We evaluated the clinical utility of ultra-widefield imaging as an adjunctive tool for training resident ophthalmologists in the detection of retinal breaks. This was a prospective study conducted at a secondary health care center  in Taiwan. Participants were 44 patients (53 eyes) who were referred to our hospital after being diagnosed with retinal breaks. Patients first underwent an indirect ophthalmoscopy examination of the total fundus without scleral depression by our junior (first and second year) or senior (third and fourth year) resident ophthalmologist and then underwent an ultra-widefield imaging examination with a central image and four gaze-steered  images to determine the number of retinal breaks in the total fundus and the four quadrants. Of the total 53 eyes, 31 were examined by junior residents and 22 were examined by senior residents. In the group of junior residents, ultra-widefield imaging was significantly better at detecting retinal breaks of the total fundus  and the temporal quadrant  than indirect ophthalmoscopy. In the group of senior residents, there was no significant difference in the ability to detect retinal breaks in the total fundus or each of the four quadrants with ultra-widefield imaging or indirect ophthalmoscopy. Our results indicate that, compared to indirect ophthalmoscopy, ultra-widefield imaging with a central image and four gaze-steered images has a better performance and is a useful adjunct tool for the detection of retinal breaks in junior resident training. Additionally, it could be a useful method for teaching indirect ophthalmoscopy examination to junior residents. Retinal breaks are a well-recognized complication following separation of the cortical vitreous and posterior hyaloid membrane from the inner retina . An estiBesides indirect ophthalmoscopy, photographic imaging of the fundus can also be used to identify retinal breaks. Traditional color fundus photographic imaging can only provide a small angle, about a 30° to 45° field of view of the fundus . MultiplBecause indirect ophthalmoscopy is difficult to perform for junior residents and UWF retinal imaging provides up to 97% visualization of the retina, this technique may be used as a teaching method to help junior residents to improve their performance of indirect ophthalmoscopy for the detection of retinal breaks. The purpose of this study was to compare the ability of UWF retinal imaging and indirect ophthalmoscopy to detect retinal breaks in examinations performed by junior and senior ophthalmologists. This allowed us to evaluate whether UWF imaging is a useful, adjunctive tool in the detection of retinal breaks, especially for junior residents, and whether it can be used as a method to teach indirect ophthalmoscopy to the aforementioned group.This prospective observational study was performed at Tri-Service General Hospital, National Defense Medical Center, Taipei City, Taiwan, from April 1st, 2019 to September 30th, 2020. The study was conducted with the approval of the Institutional Review Board (Registration No. C202005046) and adhered to the tenets of the Declaration of Helsinki. All patients provided informed consent for participation in the study.This study included patients with symptoms of floaters and/or photopsia who came to our clinic or the emergency department of the Tri-Service General Hospital, National Defense Medical Center, Taipei City, Taiwan during the study period and were diagnosed with a retinal break. Patients with a disease causing corneal opacity or vitreous opacity, such as cornea decompensation or vitreous hemorrhage, which cause poor image quality, were excluded. Patients who were not willing to take part in the UWF imaging or indirect ophthalmoscopy examination were also excluded. Finally, data from 53 eyes of 44 patients with retinal breaks were collected. Nine patients had retinal breaks in both eyes.Patients first underwent an indirect ophthalmoscopy examination with pupil dilatation and without scleral depression of the total fundus, followed by UWF imaging examination with pupil dilatation, using Optos California UWF retinal imaging . These examinations were perforemed by junior ophthalmology residents (31 eyes of 25 patients) or senior ophthalmology residents (22 eyes of 19 patients). Indirect ophthalmoscopy examination was done using a binocular indirect ophthalmoscope  with a 20D lens (Ocular MaxAC® 20D). Patients were randomized to be examined by either junior or senior residents. In Taiwan, ophthalmology residency training is a 4-year program. Junior residents were defined as residents in their first or second year of resident ophthalmologist training, and senior residents were defined as those in their third or fourth year of resident ophthalmologist training. Overall, 6 junior residents and 5 senior residents were included in this study. After the indirect ophthalmoscopy examination was performed by the junior or senior residents, the examination was repeated by one of two randomly assigned qualified attending ophthalmologists, Ching-Long Chen and Shu-I Pao.A central image and four gaze-steered images  were taken during the UWF imaging examination . On the Statistical analysis was performed using IBM-SPSS for Windows software, version 22 . Due to a small sample and because we wanted to study if there are non-random associations between the two categorical variables , Fisher’s exact test was used to compare retinal break identification ability between UWF imaging and indirect ophthalmoscopy within the junior and senior resident groups. A p-value smaller than 0.05 was considered to be statistically significant.Data from 53 eyes of 44 patients  with retinal breaks were collected. The mean age of patients was 52.5 years . The lens status was phakic, pseudophakic, and aphakic in 43, 10, and 0 eyes, respectively. We divided patients into two groups–the group in which examinations were conducted by junior residents and the group in which examinations were conducted by senior residents. For the group examined by junior residents, 31 eyes of 25 patients  were included. The mean age of these patients was 52.3 years . The lens status was phakic, pseudophakic, and aphakic in 26, 5, and 0 eyes, respectively. For the indirect ophthalmoscopy examination made by junior residents, a total of 33 retinal breaks were detected in the 31 eyes; 5, 10, 11, and 7 retinal breaks were detected in the superior, inferior, temporal, and nasal quadrants, respectively. For the UWF imaging examination, a total of 49 retinal breaks were detected in the 31 eyes, and there were 9, 13, 17, and 10 retinal breaks detected in the superior, inferior, temporal, and nasal quadrants, respectively . Every bFor the group examined by senior residents, 22 eyes of 19 patients  were included. The mean age of patients was 52.7 years . The lens status was phakic, pseudophakic, and aphakic in 17, 5, and 0 eyes, respectively. For the indirect ophthalmoscopy examination made by senior residents, a total of 22 retinal breaks were detected in the 22 eyes, with 6, 2, 9, and 5 retinal breaks detected in the superior, inferior, temporal, and nasal quadrants, respectively. For the UWF imaging examination, a total of 27 retinal breaks were detected in the 22 eyes, with 7, 3, 10, and 7 retinal breaks detected in the superior, inferior, temporal, and nasal quadrants, respectively . As obseIn this study, UWF imaging had a significantly better ability to detect retinal breaks of the total fundus and temporal quadrant compared to indirect ophthalmoscopy when performed by junior residents. Daniel et al. reported that the detection rate of retinal holes and tears in patients with rhegmatogenous retinal detachment is increased in nasal quadrants, but decreased in superior and inferior quadrants, when using UWF imaging to take the central image as compared to indirect ophthalmoscopy . HoweverThe better retinal break detection rate in the total fundus for UWF imaging compared to indirect ophthalmoscopy when examined by junior residents could be explained in two ways. First, UWF imaging examinations allow up to 97% of the retina to be visualized, by taking a central image and four gaze-steered images. Therefore, it can be used to visualize the peripheral retinal break, which is easily missed. Second, junior resident ophthalmologists did not have proficient skills or profound experience with the indirect ophthalmoscopy examination. In contrast, senior resident ophthalmologists have proficient skills and profound experience with the indirect ophthalmoscopy examination. Therefore, there was no significant difference in the ability to detect retinal breaks in the total fundus or each of the four quadrants with UWF imaging or indirect ophthalmoscopy when performed by senior residents. Our results indicate that UWF may be a valuable tool for ophthalmology residents to gain experience and proficiency in the examination of retinas and the detection of breaks.It was interesting to find that UWF imaging also had a better retinal break detection rate in the temporal quadrant than that of indirect ophthalmoscopy when examined by the junior residents. While our results may seem at odds with other examples which showed a better retinal break detection rate in the nasal quadrant from the literature , They caOur study has some limitations. First, although using indirect ophthalmoscopy with scleral depression is considered as the gold standard for the diagnosis of retinal breaks, our indirect ophthalmoscopy examination did not use scleral depression because it can be painful for conscious patients. However, this could lower the detection rate for retinal breaks in peripheral areas. Second, due to the small sample size, this study might be underpowered. Future large-scale studies are needed to validate our results. Third, we did not have a large enough sample size to perform a subgroup analysis between the phakic, pseudophakic, or different cataract severities patients, in whom the ability to detect retinal breaks might differ between UWF imaging and indirect ophthalmoscopy examinations.UWF imaging using a central image and four gaze-steered images is a useful adjunct tool for the detection of retinal breaks in the superior, inferior, temporal, and nasal quadrants, especially for junior residents. For this group of trainees, UWF imaging gave them a significantly better ability to detect retinal breaks of the total fundus and temporal quadrant than that of indirect ophthalmoscopy. Therefore, UWF imaging can be considered as a useful, adjunctive tool in training of residents for retinal break detection. Additionally, it could be a useful method for teaching indirect ophthalmoscopy examination to junior residents.S1 Table(DOCX)Click here for additional data file.S1 Dataset(XLSX)Click here for additional data file.


