induction of heart failure relative to control. In the transition from exercise to muscle metaboreflex activation in heart failure significant increases in heart rate, mean arterial pressure, and non-ischemic vascular resistance occurred. Conversely a significant reduction in stroke volume occurred while no significant increase in cardiac output occurred in response to muscle metaboreflex activation during heart failure. Heart failure induction after SAD induced significant reductions in stroke volume, mean arterial pressure, and cardiac output during muscle metaboreflex activation whereas heart failure induced significant increases in non-ischemic vascular resistance and heart rate. There was no significant difference between hindlimb blood flow during metaboreflex activation in SAD or SAD after induction of heart failure.a) and an index (stroke work) of ventricular-vascular coupling at rest, exercise, and muscle metaboreflex activation in both the Controlgroup before (white) and after induction of heart failure (gray). In response to mild exercise no significant changes occurred in Ea whereas stroke work was significantly increased. With muscle metaboreflex activation significant increases in stroke work and Ea occurred albeit the increase in Ea was small but this is likely a result of this conservative assessment of Ea as shown previously by a were only in response to muscle metaboreflex activation. Ea during rest, exercise, and muscle metaboreflex activation was significantly increased relative to control. Stroke Work was significantly lower in rest, exercise, and muscle metaboreflex activation after induction of heart failure, however, significant increases in the responses from rest to exercise and exercise to muscle metaboreflex activation were observed. a and stroke work in the SADgroup before (white) and after SAD (orange) as well as with SAD after induction of heart failure (red). Responses in Ea and stroke work before SAD in normal animals were similar to the Controlgroup. After SAD (orange) Ea was significantly increased at all workloads relative to control whereas stroke work was not significantly different at rest or during exercise or muscle metaboreflex activation relative to SADgroup control. Significant increases were observed between exercise and muscle metaboreflex activation in both Ea and stroke work, furthermore the increase in Ea was significantly greater compared to SADgroup control. After induction of heart failure (red) Ea was significantly enhanced, and stroke work was significantly attenuated at all workloads relative to control. In response to exercise Ea was significantly reduced and no significant change was observed in stroke work. With muscle metaboreflex activation in heart failure, significant increases in Ea and stroke work occurred, however, the level of stroke work observed during muscle metaboreflex activation was significantly attenuated and the level of Ea was significantly increases relative to SAD (orange).a and stroke work. group where the change in Ea was significantly increased and the change in stroke work was significantly attenuated in heart failure. a from exercise to muscle metaboreflex activation with no significant change in stroke work. group between SAD prior to and after induction of heart failure. Significant increases in the relative change of Ea were observed in the heart failure group relative to control. The relative change in stroke work was significantly less in heart failure when compared to control. group and the SADgroup. This assessment was done using a Welches t-test for assumed unequal variances due to the different treatment of SAD. The SAD heart failure Ea response was larger but not significantly different from control. Furthermore, no significant relative change from exercise to muscle metaboreflex activation in stroke work was observed.group and SADgroup before and after induction of heart failure. No significant changes were observed in central venous pressure across rest, exercise, and exercise with muscle metaboreflex activation before induction of heart failure  or maintain an appropriate effective arterial elastance will ultimately upend this relationship, such as occurs in aging populations, heart failure, and hypertension  and thusa/Emax) declines which favors the large increases in cardiac output and stroke work seen in the present and previous studies (n = 6). Shown are the average values at rest, mild exercise, and muscle metaboreflex activation before (closed circles) and after (open circles) the induction of heart failure. In these settings there was a markedly linear relationship between Emax and stroke work: as Emax rose with exercise and metaboreflex activation, highly proportional increases in stroke work also occurred (R2 = 0.986). In the present study or previous studies, we have not measured Emax after SAD, however we could calculate SW. In the normal animal after SAD, large increases in Ea occurred with similar increases in SW. Assuming the relationship shown in a and little change in Emax, the ventricular—vascular relationship would become slightly less efficient thereby limiting the increase in cardiac output, as was observed  and given the same small increase in stroke work, any small rise in Emax is likely little changed .DO’L and JM contributed to conception, design of research, performed the experiments, interpreted results of experiments, and drafted the manuscript. DO’L, JM, J-KK, M-HA-H, BL, AA, LM, TB, JS-M, and KA analyzed the data and performed the experiments. JM prepared the figures. DO’L, J-KK, M-HA-H, and JM edited and revised the manuscript. All authors approved final version of 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.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.