In patients with chronic coronary syndromes, hyperventilation followed by apnea has been shown to unmask myocardium susceptible to inducible deoxygenation. The aim of this study was to assess whether such a provoked response is co-localized with myocardial dysfunction.n = 12). Participants hyperventilated for 60s followed by brief apnea. Oxygenation-sensitive images were analyzed for changes in myocardial oxygenation and strain.A group of twenty-six CAD patients with a defined stenosis (quantitative coronary angiography > 50%) underwent a cardiovascular magnetic resonance (CMR) exam prior to revascularization. Healthy volunteers older than 50 years served as controls (p < 0.001) and augmented peak circumferential systolic strain . At the end of apnea, myocardial signal intensity had increased  and strain had normalized to baseline. CAD patients had a similar global oxygenation response to hyperventilation  but showed no change in peak strain from their resting state (-1.3 ± 1.6%), which was significantly attenuated in comparison the strain response observed in controls (p = 0.008). With apnea, the CAD patients showed an attenuated global oxygenation response to apnea compared to controls . This was accompanied by a significant depression of peak strain , which also differed from the control response (p = 0.025). Regional analysis demonstrated that post-stenotic myocardium was most susceptible to de-oxygenation and systolic strain abnormalities during respiratory maneuvers. CMR measures at rest were unable to discriminate post-stenotic territory (p > 0.05), yet this was significant for both myocardial oxygenation  and peak strain  measured with apnea. A combined analysis of myocardial oxygenation and peak strain resulted in an incrementally higher AUC of 0.91, p < 0.001 than strain alone.In healthy subjects, hyperventilation resulted in global myocardial deoxygenation (-10.2 ± 8.2%, In myocardium of patients with chronic coronary syndromes and primarily intermediate coronary stenoses, cine oxygenation-sensitive CMR can identify an impaired vascular and functional response to a vasoactive breathing maneuver stimulus indicative of inducible ischemia. Coronary artery disease (CAD) can be classified into subcategories of acute coronary syndromes (ACS) and chronic coronary syndromes (CCS) . CCS encNon-invasive imaging of myocardial ischemia is a rapidly developing field, with a significant expansion in the variety of imaging techniques available to investigate changes in the myocardial tissue perfusion and oxygenation. A concomitant deoxygenation response has been demonstrated using Oxygenation-Sensitive (OS)-CMR . OS-CMR Regional analysis of myocardial strain using CMR feature tracking (FT) is a more recent technique to assess myocardial function. Myocardial strain provides insight into contractile and lusitropic function in which feature tracking techniques follow the relative movement of unique features in the image throughout the cardiac cycle in the longitudinal, circumferential and radial axis. Post-processing software allows for quantification of multiple systolic and diastolic deformation parameters, such as peak systolic strain (PS), time to PS (TTP), and myocardial diastolic strain rate (dSR). The association of changes of OS-CMR-derived myocardial oxygenation with regional myocardial function has not been studied so far in cardiovascular patients. In swine, this combined analysis was performed and FT measurements from OS images were shown to be linked with myocardial deoxygenation at low perfusion pressures . With th2) partial pressures. Hyperventilation induces hypocapnia, which is known to be a potent coronary vasoconstrictor. Apnea has an opposing effect increasing CO2 and this subsequent hypercapnia induces significant vasodilation in healthy coronary vessels , and changes in breathing patterns. The mechanisms of hyperventilation and apnea on myocardial oxygenation balance are not fully understood, but a key regulatory pathway appears to be through local blood carbon dioxide  were included. Seventeen (45%) of the participants had been included in previous publications , 18. AllAll participants underwent a contrast-free exam in a 3T MRI scanner . A short-axis stack along with two long-axis images were obtained for the analysis of baseline ventricular function parameters. Additionally, native T1 and T2 maps were acquired in a basal and mid-ventricular slice. OS-CMR cines were obtained in these same slice positions. Under resting conditions, a baseline OS cine was acquired during a brief (5–8 s) breath-hold. Participants were then instructed to hyperventilate for 60 s (30 breaths/min paced by a metronome), and immediately following hyperventilation, to maintain apnea at a comfortable exhalation level. Throughout the entire duration of this apneic period, OS-cines were acquired continuously until participants indicated their need to resume breathing .All images were obtained at an end-expiratory breath-hold. OS-CMR images were obtained with an ECG-triggered balanced steady-state free precession sequence . Standard cine images were acquired with a standard gated balanced steady-state free precession cine sequence . T2 maps were generated after acquiring three single-shot gradient echo images . A 5(3)3-modified Look-Locker sequence was used for T1 mapping, .42 . To analyse clinical CMR measures at rest, T1 and T2 maps were quantified, and left-ventricular function and feature tracking strain analysis at rest was performed on the full short axis (SAX) stack cines. For the analysis of images acquired during the breathing maneuver stimulus, the relative changes of OS signal intensity (SI) in end-systolic frames, and myocardial strain as measured by CMR-FT were acquired from the same OS cines. For CMR-FT analysis, each cardiac cycle was assessed for circumferential peak strain (PS), time to PS (TTP), and peak early diastolic strain rate (dSR). Measurements for the radial orientation are provided in the supplement. All parameters were determined and reported for global measurements and for the American Heart Association segment model.All analysis was blinded and conducted with cmrIndependent readers analyzed the angiography images to quantify the percent diameter of the stenosis. Afterwards to allocate the coronary angiogram findings to the regional CMR analysis, the angiography readers classified each myocardial segment into one of three categories based on the individual coronary anatomy: (1) territories subtended to a current stenosis  that had no previous reperfusion treatment, (2) territories revascularized at the initial angiography by coronary stenting (reperfused), or (3) territories perfused by a patent native coronary artery (remote). This allocation was primarily based on the classical perfusion territories , with thpost-hoc analysis if applicable. Thereafter, both strain (Δ) and myocardial oxygenation responses (%) were compared for each breathing maneuver step. Pearson's correlation coefficients were used to investigate the association of strain and OS-SI with mapping values.Continuous data are reported as mean ± standard deviation (SD), categorical data as frequency and percentage. Statistical analysis compared datasets acquired at three time points: at rest, immediately post-hyperventilation, and closest to 30 s of apnea. Myocardial oxygenation response to hyperventilation is given as percent change of OS-SI relative to the image at resting conditions. For the apnea-provoked response at 30 s, the first image acquired during full breath-hold was used as reference. Strain parameters are reported as Δ-change. First, the global myocardial response was compared between participant groups using a linear regression model accounting for sex and age as covariates. Strain data from the three time points were compared within-group only, in order to assess whether strain changed globally, or within the respective territory during the breathing maneuvers. Here, a mixed-effects model was used, accounting for repeated measures and with Tukey's SAXStack). ROC curves were then created for both the myocardial oxygenation response and the CMR-FT measured from the OS cine at the end of apnea. A curve combining both features at the end of the stimulus was created using binary logistic regression. Area under the curve (AUC) between correlated curves was compared using the Hanley and McNeil test.Receiver operating characteristic curves (ROC) were used to calculate the discriminating ability of imaging parameters for the detection of post-stenotic myocardium defined by