Right ventricular function is an important prognostic marker for pulmonary arterial hypertension. Native T1 mapping using cardiovascular magnetic resonance imaging can characterize the myocardium, but accumulating evidence indicates that T1 values of the septum or ventricular insertion points do not have predictive potential in pulmonary arterial hypertension. We aimed to elucidate whether native T1 values of the right ventricular free wall (RVT1) can predict poor outcomes in patients with pulmonary arterial hypertension.This retrospective study included 30 patients with pulmonary arterial hypertension  and 16 healthy controls  who underwent native T1 mapping. RVT1 was obtained from the inferior right ventricular free wall during end systole.Patients with pulmonary arterial hypertension had significantly higher native RVT1 than did controls . Compared with T1 values of the septum or ventricular insertion points, RVT1 correlated better with the effective right ventricular elastance index , ventricular-arterial uncoupling , and serum brain natriuretic peptide levels . Moreover, the baseline RVT1 was an accurate predictor of the reduced right ventricular ejection fraction at the 12-month follow-up (delta -3%). RVT1 was independently associated with composite events of death or hospitalization from any cause .RVT1 was predictive of right ventricular performance and outcomes in patients with pulmonary arterial hypertension. Thus, native T1 mapping in the right ventricular free wall may be an effective prognostic method for pulmonary arterial hypertension. Pulmonary arterial hypertension (PAH), a progressive life-threatening disease of the pulmonary vasculature, can result in increased pulmonary vascular resistance (PVR), elevated pulmonary arterial pressure (PAP), and right ventricular (RV) failure . DespiteAlterations of RV myocardial components  are observed in patients with PAH –8, and RNative T1 mapping, an emerging CMR technique, can quantify the native T1 relaxation time per pixel and is validated to detect tissue changes, such as lipid accumulation, myocardial edema, and fibrosis, in the left ventricle (LV) . A few sData collection and volumetric analysis are described in We retrospectively investigated 30 patients with PAH who underwent CMR, including quantitative imaging and native T1 mapping, between September 2015 and March 2017. They were diagnosed with idiopathic PAH (n = 18), PAH associated with connective tissue disease (n = 5), portopulmonary hypertension (n = 3), PAH associated with congenital heart disease (n = 3), or drug-induced PAH (n = 1) according to the 2015 European Society of Cardiology/European Respiratory Society guidelines [2. Imaging was performed during suspended respiration. Native T1 values were assessed using regions of interest (ROIs) at the septum, ventricular insertion point (VIP), and RV inferior free wall of the mid-ventricular short-axis T1 maps in the analysis software . ROIs were traced manually  . Native manually  by experThe single-beat method was employed to assess RV pressure-volume relationships using separately acquired pressure data from RHC and volume data from CMR, as described previously , 20. TheFollow-up CMR studies were performed in 18 patients with PAH . We analyzed follow-up CMR imaging over 12 months after baseline CMR imaging , or percentage. Student’s t-test was used for between-group comparisons of continuous variables with a normal distribution, whereas the Mann–Whitney U test was used for between-group comparisons of skewed continuous or discrete variables. Nominal variables were compared using the chi-squared test. The strength of correlations was determined using Pearson’s correlation coefficient. The receiver operating characteristic (ROC) curve analysis was used to evaluate the predictive accuracy and cut-off value using the Youden’s index. Univariate Cox proportional hazards analysis was employed to evaluate the relationship between composite outcomes and various selected factors. Variables with a p-value<0.25 in the univariate analysis were subsequently evaluated using a multivariate model with the forward selection method. Kaplan–Meier survival curves were constructed, and the log-rank test was used to compare event-free survival in patients stratified by the risk models. A two-tailed p-value<0.05 was considered statistically significant. Interobserver variability was assessed for native T1 values in all patients using the intraclass correlation coefficient (ICC). All analyses were performed using the Statistical Package for the Social Sciences software version 24.0  and GraphPad Prism 8 version 8.2.1 .As shown in 2, and PVR of 9.0±5.4 Wood units. CMR imaging data analysis indicated an increased RV end-diastolic volume index (RVEDVi) and RV end-systolic volume index (RVESVi) and a reduced RVEF in patients with PAH compared to healthy controls .World Health Organization functional classes (WHO-FC) II, III, and IV were observed in 50%, 47%, and 3% of the patients, respectively. A PAH-specific drug and continuous intravenous epoprostenol were used in 97% and 50% of the patients, respectively. Analysis of hemodynamic parameters demonstrated a mean PAP of 40.80±13.1 mmHg, cardiac index of 2.9±0.9 L/min/mAs shown in Correlations between T1 values at each measurement site and clinical parameters are shown in The estimated pressure-volume relationship analysis is shown in A total of 18 patients underwent 12-month follow-up CMR examinations . The RVEThe median follow-up time was 703 (IQR: 551–810) days, and nine composite events  were observed. Four patients died due to right heart failure in the hospital and one at home.The Cox proportional hazards model was applied to evaluate the significance of RVT1 using the T1 values of the septum, VIPs, and RV free wall. Multivariate analysis revealed that RVT1 was independently associated with composite events  had significantly poorer prognoses than did those with lower RVT1 (< 1385 ms) in terms of composite events, survival rates, and the incidence of hospitalizations including right heart failure related events .We employed a modified T1 mapping technique to evaluate myocardial T1 values of the RV free wall using 3.0-T CMR with a MOLLI sequence. We found that RVT1 was higher in patients with PAH compared to healthy controls, and compared to septal or VIP T1, RVT1 correlated strongly with RV performance, but not with hemodynamic parameters, in patients with PAH. Moreover, RVT1 was an independent predictor of composite outcomes including right heart failure related events. These findings suggest that native T1 mapping could be used to characterize advanced RV myocardial changes and has a prognostic potential in patients with PAH.Right heart failure is the predominant cause of death in patients with PAH, and RV function is the most important determinant of prognosis . HoweverNative T1 mapping quantifies the native T1 relaxation time per pixel; thus, tissue characteristics, such as lipid accumulation, myocardial edema, and fibrosis , can be To date, no study has evaluated the association between RVT1 and hemodynamic parameters , 26. ThiThis study has several limitations. First, this was a single-center retrospective study with a relatively small number of patients. A larger cohort including each type of PAH is essential to validate the present findings since the pathophysiology of PAH varies between subtypes. Second, we did not investigate the correlation between T1 values and the degree of histological remodeling. Thus, future histological studies involving endomyocardial biopsies, explanted hearts, or autopsy materials are required. Third, RVT1 was assessed only at the inferior wall, not the entire free wall. In our preliminary study, T1 values of the overall free wall varied largely because of the partial volume effects of the surrounding tissues or the blood pool. Fourth, CMR measurements were performed using a 3.0-T system. Further research is needed to confirm our results with 1.5-T systems which is in more widespread use at present.Using native T1 mapping, we found that higher RVT1 was associated with BNP levels, RV performance, composite outcomes, and survival in patients with PAH. These findings suggest that native T1 mapping could be used to characterize advanced RV myocardial changes and has a prognostic potential in patients with PAH. Further global, multicenter studies are needed to validate the clinical utility of RVT1 mapping in patients with PAH.S1 Appendix(DOCX)Click here for additional data file.S1 TableAbbreviations: PAH, pulmonary arterial hypertension; RV, right ventricle.(DOCX)Click here for additional data file.S2 Table†p<0.01, ‡p<0.001.Abbreviations: BNP, brain natriuretic peptide; Ea-pa_i, effective pulmonary arterial elastance index; Ees-rv_i, effective right ventricular elastance index; PAP, pulmonary arterial pressure; PVR, pulmonary vascular resistance; RAP, right atrial pressure; RVEF, right ventricular ejection fraction; RVEDVi, right ventricular end-diastolic volume index; RVESVi, right ventricular end-systolic volume index; RV T1, native T1 values in the RV free wall; VIP, ventricular insertion point. *p<0.05, (DOCX)Click here for additional data file.S3 TableAbbreviations: CI, confidence interval; HR, hazard ratio; RV, right ventricle; VIPs, ventricular insertion points.(DOCX)Click here for additional data file.S1 FigNative T1 values were measured using regions of interest. Abbreviations: ROIs, regions of interests.(DOCX)Click here for additional data file.S2 FigAccording to a previous report, a +3% change defines an increased RVEF, while a −3% change defines a decreased RVEF at follow-up (see Methods). The baseline right ventricular (RV) T1 values were higher in patients with a decreased RVEF (n = 4) than in those with a stable/increased RVEF at follow-up examinations (n = 14). Abbreviations: RVEF, right ventricular ejection fraction.(DOCX)Click here for additional data file.


Takotsubo syndrome (TTS), a transient form of dysfunction in the heart’s left ventricle, occurs predominantly in postmenopausal women who have emotional stress. Earlier studies support the concept that the human circulatory system is modulated by a cortical network ) that plays a pivotal role in the central autonomic nervous system in relation to emotional stressors. The Ic plays a crucial role in the sympathovagal balance, and decreased levels of female sex hormones have been speculated to change functional cerebral asymmetry, with a possible link to autonomic instability. In this review, we focus on the Ic as an important moderator of the human brain–heart axis in association with sex hormones. We also summarize the current knowledge regarding the sex-specific neuroanatomy in TTS. Takotsubo syndrome (TTS)—a transient form of left ventricular (LV) dysfunction in individuals who are under emotional stress—has been known as an acute syndrome with akinesis from the heart’s mid-left ventricle to the apex . SeveralStudies of gender-specific responses to changes in sympathovagal balance and asymmetry in cerebral function have suggested that a dominant pattern in females is determined by the left hemisphere, since functional cerebral asymmetry appears to be changed according to the body’s estrogen levels. The sympathovagal autonomic balance might be shifted via changes in CAN outflow due to functional cerebral asymmetry variability .The relationship between TTS and the Ic has been reviewed . The preThe CAN is composed of the periaqueductal gray matter, parabrachial nucleus (PBN), nucleus tractus solitarius (NTS), ventrolateral medulla (VLM), hypothalamus, amygdala, and the Ic . The CANSeveral neuroimaging studies revealed that activation of the Ic is involved in the processing of negative emotions such as anger, fear, and anxiety . In an iThe Ic is thus suspected to play an important role in coordinating the autonomic nervous system with the information of emotion . The aboA.Animal StudiesA study using anesthetized rats revealed the cardiac chronotropic sites. While stimulations in rostral posterior Ic derived tachycardia, those in the caudal posterior Ic derived bradycardia ,14. In aIn another investigation using rats, ischemic stroke in Ic was associated with left atrium (LA)-pulmonary vein (PV) border fibrosis, which is thought to be the pathophysiology of the generation of atrial fibrillation (AF) . LA-PV bIn a model of permanent middle cerebral artery occlusion (MCAO), the severity of left Ic lesion and the serum and heart norepinephrine levels were significantly higher in MCAO mice with LV dysfunction than those with normal cardiac function . In anotThe cardiovascular, autonomic, and cardiac changes produced in a focal experimental model of intracerebral hemorrhage (ICH) in the Ic were evaluated by Marins and colleagues . AlthougAlthough the type of Ic ischemia or ICH model might have differing impacts on the target organs in these animal studies, these studies’ findings reveal that Ic stroke is associated with arrhythmia, LV dysfunction, LA-PV border fibrosis, and kidney injury. Because there were few observations from the viewpoint of gender differences, in the future, it would be necessary to examine the gender-specific brain–heart relationship in these animal experiments.B.B.1.The Role of Hemispheric Laterality in Sympathovagal ModulationHuman StudiesIn epileptic patients who were undergoing a preoperative evaluation, the HR decreased after an amobarbital injection to the right carotid artery that inactivated the right hemisphere, whereas the HR increased after an amobarbital injection to the left carotid artery that inactivated the left hemisphere . In theiThese findings suggest that the left and right hemisphere might have different cerebral impacts on autonomic function: the right side of the brain is involved in sympathetic cardiac function, whereas the left side of brain is involved in parasympathetic cardiac function.B.2.B.2.1.Epilepsy StudiesThe Insular Cortex and Heart Rate, Arrhythmia, and Sympathovagal BalanceNeuroanatomic brain–heart connections are involved in cardiac arrhythmias that occur in response to abnormal brain activation including the Ic. Seizures induce a variety of transient cardiac effects such as arrhythmias, asystole, and other electrocardiography (ECG) abnormalities that can trigger sudden unexpected death in individuals with epilepsy . For exaFocal cortical dysplasia in the temporal region including the Ic is suggested to cause ictal bradycardia and ictal asystole. A 15-year-old epileptic patient with focal dysplasia of the cerebral cortex that included both the right and left Ic showed prolonged asystole in relation to seizures and syncope . In addiStimulation of the Ic prior to a lobectomy for the purpose of seizure control has been performed in patients with epilepsy; while depressor and bradycardia responses were frequently observed when left Ic stimulation was applied, pressor and tachycardia responses were frequently observed when right Ic stimulation was applied . In contIn a study that applied 100 electrical stimulations to the Ic in 47 patients with epilepsy, 26 stimulations (26%) induced bradycardia and 21 stimulations (21%) induced tachycardia . BradycaA study using stereo-electroencephalography (SEEG) demonstrated that a left amygdalo-hippocampal seizure induced asystole with ipsilateral spread to the Ic . AlthougB.2.2.Neuroimaging StudiesThe activation of interconnected regions of the brainstem, ACC, amygdala, and Ic has been shown to predict HR acceleration in relation to emotional facial stimuli . In a stWithin the whole cortex, the highest α4β2 nicotinic acetylcholine receptor (nAChRs) densities are in the anterior Ic and the dorsal ACC. A PET study investigated the association between parasympathetic tone as assessed by HRV and the regional brain availability of nAChR assessed by the potential of 18F-F-A-85380 binding; higher availability of nAChRs in the right dorsal anterior Ic and the bilateral dorsal ACC was associated with lower HF power. The increased nAChR availability in the right anterior Ic was suggested to participate in reduced parasympathetic activity . In a voIn another fMRI study, the increased activity in the dorsal ACC and right anterior and posterior Ic plus the decreased activity in the ventral ACC and left posterior Ic had significant correlations with muscle sympathetic nerve activity burst frequency . In a laSong et al.  investigIn a vagus nerve stimulation study of child patients with treatment-resistant epilepsy, the responders to this treatment showed greater increased anisotropy in the left limbic, thalamocortical, and association fibers, and they demonstrated increased functional connectivity in a network within the thalamus, temporal nodes, and left Ic .These neuroimaging findings identified a substrate for central nervous system mechanisms that contribute to the sympathovagal balance of the Ic, suggesting that the right Ic has an association with sympathetic nervous system activity while the left Ic has an association with parasympathetic nervous system