angiography. This was performed first for traditional CMR measures acquired at rest including T1 and T2 mapping, ejection fraction, and circumferential peak strain (PSn = 25) were compared to strain measurements of the function stack cines using a two-way mixed intra-class correlation (ICC) for absolute agreement. ICC was further calculated for inter-observer agreement with a second blinded reader (n = 25). Statistical analyses were performed with GraphPad Prism version 9.0  and R software . Results were considered statistically significant at a two-tailed value p < 0.05.For validation purposes, global and regional strain measurements from all the resting OS cines of the CAD patients  and cardiac index  acquired at resting conditions did not differ between controls and patients. Nor did global peak circumferential strain acquired from the standard short axis stack differ between the groups . Similarly, there was no difference in the tissue characterization in global native T1  and T2 mapping  between groups. Nor were there regional differences between post-stenotic, reperfused and remote territory for either native T1  or T2 .Standard left ventricular function measures of ejection fraction  between sequence types. The ICC for inter-observer agreement for PS from the OS cines was excellent at 0.907 .For global and post-stenotic myocardium strain results from OS cines there was moderate to good intra-class correlation with results derived from the function stack for both global and territorial measurements n = 25, . Global Myocardial oxygenation response in healthy subjects was characterized by a reduction of myocardial SI after 60 s of hyperventilation (-10.2 ± 8.3%) and an increase (+9.1 ± 5.3%) after 30 s of apnea. At the end of hyperventilation, PS was significantly augmented compared to baseline . This wap = 0.085 vs. controls), and in response to apnea a smaller global OS-SI increase , when compared to healthy controls. Moreover, this attenuated global response was correlated with increasing T1 . By 30 s of subsequent apnea, PS had significantly worsened beyond values at rest (p < 0.001). This peak strain response during apnea was also significantly attenuated in comparison to controls (p = 0.025). Global TTP of patients did not respond significantly to hyperventilation, in contrast to TTP of healthy controls. Apnea however prolonged global TTP in patients (p = 0.002). Global early dSR was attenuated both during hyperventilation and during apnea in CAD patients . Radial strain data are given in In response to hyperventilation, CAD patients showed a global myocardial OS-SI response of −5.8 ± 9.6 % (p = 0.350). The subsequent apnea consistently provoked regional oxygenation heterogeneities in post-stenotic  and reperfused territories 1.3 ± 6.0%; p = 0.024) compared to the response in remote territories (+4.9 ± 5.7%). Strain and myocardial oxygenation responses of territories and provocation maneuvers steps are detailed in p < 0.05), while post-stenotic myocardium was the only territory to have a further reduction in strain with apnea beyond baseline (p = 0.004). Similarly, post-stenotic myocardium was the only territory to have a significantly prolonged TTP . This can also be seen in p = 0.008) with recovery to baseline during apnea (p < 0.001), which was comparable to the respective global response of healthy controls, while no response in TTP was observed in reperfused myocardium. There were no significant territorial changes or differences in dSR. Medications taken by the patients such as beta-blockers did not have a statistical impact on the post-stenotic myocardial oxygenation response or on the strain parameters measured during hyperventilation or apnea (Hyperventilation did not induce oxygenation differences between post-stenotic (-5.5 ± 10.5 %), remote myocardium (-7.1 ± 11.3%) and reperfused territories . For CMR measures obtained with the breathing maneuver stimulus, both OS-CMR  and PS measured from the OS-cine  were able to individually detect post-stenotic territories at the end of apnea. The combination of the two measures of OS-CMR and PS yielded an AUC of 0.91  and was significantly better at defining post-stenotic territories than the post-apneic PS measurement alone (p = 0.036).The ROC analysis in The major finding of this study is that in patients with chronic coronary syndromes and primarily intermediate coronary stenoses, regional impairment of myocardial kinetics provoked by voluntary breathing maneuvers is detected by feature tracking strain analysis on oxygenation-sensitive (OS) cine acquisitions. Moreover, myocardial oxygenation is compromised in these same territories, with the combined analysis of tissue and wall function improving the detection of post-stenotic myocardium. In fact, this could only be differentiated with the breathing maneuver as traditional contrast-free tissue and functional measures at rest were unable to discriminate post-stenotic myocardium of primarily intermediate-grade stenoses from healthy controls with similar age. These measurements of myocardial oxygenation and strain can be simultaneously obtained from the same set of OS cines, ensuring both measurements are of the same territory and represent the same timepoint during the breathing maneuver provocation stimulus.2 manipulation to be observed with the apnea and also allow the patient to maintain a longer breath-hold. The second phase of the combined breathing maneuver, the apnea component, is the focus of the analysis where oxygenation and functional deficits are more consistently revealed.As previously reported, healthy participants respond to hyperventilation with decreasing myocardial oxygenation, and to apnea with increased tissue oxygenation , 17, 21.2 levels in CAD patients, the post-stenotic vasculature cannot dilate further and the observed regional heterogeneity may be further explained by redistribution of blood flow and possibly inter-coronary steal away from territory distal to a fixed stenosis, which may lead to a net decrease in OS-SI  and extracellular volume mapping (ECV). Thus, the presence or absence of scar cannot be confirmed in this cohort, nor can the impact of scar on the strain response to breathing maneuvers be determined at this point. In patients with myocardial infarction, resting strain has been reported to be related to the extent of LGE . HoweverThe fact that majority of the enrolled CAD patients were under chronic medication with beta-blockers and ACE inhibitors could confound the heart rate increase, oxygenation and strain response observed in the patient group. In this population, patient medications were not statistically associated with the oxygenation or strain results during hyperventilation or apnea. Pharmacological beta-blockade would not explain or confound the inter-territorial differences seen within our CAD patient cohort. Similar to our findings, it has been demonstrated that beta-blocker therapy did not impact myocardial perfusion imaging with adenosine , or the In myocardium subtended to an anatomically defined intermediate-grade coronary stenosis of patients with chronic coronary syndromes, an oxygenation-sensitive (OS)-CMR cine acquisition during a breathing maneuver can simultaneously unmask an impaired vascular and functional response. The detection of post-stenotic myocardium was improved with a combined approach of measuring an attenuated myocardial oxygenation reserve along with CMR feature-tracking. Furthermore, peak strain is attenuated and time to peak strain is prolonged exclusively in post-stenotic segments at apnea. These findings may be indicative of inducible early myocardial ischemia.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The study protocol was approved by the Ethics Board of the Canton of Bern. The patients/participants provided their written informed consent to participate in this study.DG, KF, BE, and BJ: conceptualization and methodology. DG, KF, BS, KY, YU, ZZ, CB, TO, MB, CG, and LR: investigation and analysis. BS, KF, and DG: original manuscript draft. KY, YU, BJ, TO, MB, CG, HvT-K, LR, BE, and DG: manuscript revision and editing. KF: visualization. DG, BE, HvT-K, and LR: supervision. DG and BE: project administration. All authors contributed to the article and approved the submitted version.This work was supported by institutional research funds of the Department of Anaesthesiology and Pain Medicine at Inselspital, Bern University Hospital, Switzerland, and by the European Society of Anaesthesiology Research Project Grant.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.


Aggressive myectomy through transapical approach not only relieves basal and midventricular obstructions but also may augment diastolic dysfunction in hypertrophic cardiomyopathy.See Article page 71.The video clip by Sun and colleagues,First, how do we determine whether symptoms are secondary to LVOT obstruction or diastolic dysfunction? In reality, many patients suffer from a variable combination of both pathologies, and failure to recognize the latter may result in residual symptoms, even though transaortic septal myectomy is an excellent septal reduction therapy for relief of LVOT obstruction,Second, does an aggressive myectomy relieve diastolic dysfunction? There is a clear relationship between diastolic dysfunction and heart failure in nonobstructive HCM, and this should be evaluated with echocardiography and invasive hemodynamic catheterization to identify this larger group of patients with HCM. The Mayo group has championed a transapical approach. Their combined transaortic and transapical approach has been shown to abolish any cavitary obstruction and augment left ventricular diastolic function with good short-term outcomes.This 24-year-old male patient might have received a heart transplantation had he been treated elsewhere. While our own institutional data of 41 patients with end-stage HCM managed with heart transplantation suggest it is a good option,


Determinants of CPET parameters were investigated with multivariable linear regression analysis.A cohort of adolescents  underwent Cardiopulmonary Exercise Test (CPET) and administration of the International Physical Activity Questionnaire – Short Form (IPAQ-SF) with estimation of weekly PA , and VO2/HR max . Importantly, physical activity level was a predictor of VO2 max  whereas O2 pulse was independent from PA level .As expected, when compared to HC, PE had lower VO2 max (cardiopulmonary performance), whereas it appears not to affect O2 pulse (a measure of stroke volume at peak exercise) related to constrained diastolic filling in PE.Physical activity is a determinant of VO Pectus excavatum (PE) is the most common congenital chest wall deformity of childhood. It occurs with an incidence of approximately 1 every 300–400 children  and it oAlthough initially considered only an esthetic problem, it gradually emerged that this deformity can also cause functional disorders . Dependi2 max, predominately because of impaired cardiovascular performance, rather than ventilatory limitation  and cardiac output (O2 pulse) was highlighted in patients with PE (2 max) but would probably have limited effects on cardiac output.Anatomical severity of PE is commonly measured by Haller Index, the ratio of the transverse diameter of the rib cage to the minimum distance of the lower sternum from the vertebra . However with PE . HoweverAim of this pilot study is to explore the possible differential influence of physical activity on cardiopulmonary performance and stroke volume parameters obtained at Cardiopulmonary Exercise Test (CPET) in PE.In total, 15 consecutive patients  with PE, referred to our Unit for functional evaluation between March 2020 and August 2021 were investigated. The diagnoses were established by a thoracic surgeon (AMe) with 30 years’ experience. All the patients were in good health and had no evidence of cardiac or respiratory disease; none were taking medication that would affect cardiorespiratory fitness. Criteria for exclusion were severe lung disease, pre-existing heart disease, or an underlying causative syndrome such as Marfan’s disease, previous repair of pectus excavatum by any technique; previous thoracic surgery; congenital heart disease or pregnancy. The healthy control (HC) group consisted of 15 age- and sex-matched adolescents who responded to a local advertisement. The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Tuscany Region clinical research ethics board . All participants provided written informed consent. All participants went through the same examinations and tests throughout the study.–1⋅week–1. The mean intensity of light PA, moderate PA, and vigorous PA was assigned as 3, 4, and 8 METs, respectively  . The queectively .r = 0.67) and reliable tool (rho = 0.77–1.00)  , that isActivity ].–2) was calculated as the body mass divided by body height squared. Forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), and Tiffeneau index (FEV1/FVC) were also measured before the exercise test and expressed in percentage of the predicted value.Each participant was asked to refrain from strenuous exertion the day before the test day and to refrain from eating solid foods or carbohydrate-rich drinks in the 3 h prior to the test. The test was performed in the morning in controlled environmental conditions . Prior to exercise testing, body mass and body height were measured using an electronic scale. Body Mass Index . Briefly, participants were equipped with an oronasal face mask connected to a metabolic cart (COSMED Quark CPET). COrotocols .–1) in VO2 over the last 30 s of the test. Tests were interrupted if signs of cardiovascular distress were present . A twelve-lead ECG, and oxygen saturation were continuously monitored.Selection of the workload ramp was based on predicted values for height . Minimum2), Carbon dioxide Production (VCO2), Tidal Volume (VT), Breathing Frequency (BF), Ventilation (VE), Heart Rate (HR) and Work Rate (WR) were measured throughout the test. The ventilatory Anaerobic Threshold (AT) was determined using the V-slope and the ventilatory equivalent approaches. Other variables were the ratio of VO2 and heart rate , oxygen-uptake to work-rate relationship , the product of VO2 max (in milliliters per kilogram per minute) by systolic blood pressure .Oxygen Consumption (VO2 max) with three independent variables, height, body mass, and age/sex.Z score values were calculated by adopting the prediction model developed by 2). With an estimated standard deviation of 20%, a difference between the 2 groups of 20%, an alpha of 0.05 and a power of 0.80, the number necessary for investigation was 15 subjects for each group.Statistical analyses were performed using SPSS 27 software . Sample size determination and power calculations were made for the volume of oxygen uptake/kg .All continuous variables are expressed as mean ± SD, unless specified. A paired, two-tailed Student’s p < 0.05 was considered statistically significant.A difference of –1⋅week–1 were not significantly different from those in the HC group  and FEVo groups .Maximal heart rate was 184 ± 13 bpm in patients with pectus excavatum and 186 ± 7 bpm in controls (ns), indicating an equivalent maximal exercise effort in the 2 groups. Conversely, SBP at peak exercise showed lower values in the PE than in the HC group.2 max was lower in the PE group than in HC both in absolute  and in percentage of the predicted value  (2 max was -1.3 ± 1.0 (95% CI −1.97 to −0.58) and 0.2 ± 0.6 (95% CI −0.20 to 0.93) respectively. Similarly, O2 pulse at exercise peak (VO2/HR max) was lower in the PE group than in HC both in absolute  and in percentage of the predicted value   . Average < 0.05) . LikewisHC group .2 max), stroke volume at peak exercise , and work efficiency (VO2/W slope)  with average PA per week measured with IPAQ (independent variable) were then investigated at multivariable linear regression analysis adjusted for sex, BMI, FEV1%, and presence of pectus excavatum , whereas no association was observed with O2 pulse (VO2/HR max), a measure of stroke volume.According to the present data, the average physical activity per week measured with the IPAQ questionnaire  was asso2 pulse, a measure of this mechanical parameter, was found to characterize the difference between PE and controls, independently of the estimation of PA or ventilatory function.The relative role of psychological, anatomical and physiological alterations in determining functional impairment in PE is not easily discernible in the individual patient, although this point is crucial for the choice of the treatment strategy. A conservative strategy based on the promotion of PA may be useful to improve functional capacity, while the presence of an anatomical defect, with compression of the sternum resulting in a diastolic filling defect, could indicate a surgical choice. The results of this preliminary study seem to indicate that a cardiopulmonary test can help to assess the potential effectiveness of these two instruments. In patients with PE a reduced retrosternal space, leading to a diastolic dysfunction mainly in the right ventricle, could lead to a stroke volume reduction with a final impairment of cardiorespiratory fitness. In this study, O2 max, also lower in PE compared to controls, instead also recognized among its determinants the average PA per week measured with the IPAQ. The promotion of PA in pectus excavatum, an important element in the treatment strategy of these patients, may improve cardiopulmonary performance, whereas stroke volume (O2 pulse) impairment that might be present in this condition seems to be independent from PA. A reduced O2 pulse at the peak of exercise could thus better address toward surgery.Cardiopulmonary performance expressed by VO2 max in PE patients compared to controls  might instead suggest the surgical option.Minimally invasive Nuss procedure for PE was consistently reported to improve stroke volume independently from the distance between surgery and functional evaluation due to the acute relief of constrained diastolic filling . The inc surgery . The pre2 max the limit of normality was usually set at 80% of the predicted value  a measured value deviates from the population mean, expressed in units of the population SD. The limit of the ± 2 Z score directly identifies the 95% limit of a normal distribution and has often been chosen as the cut point to distinguish healthy from unhealthy. As a standardized measure, the Z-Score allows comparisons across different ages, genders and measurements. Most importantly, differently from adults, the use of the Z-Score allows more accurate assessments in children and adolescents, where small changes in age or pubertal stage produce big differences in sub-populations.For VOed value . This loed value , but its2 pulse. The study must be considered a proof of principle study that may offer a perspective, although requiring confirmation. Second, there is a lack of accurate investigation of the diastolic function and of the morphological parameters used to characterize these patients, such as the echocardiographic indexes and the Haller index. Third, PA was measured with a questionnaire (IPAQ) and not an objective tool as accelerometer. Fourth, in the current study, differences in perceptions of body image and social appearance were not assessed. It may be important to assess the psychological impact by comparing the patient group with controls.This is a pilot study with several limitations. First of all, an important limitation of the study is the limited number of participants studied. This limited number could be responsible for a type II error (beta) with the lack of correlation between PA and O2 max, whereas no relationship was observed with stroke volume at peak exercise, expressed by O2 pulse.In conclusion, average PA per week measured with the IPAQ was found to be associated with cardiopulmonary performance expressed as VOThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Comitato Etico Regionale per la Sperimentazione Clinica della Regione Toscana. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.PAM: conceptualization and writing—original draft preparation. LC and AP: methodology. AMo: formal analysis. LC, AP, AMe, MG, and FF: investigation. All authors have read and agreed to the published version 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.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.