activity.In the acute phase of a stroke such as a cerebral hemorrhage or subarachnoid hemorrhage (SAH), ECG changes have sometimes been observed, including corrected QT (QTc) interval prolongation, ST-segment elevation or depression, and T-wave inversion ,52,53,54Patients with a parietoinsular ischemic lesion were observed to have an increased risk of developing atrial fibrillation detected after stroke (AFDAS) . AlthougAsystole was reported in patients with ischemic stroke involving the right Ic  or rightThe role of an infarction involving the Ic in acute kidney injury (AKI) was analyzed in 172 acute ischemic stroke patients; the results demonstrated that Ic infarction, especially right Ic infarction, is an independent risk factor for AKI .In the Jichi Medical School ABPM Study Wave 2 Core, left Ic atrophy was significantly correlated with the level of brain natriuretic peptide (BNP) ,69. StroBecause it is not yet known which comorbidities and stroke characteristics are associated with elevated post-stroke cTnT levels, an ongoing meta-analysis is assessing the association between elevated cTnT and specific stroke characteristics such as infarct/hemorrhage size, stroke severity, Ic involvement, and renal failure after ischemic stroke or ICH .Ic-involved stroke is suggested to be associated with changes in ECG, disrupted diurnal BP variation, reduced BRS, cardiac injury, cardiac overload, and cardiac dysfunction. Instability of the sympathovagal balance could serve as substantial pathophysiology linking the relationship between Ic lesion and dysregulation in the cardiovascular system. A meta-analysis examining the relationship between Ic-involved stroke and cardiac injury is ongoing, and a more clinically relevant pathophysiology of Ic-involved stroke can thus be expected to be revealed in relation to cardiovascular dysregulation.TTS was first officially reported in 1991 as a reversible cardiomyopathy that appeared to be precipitated by acute emotional stress ,77. A stSympathetic autonomic nervous system overactivity is one possible pathophysiology underlying TTS. Elevated concentrations of plasma norepinephrine have been reported in acute stroke ,86, and Recent research has described a pathophysiology linking the relationship between cerebral infarction and TTS with poor outcome, and damage to the integrity of the blood–brain barrier (BBB) was suggested to explain the underlying pathophysiology. In addition to increased levels of catecholamine, post-cerebral infarction patients with TTS showed elevated blood levels of inflammatory mediators that are known to cause vascular conditions such as thromboembolism and stroke . These sUsing an in vitro model of the BBB consisting of an immortalized murine microvascular endothelial cell (cEND) line, Förster et al. (2005)  analyzedWe reported the TTS case of a 79-year-old female with LV asynergy in the mid-ventricle after a right Ic infarction . Twelve In a study of 1750 TTS patients, the apical pattern of TTS was shown to be the most common type (81.7%), and the mid-ventricular pattern was the second most common type 14.6%) . Althoug.6% . AltIn the apical pattern of TTS, the effect of increased catecholamine levels on the myocardium determined by the beta-adrenoceptor (βAR) gradient is thought to be associated with subsequent acute apical ballooning . βAR graData from the Japanese National Cardiovascular Center  revealedIn a review of patients with acute stroke concomitant with the development of TTS , the femA decrease in the level of ovarian hormones has been shown to accelerate aging in women and increase their rate of mortality due to cardiovascular disease . GreaterA study by Barros et al. (2006)  revealedAlthough it is known that the heart reacts to estrogen, it is not yet clear whether estrogen affects cardiomyocytes directly or indirectly via the immune, nervous, and/or vascular systems. In analyses of ERβ-deficient mice, enlarged hearts were observed with myocardial disarray, disrupted intercalated discs, profound nuclear structure alteration, and an increased number and size of gap junctions . In the Although the clinical features of HFrEF and those of TTS differ, the postmenopausal female status might serve as a common pathophysiology underlying HFrEF and TTS, and a reduced level of estradiol seems to be a common risk. The complex relationships between sex hormones and the cardiovascular regulatory system might give us a glimpse into the pathophysiology of HFrEF and TTS.The right hemisphere is predominantly involved in controlling spontaneously triggered emotional stimuli , and it The Ic has abundant reciprocal connections with brain regions in the frontal, temporal, and parietal lobes as well as in the thalamus and the limbic/paralimbic systems ,114,115.The Ic is involved in processing the perception of positive as well as negative emotional information. The above-described evidence supports the notion that the exaggerated right Ic activation in anxiety, fear, phobia, and happiness experienced by patients with TTS changes the predominant sympathovagal balance to cardiac sympathetic overdrive. In postmenopausal females, left-hemispheric reduced activation including the Ic shifts the sympathovagal balance to sympathetic predominance, and this might be associated with a pivotal role of the Ic in the pathophysiology of TTS in relation to positive and negative emotional events.It is not yet known whether the transient LV dysfunction observed in neurological disease has the same pathophysiology as conventional TTS that is free from overt neurological disorders. A lesion located at or close to the Ic may help explain the crucial role of sympathetic overactivation in post-menopausal women.In a resting-state fMRI study, TTS patients were observed to have reduced functional connectivity in sympathovagal-associated subnetworks including the bilateral medial orbitofrontal cortices, the left posterior cingulate cortex, and the left anterior Ic . BecauseResting-state and anatomical fMRI studies demonstrated functional and volumetric right Ic changes in TTS patients, and it was shown that in TTS, the relationship between left amygdala atrophy and right anterior Ic atrophy was associated with sympathovagal instability . In the Animal models of experimental stroke revealed that right-side MCAO was associated with neurochemical derangements in the amygdala and Ic of the ipsilateral hemisphere, which led to enhanced cardiac sympathetic outflow with an increased level of synaptic norepinephrine . IncreasRecent research concerning the relationship between the Ic and autonomic control of the cardiovascular system has been summarized and updated in this review. Stroke involving the Ic presents various types of cardio-autonomic dysregulation that are also observed in TTS. Left Ic dysfunction, which is associated with estrogen deficiency in postmenopausal status, might have a pivotal role in the sympathetic overdrive in TTS. Future research into the sex-specific neuroanatomy of the Ic in TTS may provide key insights into the pathophysiology of stress-related cardiovascular disease from a psychosomatic perspective.


The 2016 guidelines of the American Society of Echocardiography (ASE) and European Association of Cardiovascular Imaging (EACVI) for evaluation of left ventricular (LV) diastolic dysfunction by Doppler flow and tissue Doppler- echocardiography do not adjust assessment of high filling pressures for patients with aortic stenosis (AS). However, most of the studies on this patient group indicate age independent specific diastolic features in AS. The aim of this study is to identify disease-specific range and distribution of diastolic functional parameters and their ability to identify high N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels as a marker for high filling pressures.In this study, 169 patients who underwent surgical aortic valve replacement (SAVR) or transcatheter aortic valve replacement (TAVR) were prospectively enrolled. Resting echocardiography was performed including Doppler of the mitral inflow, pulmonary venous flow, tricuspid regurgitant flow and tissue Doppler in the mitral ring and indexed volume-estimates of the left atrium (LAVI). Echocardiography, and NT-proBNP levels were assessed before TAVR/SAVR and at two postoperative visits at 6 and 12 months.2, pulmonary artery pressure (PAP) 39 ± 8; 36 ± 8 mmHg, respectively. The scoring recommended by ASE/EACVI detected elevated NT pro-BNP with a specificity of 25%. Adjusting thresholds towards PAP ≥ 40 mmHg, E velocity ≥ 100 cm/s, E deceleration time < 220 ms, and E/septal e′ ≥ 20 or septal e′ < 5.0 cm/s increased prediction of NT-proBNP levels ≥500 ng/L with substantially improved specificity (> 85%).Pre- and postoperative values were septal e′; 5.1 ± 3.9, 5.2 ± 1.6 cm/s; lateral e′ 6.3 ± 2.1; 7.7 ± 2.7 cm/s; E/e′19 ± 8; 16 ± 7 cm/s; E velocity 96 ± 32; 95 ± 32 cm/s; LAVI 39 ± 8; 36 ± 8 ml/mDiastolic echocardiographic parameters in AS indicate persistent impaired relaxation and NT-proBNP indicate elevated filling pressures in most of the patients, improving only modestly 6–12 months after TAVR and SAVR. Applying the 2016 ASE/EACVI recommendations for detection of elevated filling pressures to patients with AS, elevated NT pro-BNP levels could not be reliably detected. However, adjusting thresholds of the echocardiographic parameters increased specificities to useful diagnostic levels.REK 2010/397-10.The study was prospectively approved by the regional ethical committee, REK North with the registration number: The online version contains supplementary material available at 10.1186/s12947-021-00262-1. Degenerative aortic valve stenosis (AS) is a chronic and progressive disease which gradually provokes afterload and thereby causes pressure overload on the left ventricle (LV), leading to ventricular fibrosis and consequently diastolic dysfunction over time –3. The apeak) [According to the 2016 recommendations of the American Society of Echocardiography (ASE) and the European Association of Cardiovascular Imaging (EACVI), elevated LV filling pressures should be assessed by left atrial volume index (LAVI) and blood-flow and tissue Doppler parameters, i.e. septal and/or lateral e′ average, E′\e′ ratio, peak gradient over the tricuspid regurgitation (TRpeak) . The ASEHowever, in AS, they do not recommend modification of these criteria , even thDuring progression of diastolic dysfunction, LV wall stress, pressure and volume overload induce the secretion of BNP/ NT-proBNP , a cardiac neurohormone which is secreted by cardiomyocytes in the ventricles. Several studies have shown that high plasma BNP/NT-proBNP levels correlate well with elevated filling pressures and severity of heart failure in patients with AS –13. An aIn this study, we aim to describe diastolic functional parameters in elderly patients with severe AS, at baseline and after aortic valve replacement (AVR). We also tested these parameters and their cut-off values to predict high NT-proBNP levels as a marker of elevated LV filling pressure.In a prospective study between 2010 and 2013, 169 patients with severe symptomatic AS, who were eligible either for transcatheter AVR (TAVR) or surgical AVR (SAVR) at the University Hospital of North Norway Tromsø, were consecutively included in the study. The decision for TAVR or SAVR was made by a multidisciplinary cardiology team who determined the operation type (TAVR or SAVR) based on patients’ indications, technical feasibility, the risk for open heart-surgery, age, comorbidities and mental status. Patients who were unable to give informed consent, or with life expectancy of less than 12 months, or with low motivation for interventional treatment, were not offered aortic valve replacement of any kind. All 169 included participants in the study were invited to a pre-operative clinical assessment and echocardiography and NT-proBNP measurement and two repeated control investigations at 6 (± 1 month) and 12 (± 1 month) months after the operation.Clinical characteristics, mortality and complications during and after surgery were obtained from the patients’ electronic journals. Patients were classified according to the global initiative for chronic obstructive lung disease (GOLD) classification for chronic obstructive pulmonary disease (COPD), and the patients with COPD of unknown grade were classified as having COPD grade 1. The patients who had a history of stroke or transient ischemic attacks, or significant (> 70%) stenosis of the carotid arteries, were classified as having cerebrovascular disease. Chronic and paroxysmal atrial fibrillation/flutter conditions were grouped as one variable. The patients with records, less than 2 weeks prior to surgery, of physician documented clinical signs of heart failure in the form of unusual dyspnoea on light exertion, orthopnoea, fluid retention, description of rales on auscultation, or pulmonary oedema on chest X-ray, were classified as having heart failure (HF < 2 weeks). The patients were classified as having left bundle branch block (LBBB) according to the Minnesota criteria in the resting ECG. Predominance of ventricular pacing or LBBB was assessed by the rhythm registered during echocardiography.All patients underwent preoperative echocardiography in the left lateral decubital position with an iE33 scanner . Conventional 2-dimensional grey scale images were obtained in parasternal long- and short- axes as well as apical four-chamber, two-chamber and long-axis-views. 