Successful therapy of heart failure with preserved ejection fraction (HFpEF) remains a major unmet clinical need. Device-based treatment approaches include the interatrial shunt device (IASD), conventional assist devices pumping blood from the left ventricle (LV-VAD) or the left atrium (LA-VAD) towards the aorta, and a valveless pulsatile assist device with a single cannula operating in co-pulsation with the native heart (CoPulse). Hemodynamics of two HFpEF subgroups during rest and exercise condition were translated into a lumped parameter model of the cardiovascular system. The numerical model was applied to assess the hemodynamic effect of each of the four device-based therapies. All four therapy options show a reduction in left atrial pressure during rest and exercise and in both subgroups (> 20%). IASDs concomitantly reduce cardiac output (CO) and shift the hemodynamic overload towards the pulmonary circulation. All three mechanical assist devices increase CO while reducing sympathetic activity. LV-VADs reduce end-systolic volume, indicating a high risk for suction events. The heterogeneity of the HFpEF population requires an individualized therapy approach based on the underlying hemodynamics. Whereas phenotypes with preserved CO may benefit most from an IASD device, HFpEF patients with reduced CO may be candidates for mechanical assist devices. HFpEF presents as a multifactorial pathology with several contributing factors  that are currently increasing in prevalence. Consequently, the prevalence of HFpEF is projected to steadily rise in the forthcoming decades4.Around half of all heart failure (HF) patients suffer from heart failure with preserved ejection fraction (HFpEF), a condition of diminished cardiac function, albeit with normal left ventricular ejection fraction (LVEF)6. Most HFpEF patients share the common feature of smaller left ventricular (LV) dimensions compared to those observed in patients suffering from heart failure with reduced ejection fraction (HFrEF). These small ventricular cavities are usually combined with impaired diastolic ventricular function3.In HFpEF patients, exercise intolerance is recognized as a major determinant of reduced quality of life. In fact, many HFpEF patients are free of any deterioration in cardiopulmonary and/or vascular function at rest, with respective declines being unmasked during exercise7. However, to date, effective and safe treatment approaches for the heterogeneous HFpEF population remain a major unmet clinical need. On the one hand, the established effective pharmacological treatment has not yet proven as effective in HFpEF as in HFrEF. On the other hand, the success of device-based therapies in HFrEF could not be translated toward HFpEF pathologies. In severe HFpEF cases, cardiac transplantation would remain the only viable therapeutic option. However, multiple comorbidities in this elderly population may render cardiac transplantation prohibitive in many patients.Despite differences in pathophysiology, clinical outcomes in HFpEF patients are similar to those reported for the HFrEF pathology9. Interatrial shunt devices (IASDs) that are inserted via a percutaneous approach have been shown to effectively reduce left atrial pressure (LAP) in-silico10 and in-vivo12. However, to date, no prospective study has demonstrated a corresponding reduction in HF-related adverse events13. Spring like expanders implanted in the LV chamber assist early cardiac filling by storing elastic energy during systole and releasing it during diastole in terms of expansion. To date, clinical data on safety and efficacy of these devices, however, are not available9. Mechanical circulatory support (MCS) devices, predominantly in form of third generation continuous flow rotodynamic blood pumps (RBPs), have proven effective as a therapy to support HFrEF patients14, and may also be applicable to the HFpEF population. However, the particular anatomical settings in HFpEF patients presenting with small LV cavities have triggered concerns that continuous LV unloading with an RBP may cause suction events around the inflow cannula16. These concerns are reflected by the fact that only anecdotal clinical use of MCS in adult patients with small ventricular dimensions has been reported in literature17.In recent years novel device-based therapeutic approaches have been under investigation for the treatment of the HFpEF population16 evaluated the use of RBPs in classical LV apical configuration (LV-VAD) in HFpEF patients in a numerical study during rest and exercise. Burkhoff et al.15 suggested the use of partial circulatory support that decompresses the left atrium (LA) as an LA-VAD based on a computational analysis. Recently, the CoPulse system, a novel ventricular assist device operating in synchrony with the LV19, was introduced as a promising MCS option for HFpEF patients. All these studies were restricted to either the evaluation of resting conditions solely, a single HFpEF phenotype and/or a single support strategy.Moscato et al.The aim of this study was to comparatively assess the hemodynamic effect of four different device-based therapies  in two typical HFpEF phenotypes during rest and physical activity in a numerical lumped parameter model.Accurately replicate hemodynamics during rest and physical activity of two different HFpEF phenotypes in a lumped parameter model of the cardiovascular system including an autoregulated exercise response.To investigate the effect of four different device-based therapy approaches  on the hemodynamics simulated by the same model at rest and during exercise.The approach of this numerical study was to:21 was employed to simulate the cardiovascular system of typical HFpEF patients. All heart chambers were modeled having a time varying-elastance with nonlinear end-diastolic/end-systolic pressure–volume relationships (EDPVR/ESPVR).A numerical model similar to the ones presented in previous studies0 of 0 ml20:sys and V(t) denote the vertex volume coordinate of the nonlinear ESPVR20 and the instantaneous ventricular volume [ml], respectively, and Psys denotes the ESPVR’s vertex pressure coordinate [mmHg].The ESPVR was defined as a parabolic relation with the vertex at the coordinates  representative of the smaller subgroup with infiltrative and restrictive cardiomyopathies25.Group 1: HFpEF patients with comparably low cardiac output  and elevated transpulmonary pressure gradient (TPG) of 10 mmHg (Group 116) representative of the larger subgroup with one or more co-morbid conditions such as hypertension, obesity, diabetes and others25.Group 2: HFpEF patients with elevated CO (6.3 l/min) and normal TPG of 4 mmHg  served as the input signal for the baroreflex control of heart rate (HR), systemic vascular resistance (SVR), and shift of unstressed to stressed venous volume to adapt the MCFP16. Parameters of the autoregulatory mechanisms were iteratively adapted to achieve typical hemodynamic changes observed in HFpEF patients during exercise24. The resulting SVR control changed arterial resistance by 1% per each mmHg difference between setpoint and MAP in both groups. Unstressed venous volume was adapted by 130 (Group 1) or 75 ml (Group 2) per mmHg difference between setpoint and MAP. HR was determined by the functionIn addition, simplified autoregulatory closed-loop control mechanisms were implemented following Ursino et al.Exercise was triggered by a drop in SVR by 45% and an increase of the desired systemic MAP by 32% (Group 1) and 30% (Group 2) determined by the baroreceptor setpoint.IASD was modelled as a shunting resistance (0.1 mmHg s/ml) between the left and right atrium  and the LA (LA-VAD), respectively 19.The novel pex Fig. . This deThe numerical model of the cardiovascular system was applied to comparatively assess the hemodynamic effect of four different device-based treatment strategies with respect to corresponding unsupported (baseline) condition Fig. .The IASDKey hemodynamic parameters from literature in comparison to the simulated ones are provided in Table At rest, Group 1 features smaller EDVs (93 vs. 143 ml), less CO (4.4 vs. 6.3 l/min) and a 2.5-fold elevated TPG (10 vs. 4 mmHg) as compared to Group 2. During exercise, despite higher HR