2D long-axis images were obtained at a time-resolution of was 58 ± 20 frames/s. LV EF was derived from the two- and four-chamber views using the biplane Simpson’s method . The samFor the evaluation of mitral regurgitation and aortic regurgitation, we performed a multiparametric, semiquantitative approach as recommended in the guidelines .peak) and an estimate of the systolic pulmonary arterial pressure (PAP) by adding 10 mmHg to the TRpeak, and the isovolumetric relaxation time (IVRT).Diastolic LV function was assessed by evaluation of the following parameters: Mitral E- and A-wave velocity, E/A ratio, E deceleration time (DT), septal, lateral wall and average tissue Doppler velocities (e′) and their E/e′ ratios, systolic filling fraction of the pulmonary veins (SFF), LAVI, the velocity and peak gradient over the tricuspid regurgitation . Preoperative patient-characteristics of the TAVR and SAVR groups were compared using either t-test or chi-square test. The frequencies of categorized diastolic parameters were compared using chi-square test to analyse the differences between the age groups (≥ or < 80 years) and pre- and postoperative data baseline and control after TAVR/SAVR. We compared further pre-operative to post-operative echocardiographic diastolic parameters using paired t-test. For this comparison, one average value of each parameter was calculated for parameters of the first and second post-AVR control.Receiver operating characteristic (ROC) curve analysis was performed on pre- and post-operative echocardiographic measurements when NT-proBNP values were available. The NT-proBNP level > 500 ng/L was chosen from the clinical cut-off value in our hospital for the largest age group of patients in our study . Age-related cut-off values were not chosen, since the NT-proBNP threshold increased in many patients during the first control-year. To identify predictors of elevated NT-proBNP levels, three cut-off values of similar sensitivity-specificity-sum were chosen for each diastolic parameter, among the values with high sensitivity and moderate specificity and high specificity combined with moderate sensitivity.p ≤ 0.05 and deemed clinically relevant were selected and tested to analyse interaction and co-linearity prior to forward and backward multivariable logistic regression analysis. When the interaction terms in the backward analysis were non-significant, the forward model was used. For the final inclusion into a multiple regression model, a p-value of ≤0.05 was considered significant. Independent predictors of the multivariable analysis were combined in a scoring system. For this new score, sensitivities and specificities were calculated for different cut-off values using ROC curve analysis.For the independent and dependent correlation of diastolic echocardiographic indices with the presence of NT-proBNP value > 500 ng/L, univariate and multivariate logistic regression analysis was performed. Variables with Over a three-year period, 169 patients were included in this study. Twelve patients with a mean gradient < 40 mmHg and reduced stroke-volume, indicating a low-flow low gradient AS, while two patients were referred to AVR and CABG presented with a moderate aortic stenosis. One patient referred to TAVR had a gradient of 38 mmHg and normal stroke volume. At the time of AVR referral, all patients presented with exertional dyspnoea at least NYHA II, 46% presented with angina, 6% with dizziness or syncope and 10% of patients presented with additional angina and dizziness.There was no statistical difference for type of symptoms between the TAVI and AVR groups. Eighteen patients died during the procedure or during the first 6 months after SAVR or TAVR. One hundred thirty-five patients returned to either follow-up control, 132 participants attended the first postoperative control at 6 months, and 121 patients attended the second control at 12 months. Of 388 visits of the 169 included patients with NT-proBNP measurements, NT-proBNP values could be linked to echocardiographic parameters in 358 visits.We compiled baseline demographic and clinical characteristics of the patients who underwent TAVR and SAVR Table . The TAVComparing diastolic echocardiographic parameters and NT-proBNP levels in patients who were 80 years or older to patients younger than 80 years, we found no differences regarding mitral-inflow and tissue-Doppler parameters. We observed a borderline significantly higher LAVI in the older patients, while only NT-proBNP and PAP values in the older patients were significantly higher compared to those younger than 80 years.Figure 2 and 346 of 392 (88%) with septal e′ < 7 cm/s. The NT-proBNP level was found to be ≥500 ng/L in 256 of 388 (66%) visits.Using the 2016 ASE/EACVI recommended cut of values, we found 33 of 382 (8.6%) of measurements with PAP > 40 mmHg, 233 of 392 (59%) with E/e′ > 14 cm/s, 336 of 393 (85%) with LAVI> 34 ml/mFigure Table Table This study demonstrates range and distribution of echocardiographic parameters in the elderly population with high grade aortic stenosis. Independent predictors of elevated NT-proBNP levels (> 500 ng/L) are PAP, mitral peak E, DT and septal E/e′ or septal e′ which can be used interchangeably. Parameters which are recommended for the assessment of diastolic dysfunction according to the 2016 ASE and EACVI guidelines  result in comparable AUC in ROC curve analyses as reported in the guidelines. However, specificities at sensitivity > 60%; > 45% could be increased from 23 to > 75%; 85%, respectively, by appropriate change of threshold-values.Delayed relaxation and relaxation velocity of the mitral ring might be associated with increased afterload and left ventricular hypertrophy . FillingIncreased filling pressures can be determined by invasive measurement of ventricular pre-A pressure, which is a condition often followed by increased end-diastolic pressure and pulmonary capillary wedge pressure (PCWP). Increased filling pressures in AS are often reversible and can occur at superimposed afterload in a ventricle with reduced relaxation properties and initially normal filling pressures . FillingVentricular hypertrophy, fibrosis and molecular mechanisms of diastolic dysfunction  might afAortic stenosis modifies ventricular diastolic properties with three different mechanisms:Most echocardiographic parameters of diastolic dysfunction have a U-shaped function with normal values between two extremes of either impaired relaxation or increased filling pressures . For corAge alone is one important factor for reduced relaxation properties. However, the patient population with TAVR, typically ages > 75 years, is scarcely represented in epidemiological studies  or in coCompared to the high age group of the guidelines, the septal and lateral e′ are significantly lower, and LAVI and DT are significantly higher in the present study. To a smaller extent, age might reduce relaxation properties in higher age groups, however, most of the diastolic parameters were not different between the two age groups ≥80 and < 80 years in the present study.Steine et al.  investigEven though the present study represents an older patient population with higher degree of AS compared to Steines and other younger study populations , 23, 25,Even though e′ increases after TAVR/SAVR , 25–27, The correlation of e′ and improvement of s′ and their increase after AVR, indicate an association between ventricular contraction and relaxation velocities, which are both influenced by afterload changes , 28. TheKjønås et al. investigated echocardiographic systolic and diastolic parameters as predictors of mortality in the TAVR population of this study. These data showed that only increased pulmonary artery pressure was a predictor for early death, while other echocardiographic parameters of systolic or diastolic function did not indicate the outcome during the first 2 years.The present study refers to the 2016 ASE/EACVI recommendations for the evaluation of LV diastolic dysfunction , which pThe current results reflect the difficulties of estimating filling pressures in ventricles with highly impaired relaxation. Impaired relaxation will naturally change thresholds for increased filling pressures due to the U-shaped function of many Doppler-based parameters. This applies for mitral peak E velocity, DT, IVRT and PV SFF . In oppoPlasma NT-proBNP levels correlate well with elevated filling pressures in many different settings , 11, 13.Significantly reduced NT-proBNP levels after AVR indicate moderately improved but not normalized filling pressures following afterload reduction. ROC curve analyses for several diastolic parameters distinguish high and low NT-proBNP values with AUC values between 65 and 76%, which indicates moderate diagnostic value when values are measured in the intermediate range. In line with our findings, Sasaki et al. showed that E/e′ was a highly sensitive and specific predictor of NT-proBNP levels, even after adjustment for clinical and systolic parameters . NotablyHigh PAP is a consistent and independent marker of elevated filling pressures , 4, 14 aPreoperatively and postoperatively, 91 and 78% of patients with AS, respectively, displayed at least 2–3 of 3 criteria of grade I-III diastolic dysfunction, which include septal e′, lateral e′, LAVI, according to the 2009 ASE/EACVI guidelines.Following the 2016 guidelines, all mitral flow and tissue-Doppler based parameters indicated elevated filling pressures in the majority of AS patients with unacceptably low specificity (25%). Only TR velocity > 2.8 m/s indicated high NT-proBNP levels with high specificity at acceptable sensitivity.According to the results of the present study, we suggest the use of an adjusted model for elderly patients with AS by taking the following considerations into account:First, E/e′ and e’are good indicators of elevated filling pressures. Because of high correlation with each other, they have no significant additive value and can be used interchangeably. Septal or average E/e′ and e′ seemed to be more accurate than lateral e′ measurements in assessment of increased filling pressure.Second, LA volume was not a significant indicator of increased NT-proBNP levels and thus of lesser value in the assessment of increased filling pressures in AS patients. LA size changes with atrial fibrillation, which was present in 25% of the AS patients, and it increased due to impaired relaxation which is present in the majority of AS patients. LA size might be a better indicator for long-term increased filling pressures when seperatedly assessed for patients with sinus-rhythm or atrial fibrillation.Third, our study confirms a highly specific PAP cut-off level of 40 mmHg which is the equivalent of TR peak velocity of 2.8 m/s suggested in the 2016 guidelines.Fourth, E wave velocity and E DT, are independent indicators of elevated NT-proBNP levels in the multiple logistic regression analysis. E wave velocity decreases and DT is prolonged after AVR, indicating a closer relationship with reversible pressures. However, E velocity, DT, E/e′ and e′ cut-off values have to be adjusted towards cut-off values with higher specificities to be relevant for clinical use. According to our results, at least one of the following parameters need to cross their thresholds to indicate high filling pressures in patients with pre- or postoperative aortic stenosis: E/e’sept > 20; E velocity > 100 cm/s; DT < 220 ms; PAP > 40 mmHg or e’sept < 5.0 cm/s.The gold standard for diastolic filling pressures is invasive pressure measurements by right or left-heart catheter, which were not available in the present study. We used NT-proBNP as a surrogate marker of increased filling pressure, as previously practiced in other studies , 19. EveThe present study was performed on one ultrasound-system and the same reader, resulting in highly robust tissue velocity measurements. However, tissue Doppler indices are known to differ between ultrasound-systems with vendor specific machine-settings . CompariIn the TAVR population of this study, we could show that pulmonary hypertension is a strong predictor for early death . Early dMany factors like valvular heart disease, atrial fibrillation, ejection fraction, age, gender, ischemic heart disease, hypertension, amyloidosis, mitral ring calcification  and otheDiastolic echocardiographic parameters in AS indicate persistent impaired relaxation and NT-proBNP indicate higher filling pressures in most of the patients, improving only modestly 6–12 months after TAVR and SAVR. Applying the 2016 ASE/EACVI recommendations for detection of elevated filling pressures to patients with AS, elevated NT pro-BNP levels could not be reliably detected. However, adjusting thresholds of the echocardiographic parameters increased specificities to useful diagnostic levels.Additional file 1: Table S1. ROC curve analysis of echocardiographic parameters to predict NT-proBNP ≥500 ng/L in patients with severe aortic stenosis. Table S2. Cut-off values, sensitivity and specificity for detection of elevated NT-proBNP.