in Group 1 (125 vs. 103 bpm), CO remains lower (7.7 vs. 9.6 l/min) with elevated LAPs (32 vs. 26 mmHg) compared to Group 2.Simulated hemodynamics for both groups with the four device-based therapy options at rest and exercise are summarized in Figs. All four devices lead to LAP reduction of at least 20% (− 41.7 ± 18.0%). The three MCS strategies  promote CO (+ 6.1 ± 1.7%) with subsequent reduction in sympathetic activation, exemplified by lower HR (− 7.0 ± 2.6%). In contrast, with the IASD, CO is slightly reduced − 5.6 ± 0.6%), and sympathetic activation elevated (HR: + 3.3 ± 0.9%). The four devices affect cardiac mechanics in a different way . Of note, although LAPs in the resting condition are comparable between both groups (7.0 ± 3.1 vs. 8.4 ± 3.1 mmHg), during exercise the LAP in Group 1 is considerably higher compared to Group 2 (22.2 ± 2.0 vs. 17.6 ± 2.0 mmHg).All devices lead to a reduction of mean pulmonary artery pressure . Whereas for all MCS devices the drop in LAP is accompanied by a comparable decrease in PAP, with the IASD the decline in PAP is less pronounced compared to LAP changes (− 9.0 ± 3.7 vs. − 24.9 ± 5.2%). Further, all MCS devices cause a decline in right atrial pressure (RAP) and right ventricular stroke work (RVSW) . In contrast, with the IASD, RAP and RVSW are elevated by + 28.3 ± 10.9% and + 8.0 ± 5.6%, respectively.With the IASD, Group 1 indicates a lower reduction of PAP (− 6.3 ± 1.5 vs. − 11.7 ± 3.1%) but more pronounced elevation of RVSW than Group 2 (+ 12.7 ± 1.9 vs. + 3.3 ± 1.5%).The mean flow across the IASD from the left to the right atrium in Group 1 is 1.6 and 2.7 l/min for rest and exercise, respectively. In Group 2 the shunt flow is 1.8 and 2.3 l/min for the two respective conditions. Pump speed settings for the HeartMate 3 are lower in Group 1 compared to Group 2 with 5000 and 5300 rpm vs. 5700 and 5900 rpm for LV-VAD and LA-VAD, respectively. Accordingly, pump flow rates are lower in Group 1 . The different mechanisms of IASD and MCS devices were reflected by opposing trends in CO, sympathetic activity, as well as right ventricular pre- and workload.10 and clinical evidence31. The shunt flow across the IASD is in a similar range than simulated for a HFpEF population similar to Group 2 at rest and exercise 10. In line with the trends observed in clinical studies with the IASD31, the LAP reduction comes at the cost of elevated right ventricular pre- and workload . Our results show that the burden on the right heart is more pronounced in patients with higher pulmonary vascular resistance (PVR) and weaker right ventricular function (Group 2). This indicates that the IASD may be more effective in patients with lower PVRs and maintained right ventricular function. In addition, our approach to incorporate baroreflex function in the numerical model resembled clinically reported hemodynamic effects with the IASD31 (including a slight increase in HR (2–4 bpm) and a marginal change of − 2 mmHg in MAP) more closely than previous numerical models without baroreflex function (constant HR and more than − 10 mmHg drop in MAP)10. These improvements can be explained by the sympathetic stimulation of the autoregulatory baroreflex mechanisms as a response to a drop in systemic CO caused by the shunt flow across the IASD. Of note, the clinically observed trend towards even higher systemic COs and MAPs with the IASD in place could still not be mimicked by the numerical model. All these findings support the hypothesis that the IASD may be a viable treatment option for selected HFpEF patients with preserved CO, low PVR and good right ventricular function (e.g. Group 2).Although the lack of standardized hemodynamic HFpEF phenotypes renders a quantitative comparison to other studies difficult, our findings with the IASD are consistent with previous simulation studies16 investigating the use of an LV-VAD in Group 2 within a similar numerical model including a baroreflex mechanism. Further, the results of Burkhoff et al.15, comparing the use of LV- and LA-VAD in patient populations similar to Group 1 and 2 in a numerical model without baroreflex, are qualitatively consistent with our observation in terms of hemodynamic trends and PV-loop morphology. Our results confirm the findings of these previous studies that LV-VAD excessively unloads the LV cavity during systole (low ESV) with a high risk for suction events around the inflow cannula32, whereas the ESV is only slightly reduced or even elevated for the LA-VAD and the CoPulse, respectively. These results imply that LA-VAD and CoPulse may be viable treatment options for HFpEF patients with reduced CO and/or elevated PVR (e.g. Group 1) with almost equivalent efficacy in terms of hemodynamic changes. The CoPulse system with a stroke volume of 30 ml improves hemodynamics similar to the LA-VAD. Of note, this system operates in co-pulsation to the native LV and therefore relies on the chronotropic response of the patient. The dependency of more unloading with higher HRs explains the observation that Group 1 benefits more from this device in terms of LAP reduction during exercise as compared to Group 2 (126 vs. 106 bpm).All three MCS options resulted in lower LV preload (reduced LAP and EDV) and an increase in CO with subsequent reduction of sympathetic activity during rest and exercise in both groups. Consequently, RAP was slightly reduced, and arterial pressure elevated compared to baseline. These hemodynamic trends are consistent with the results of Moscato et al.Our results suggest that IASD, LA-VAD and CoPulse may be viable device-based treatment options to support selected HFpEF patients, while a small ventricular cavity may impair the efficacy of LV-VADs. The IASD, LA-VAD and CoPulse may serve different patient populations. Whereas the IASD may be most beneficial for patients with higher CO, lower PVR and a good right ventricular function, the two MCS strategies may be preferable in HFpEF patients with lower CO.In this context, the consideration of an LA-VAD as potential RBP-based treatment option in selected HFpEF patients requires particular attention regarding pump speed setting and respective unloading. On the one hand, the objective to achieve an adequate unloading without negative pump flows during diastole led to low LAPs of < 7 mmHg at rest. On the other hand, at exercise, higher pump speeds would have been required for adequate unloading, especially in Group 1 with LAPs > 20 mmHg. Combined with the observation of backflow through the pump during diastole in Group 2 with LA-VAD treatment  renders a personalized selection of device-based treatment option indispensable. Further research should focus on hemodynamic phenomapping and definition of adequate hemodynamics to select the appropriate and individualized treatment strategy.This simulation study has intrinsic limitations of numerical modelling approaches: whereas most parameters of the basic numerical model were computed based on the available data from literature, the simplified baroreflex function was only empirically tuned to match the hemodynamics at rest and exercise. Therefore, the model does not capture exercise and baroreflex mechanisms in its entire complexity but focuses on the resemblance of realistic trends in hemodynamic parameters only. Of note, imperfection of available clinical data makes assumptions and manual imputation of many parameters unavoidable.Long-term auto-regulation effects such as the renin-angiotensin system are not considered in this model. Nevertheless, such models proved valuable to understand mechanisms and effects related to device-based therapy in HF patients.33 may provide insights into the hemodynamic effect of these devices.In this study we did not consider LV expanders as their functional principle cannot be accurately assessed by a lumped parameter model. More complex models combining lumped parameter modelling in combination with Finite Element ModelingAnother important therapy objective for HF treatment is the ability to stop or even reverse adverse remodelling of the cardiovascular system as a response to hemodynamic stimuli. To date it remains unclear how any of these devices affect the heart in terms of structural and functional remodelling.


Pacemakers are widely utilised to treat bradycardia, but right ventricular (RV) pacing is associated with heightened risk of left ventricular (LV) systolic dysfunction and heart failure. We aimed to compare personalised pacemaker reprogramming to avoid RV pacing with usual care on echocardiographic and patient-orientated outcomes.A prospective phase II randomised, double-blind, parallel-group trial in 100 patients with a pacemaker implanted for indications other than third degree heart block for ≥2 years. Personalised pacemaker reprogramming was guided by a published protocol. Primary outcome was change in LV ejection fraction on echocardiography after 6 months. Secondary outcomes included LV remodeling, quality of life, and battery longevity.versus -0.21±1.7%; p<0.01), improved LV function  0.48 to 5.70%; p = 0.02]) and LV dimensions . Intervention also preserved battery longevity by approximately 5 months ) with no evidence of an effect on quality of life .Clinical and pacemaker variables were similar between groups. The mean age (SD) of participants was 76 (+/-9) years and 71% were male. Nine patients withdrew due to concurrent illness, leaving 91 patients in the intention-to-treat analysis. At 6 months, personalised programming compared to usual care, reduced RV pacing (-6.5±1.8% Personalised programming in patients with pacemakers for bradycardia can improve LV function and size, extend battery longevity, and is safe and acceptable to patients.NCT03627585.ClinicalTrials.gov identifier:  Pacemaker implantation is a common and safe procedure that can be lifesaving and is associated with a marked improvement in quality of life . Over onRV pacing is associated with an immediate reduction in left ventricular (LV) function . ObservaThe aims of this trial were therefore to describe the effects of personalised reprogramming to limit ventricular pacing on echocardiographic and patient-orientated clinical outcomes in patients with avoidable RV pacing.governance-ethics@leeds.ac.uk).Data that support the findings of this study contain potentially identifying patient information. As per the study sponsor regulations, they are therefore available upon reasonable request  between baseline and 6 months, with secondary outcomes of LV dimensions, quality of life (QoL), serum NT-pro-BNP concentrations and pacemaker generator longevity.Unselected consecutive patients attending pacemaker follow-up clinics at Leeds Teaching Hospitals NHS Trust and Harrogate District Hospital NHS Foundation Trust were approached and invited to participate. To achieve a generalisable cohort representative of patients attending a pacemaker clinic, potential participants had to have had a RV pacemaker for at least two years, and we only included those able to provide written informed consent. We excluded people with third degree heart block, those with cardiac resynchronization therapy devices, and a pre-existing diagnosis of heart failure. Potential participants were offered a participant information sheet and contacted after one week. Those agreeing to participate attended for study visits at the NIHR Cardiovascular Clinical Research Facilities at either site and provided written informed consent .During the baseline visit, information was collected on co-morbidities, past medical history, medication, pacemaker settings and a QoL assessment was undertaken using EuroQoL and a visual analogue scale of overall quality of life. A pacemaker interrogation was performed to document implant indication, percentage atrial and ventricular pacing, and programmed mode. We also undertook a transthoracic echocardiogram and a blood test to measure NT-pro-B-type natriuretic peptide (NT-pro-BNP).Full two-dimensional transthoracic echocardiography was carried out with images recorded in two- and four-chamber views . Images were stored in the EchoPAC digital imaging system  and analysed off-line. This analysis included a calculation of LV end-diastolic volume (LVEDV), LV end-systolic volume (LVESV) and LV ejection fraction (LVEF) using the biplane disks (modified Simpson) method by tracing the endocardial border, excluding the papillary muscles. The frame at the R-wave was taken as end-diastole, and the frame with the smallest LV cavity was considered to represent end-systole. The LVEDV and LVESV indexed to body surface area (LVEDVi and LVESVi) were calculated as LV volume/body surface area, where body surface area was calculated using the Mosteller equation . To miniFollowing baseline testing, patients were allocated into two groups corresponding to either ‘usual care’ or ‘personalised reprogramming’. Usual care followed the National Institute for Health and Care Excellence (NICE) guidelines  and BritPatients were contacted at one week and one month by the unblinded team member to ensure short term acceptability and safety, and were then reviewed at six months when all tests  were repeated.Our primary outcome was change in LVEF between baseline and 6 months post-randomization. Key secondary outcomes, assessed simultaneously, included remodeling variables , QoL (EQ5D-3L), and remaining estimated battery longevity.Our sample size was influenced by our pilot data . We estiParticipants were allocated to usual care or reprogramming using random number generation, stratified by centre. If allocated to intervention, their device was programmed according to our previously published algorithm  by an unth-75th percentiles. Categorical variables were presented as count and percentages. Differences between interventional groups’ baseline characteristics were assessed using the 2-sample Student’s t-test for normally distributed data and the Mann-Whitney U test for non-normally distributed data, whilst categorical variables were compared using the χ2 test. Analysis of covariance (ANCOVA) was conducted to assess inter-group significant differences for outcome variables controlling for baseline values, with Bonferroni correction to adjust for multiplicity. All across-treatment group comparisons were two-sided and are presented as mean change with 95% confidence intervals (95% CI). A p-value <0.05 was deemed statistically significant for comparisons.Analyses followed a predefined plan as set out in the trial protocol (NCT: 03627585). Normality for all continuous variables was tested using the Shapiro-Wilk test. Normally distributed continuous variables were reported as mean and standard deviation (SD), and non-normally distributed continuous variables as median and 25Reproducibility of echocardiographic measures between two blinded echocardiographic readers (MFP and CAC) were described by intraclass correlation coefficient (ICC). Data were analysed using the Statistical Package for the Social Sciences SPSS version 26 , R: A Language and Environment for Statistical Computing version 3.2.3 , and SAS version 9.4 .The research question was driven by patients with pacemakers presenting to local HF clinics with symptoms suggestive of CHF, a deterioration in cardiac function and a high burden of RV pacing. The study was initially discussed with a well-established local patient and public involvement advisory group (PPI-AG) consisting of people with cardiac devices, cardiovascular disease and their families. The PPI-AG advised on suitable follow-up periods, study procedures, information sheets and dissemination plans. They were particularly interested to know the potential effect on battery longevity of the intervention, as their primary concern was the number of generator replacements required over a lifetime, particularly for an increasingly frail population.Funding for the trial was through an NIHR Doctoral Fellowship award (MFP). Following ethical review by East Midlands Research Ethics Committee, the trial was approved by the Health Research Authority of the United Kingdom (16/EM/0337) and was registered on ClinicalTrials.gov (NCT:03627585). Full registration was retrospective due to an error in the submission process. However the authors confirm that all ongoing and related trials for this drug/intervention are registered.A total of 100 patients were recruited from two centres between January 2017 and September 2018. Of the 100 patients, 9 withdrew due to serious illness, all of which were non-cardiovascular. No patients reported changes to their medical therapy during the study period. No patient randomised to intervention reported adverse effects from device reprogramming .Patient and clinical characteristics were similar between intervention groups for age, sex, baseline RV pacing burden, LVEF, NT-proBNP and pacemaker battery longevity . More thDistribution of device manufacturers