Immune-inflammatory myocardial disease contributes to multiple chronic cardiac processes, but access to non-invasive screening is limited. We have previously developed a method of echocardiographic texture analysis, called the high-spectrum signal intensity coefficient (HS-SIC) which assesses myocardial microstructure and previously associated with myocardial fibrosis. We aimed to determine whether this echocardiographic texture analysis of cardiac microstructure can identify inflammatory cardiac disease in the clinical setting.We conducted a retrospective case-control study of 318 patients with distinct clinical myocardial pathologies and 20 healthy controls. Populations included myocarditis, atypical chest pain/palpitations, STEMI, severe aortic stenosis, acute COVID infection, amyloidosis, and cardiac transplantation with acute rejection, without current rejection but with prior rejection, and with no history of rejection. We assessed the HS-SIC’s ability to differentiate between a broader diversity of clinical groups and healthy controls. We used Kruskal-Wallis tests to compare HS-SIC values measured in each of the clinical populations with those in the healthy control group and compared HS-SIC values between the subgroups of cardiac transplantation rejection status.N = 338, the mean age was 49.6 ± 20.9 years and 50% were women. The mean ± standard error of the mean of HS-SIC were: 0.668 ± 0.074 for controls, 0.552 ± 0.049 for atypical chest pain/palpitations, 0.425 ± 0.058 for myocarditis, 0.881 ± 0.129 for STEMI, 1.116 ± 0.196 for severe aortic stenosis, 0.904 ± 0.116 for acute COVID, and 0.698 ± 0.103 for amyloidosis. Among cardiac transplant recipients, HS-SIC values were 0.478 ± 0.999 for active rejection, 0.594 ± 0.091 for prior rejection, and 1.191 ± 0.442 for never rejection. We observed significant differences in HS-SIC between controls and myocarditis (P = 0.0014), active rejection (P = 0.0076), and atypical chest pain or palpitations (P = 0.0014); as well as between transplant patients with active rejection and those without current or prior rejection (P = 0.031).For the total sample of An echocardiographic method can be used to characterize tissue signatures of microstructural changes across a spectrum of cardiac disease including immune-inflammatory conditions. Accumulating evidence suggests that immune or inflammatory processes contribute to a wide variety of myocardial disease processes which may transition over time to clinical heart failure , 2. Non-We used retrospective chart query with adjudication to identify patients in our Cedars Sinai Health System with clinical evidence of having 1 of 9 distinct myocardial disease entities at the time of transthoracic echocardiography and compared to a healthy control group. Each disease diagnosis was adjudicated based on ICD9 and ICD10 codes, laboratory data, imaging, and chart review. The following non-overlapping myocardial disease entities were identified with clinical cardiologist adjudication: myocarditis, atypical chest pain or palpitations without medical comorbidities, acute left anterior descending coronary artery STEMI, severe aortic stenosis with normal ejection fraction, acute COVID infection with positive troponin, TTR amyloidosis, and cardiac transplantation status undergoing screening biopsy in 3 groups - active rejection on histopathology, no active rejection but with history of prior rejection, and no active and no history of rejection. All samples except for COVID were drawn from 2019 and prior, avoiding overlap with the COVID population. The atypical chest pain or palpitations excluded any patients with suspected myocarditis or pericarditis. Patients were included in the clinical cohort if they had a contemporaneous transthoracic echocardiogram performed during the index hospitalization for acute conditions ; performed in association with a clinical encounter with ICD coding for chronic conditions ; or, performed at the time of screening endomyocardial biopsy for cardiac transplantation.For the healthy control reference group, we selected participants of an established community-based cohort study who had normal range laboratory diagnostics and no known cardiovascular risk factors at the time of transthoracic echocardiography . IdentifThe echocardiographic method for quantifying myocardial microstructure alterations has been detailed previously –5. This P < 0.05.We used Kruskal-Wallis tests to compare HS-SIC values measured in each of the clinical populations with those in the screening control group; we also compared HS-SIC values between the subgroups of cardiac transplantation rejection status. We used R v4.0.0 for all statistical analyses and defined the threshold of significance as a two-tailed n = 338 patients, with 318 in the clinical cohort and 20 in the screening cohort. For the total study sample, mean age was 49.6 ± 20.9 years and 50% were men, with expected variation in characteristics across clinical diagnosis groups. The number of individuals in each group ranged from 5 in cardiac transplantation patients without either active or prior organ rejection to 127 in the atypical chest pain or palpitations group , myocarditis , and active rejection . We also observed differences within the transplantation subset. Patients with active rejection had lower HS-SIC values versus patients without current or prior rejection .We observed that patients with more acute inflammatory conditions  had lower HS-SIC values, patients with more fibrotic myocardial conditions  had higher HS-SIC values Fig. . There wlower HS-SIC values in cardiac conditions known to involve acute immune-inflammatory activity (e.g. myocarditis and acute cardiac transplant rejection). These findings suggest that presence of immune-inflammatory edema or cellular infiltration may lead to changes in acoustic substrate that is detectable and quantifiable. Intriguingly, our findings of mildly reduced HS-SIC levels in patients presenting with atypical cardiac symptoms  raises the specter of subclinical inflammation in this setting.In this clinical proof-of-concept study, we found that a highly accessible echocardiographic texture analysis method was able to distinguish myocardial pathologies from healthy control status. We and others have shown that echocardiographic texture analysis can identify microstructural alterations associated with hypertensive disease , preclinWhile our results should be interpreted as a proof-of-concept study and requires off-line analysis of echocardiographic images, we believe that this method has potential for future clinical implications. The calculation of the HS-SIC itself is not complex and is software agnostic. If identification of the appropriate view and region of interest can be solved, this measurement could be provided within a clinical interpretation pipeline as supplementary information to clinical readers. This may provide incremental benefit over qualitative estimates of intensity by incorporating both signal intensity and signal distribution information into a quantitative measurement. Preliminary analyses for deep-learning based placement of the ROI are ongoing .Several limitations of our study merit consideration. Because healthy control participants lack indications for clinical echocardiography, our control sample is from a screening dataset with imaging obtained externally. Our study cohort included clinical subgroups that were small in size, precluding multiple statistical testing or multivariable-association analyses. Although the HS-SIC has been validated as measure of myocardial fibrosis , we lackIn summary, we found that an accessible echocardiographic imaging method can be used to characterize microstructural changes across a spectrum of myocardial disease including active immune-inflammatory conditions. Given the relatively low cost and wide availability of echocardiography in practice, our results underscore the benefit of potential future immune-inflammatory targeted applications, including early detection of immune-inflammatory cardiac disease , serial monitoring of response to therapies (e.g. in acute cardiac transplant rejection), and longitudinal phenotyping of the progression from immune-inflammatory risk to overt clinical heart failure over time.