is shown in . There wPatients were followed for a median of 189 days , similar between intervention groups. No patient developed third degree AV block and no patient experienced an acute coronary syndrome or new or worsening heart failure event requiring hospitalisation or urgent ambulatory visit during follow-up. At baseline, most patients were programmed in DDD or VVI mode with rate response active in 40%, and an average base rate of 54(±6)bpm . DespiteThere was an improvement in the primary endpoint of LV systolic function, measured by LVEF, at 6 months in patients randomised to receive personalised pacemaker programming when compared with those receiving usual care  .2  mL/m2 in those allocated to personalised care, compared to those receiving usual care, when corrected for baseline LVEDVi, although our sample did not provide sufficient statistical evidence to conclude this effect exists. Moreover, patients randomised to personalised programming had a significantly smaller LVESVi at follow-up than those randomised to usual care  (There was a reduction in mean LVEDVi of -2.88mL/m= 0.03]) . Of thosPersonalising pacemaker settings to avoid unnecessary RV pacing had no detrimental effect on quality of life as measured by EQ5D-3L  and visual analogue scale (VAS)  when adjusted for baseline quality of life.Furthermore, personalised programming led to an extension of remaining minimum battery longevity by approximately 5 months compared with usual care  .An exploratory subgroup analysis showed in those with a preserved LVEF at baseline, LVEF improved by a mean of +4%  with personalised programming. In participants with a reduced LVEF (<50%) at baseline, there was a non-significant mean increase in LVEF of 2%  in those allocated personalised programming.”Analysis of the primary outcome in the first 70 recruited patients shows an improvement in LVEF with personalised programming which did not meet statistical significance  .Echocardiographic outcome measurements demonstrated strong inter-observer agreement for LVEF [ICC 0.968 (0.948 to 0.980)], LVEDV [ICC 0.955 (0.931 to 0.975)], and LVESV (ICC 0.964 (0.941 to 0.979)].The present study is the first to provide evidence that even when right ventricular pacing burden is already low, and pacing avoidance algorithms are already activated, personalising pacemaker programming to limit RV pacing even further leads to a clinically relevant improvement in LV systolic function and prevents further remodeling, with no evidence of an effect on quality of life, whilst simultaneously preserving battery longevity.induced cardiomyopathy [contributor.RV pacing has a longstanding association with an acute reduction in LV contractility. In two separate cross-sectional studies of unselected patients with pacemakers, we have described and validated that the degree of LV dysfunction is strongly related to the amount of RV pacing, and that this relationship is enhanced by the presence of cardiovascular disease , 6. Hencmyopathy . rather Longer term effects on LV function are reported to include myocardial perfusion and structural abnormalities . thoughtReverse remodeling is increasingly appreciated as a surrogate for improved patient-orientated outcomes, due to a close relationship between therapy-related changes in echocardiographic variables (in HF patients) and subsequent findings in morbidity and mortality studies of the same interventions. A pooled analysis of interventional clinical trial data has shown that every 5% absolute increase in mean LVEF is associated with an odds ratio of 0.86 (95% CI 0.77 to 0.96) for mortality . SimilarObservational data in pacemaker recipients without clinical heart failure at baseline has also shown higher heart failure-associated deaths and hospitalisation rates as RV pacing burden increases, the risk of which is highest within the first 6 months post-pacemaker implantation , 16. Altpacing-induced left ventricular systolic dysfunction. We previously undertook an observational study in 66 patients with long term pacemakers to determine whether reducing RV pacing in a chronically implanted patient cohort had effects upon LV function [In experimental models, reducing RV pacing seems to correct function . On an iSince our initial work, manufacturers’ bespoke RV pacing avoidance algorithms have become standard of care, hence the present study was carried out on a background of low RV pacing burden in patients not necessarily fulfilling the precise diagnosis of pacemaker-induced cardiomyopathy. The impact of RV pacing on cardiac function is likely to be variable in the context of contributing factors such as co-morbidities, but there may be a dose-response relationship over a lifetime of pacemaker therapy. This study is the first to confirm that simple pacing adjustments are well tolerated and also that even a modest further reduction in RV pacing burden is associated with improvements in LV size and function, hence, any attempt to reduce pacing burden is a worthwhile endeavor.Exploratory subgroup analysis also showed that personalising pacemaker programming is as important to those with a preserved LVEF. Patients with preserved LVEF at baseline experienced a larger absolute increase in LVEF. One could hypothesise that potentially the earlier in the patients disease status we implement personalised programming, the more likely we are to preserve LV size and function, but certainly personalised programming seems to be beneficial in all patients. As the present study is a phase II study, a larger investigation with greater power is required to extend these findings into clinical endpoints of relevance to patients.”Whilst avoiding RV pacing and improving or maintaining LV function is likely to be beneficial, device longevity is the most important aspect of pacemaker therapy to patients and has featured in the medical and the lay press . The amoThe results of this study therefore provide the first data from a randomised, placebo-controlled trial of chronically implanted pacemakers, that even many years following implant, and despite widespread use and promotion of RV pacing avoidance technology by companies and guidelines, careful programming using our algorithm further reduced RV pacing and had other positive effects, such as a preservation of battery longevity. Addressing programming earlier in the life of a pacemaker battery is likely to have cumulative effects upon device longevity.Our protocol, which included a lowering of the base rate and deactivating rate-adaptive pacing, was well-tolerated with no patients returning with or reporting symptoms and no detriment to their quality of life. This finding is consistent with previous data where rate-adaptive pacing has been associated with highly variable effects on measures of quality of life .Currently international guidelines state that RV pacing should be avoided if possible, , 10, 20 Although this trial was performed within two centres, they reside within a single region in the UK, potentially limiting generalisability, particularly as international pacemaker programming may differ. However, baseline demographic data indicate that our population was representative of a pacemaker recipient population.We did not limit enrolment only to patients with a pacing-induced cardiomyopathy, defined by a specific reduction in LVEF from pre-implant levels due to the presence of the pacemaker , 4. We cEstimated battery longevity remaining, rather than actual battery longevity, was utilised as a pragmatic measure of longevity due to the variable data available at follow-up between manufacturers. Whilst energy consumption or battery voltage may have provided additional information, this was not routinely obtainable from all devices included in the study, nor is it routinely available clinically.Although the present study demonstrated modest benefits on LV function and battery longevity from personalised programming, these are likely to be cumulative, especially if initiated early following implantation. Longer term follow-up in a larger multi-centre trial including patients with a greater severity of sinus node disease would allow for further sub-analysis to understand which programming modifications show the greatest effect.Personalised reprogramming to avoid unnecessary RV pacing in unselected patients with RV pacemakers, beyond manufacturers’ pacing avoidance algorithms, can improve LV function, extend battery longevity, and is safe and acceptable to patients.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S1 Checklist(DOC)Click here for additional data file.S1 Protocol(DOCX)Click here for additional data file.