The main aim of this study was to assess the prognostic utility of TAPSE/PASP as an echocardiographic parameter of maladaptive RV remodeling in cardiomyopathy patients using cardiac magnetic resonance (CMR) imaging. Furthermore, we sought to compare TAPSE/PASP to TAPSE. The association of the echocardiographic parameters TAPSE/PASP and TAPSE with CMR parameters of RV and LV remodeling was evaluated in 111 patients with ischemic and non-ischemic cardiomyopathy and cut-off values for maladaptive RV remodeling were defined. In a second step, the prognostic value of TAPSE/PASP and its cut-off value were analyzed regarding mortality in a validation cohort consisting of 221 patients with ischemic and non-ischemic cardiomyopathy. A low TAPSE/PASP (<0.38 mm/mmHg) and TAPSE (<16 mm) were associated with a lower RVEF and a long-axis RV global longitudinal strain (GLS) as well as higher RVESVI, RVEDVI and NT-proBNP. A low TAPSE/PASP, but not TAPSE, was associated with a lower LVEF and long-axis LV GLS, and a higher LVESVI, LVEDVI and T1 relaxation time at the interventricular septum and the RV insertion points. Furthermore, in the validation cohort, low TAPSE/PASP was associated with a higher mortality and TAPSE/PASP was an independent predictor of mortality. TAPSE/PASP is a predictor of maladaptive RV and LV remodeling associated with poor outcomes in cardiomyopathy patients. RV dysfunction is an important prognostic factor in many cardiopulmonary disorders including left-sided heart failure ,2. Many The current, non-invasive gold standard for the assessment of RV structure, dimensions and function is cardiac magnetic resonance (CMR) imaging. It provides high accuracy and reproducibility ,6. MRI-dThe TAPSE/PASP ratio is a novel echocardiographic parameter that has been validated as a predictor of major adverse events in patients with heart failure and reduced left ventricular (LV) ejection fraction (HFrEF), as well as in heart failure patients with preserved LV ejection fraction (HFpEF) ,15,16. HHence, the aim of this study was to analyze and compare the association of TAPSE/PASP and TAPSE with the CMR parameters of RV and LV remodeling in a group of patients with ischemic and non-ischemic cardiomyopathy. Furthermore, we sought to identify a TAPSE/PASP cut-off value associated with the relevant RV maladaptation and to validate its association with mortality in another independent cohort of patients with ischemic and non-ischemic cardiomyopathy.The present analysis uses patients of two independent, ongoing registry studies. Both cross-sectional studies (BioCVI and BioProspective) are part of the Kerckhoff Biomarker Registry (BioReg). Participation in the registry, including both study cohorts, was voluntary; all patients gave written informed consent and the studies were approved by the local ethics committee. Firstly, as the imaging cohort, patients were recruited from the BioCVI study . Here, aThis imaging cohort was used to evaluate the association of TAPSE, PASP and TAPSE/PASP with CMR parameters of maladaptation known to be associated with prognosis such as RVEF, RVESVI, RVEDVI, RV Strain and T1 mapping.Secondly, as the clinical validation cohort, patients were recruited from the BioProspective study . Adult pTAPSE measurements were available in 321 patients, PASP was measured in 306 patients and 221 patients had valid TAPSE/PASP values. Hence, this was the validation cohort used for further analyses. A total of 89 of these 221 patients were known to be deceased by July 2020, and median time between enrollment and the end day of the follow-up was 6.2 years.All evaluated patients underwent transthoracic two-dimensional echocardiography, using commercially-available ultrasound systems  as part of the clinical diagnostic workup. Left and right ventricular assessment was performed as recommended by the recent guidelines. TAPSE was obtained by placing an M-mode cursor through the lateral tricuspid annulus in the apical four-chamber view. TAPSE was measured as the peak excursion of the tricuspid annulus from the end of diastole to the end of systole. Pulmonary artery systolic pressure (PASP) was obtained as the sum of the pressure gradient between the right atrium and the right ventricle, acquired from the TR jet peak velocity and the right atrial pressure (RAP) estimation, which was based on the size of the inferior vena cava and its collapsibility. In 20 BioCVI and 80 BioProspective patients, TAPSE were also measured using a commercially-available post-processing software .Imaging was performed using a 3 Tesla scanner system  with a dedicated CMR protocol containing axial, coronal and sagittal thoracic survey images, CINE sequences, steady-state-free precession sequences (SSFP) in 2-, 3-, and 4-chamber views. Typical sequence parameters were as follows: a TE/TR/flip-angle of 1.7 ms/3.4 ms/60° and aspatial resolution of 1.8 × 1.8 × 8 mm.n = 166, 6/8 half scan, 11 images corresponding to three different inversion times using a nonselective 180° prepulse in an algorithm of n-images/n-beats 3 (2) 3 (2) 5 MOLLI scheme), as published previously [The T1 mapping was performed using a modified Look-Locker Imaging  at basal, midventricular and apical SA sections. Hence, nine ROIs were manually drawn in the septum and the upper- and lower-septal right ventricular insertion points (RVIP) in each SA section. All ROIs were drawn only on the compact myocardium and did not encompass the myocardial borders. The post-processing was performed with the syngo.via software package . Post-processing of the right and left ventricular volumes was performed using the cvi42 software package . Endo- and epicardial borders were defined using an artificial intelligence-based algorithm and carefully corrected by two experienced readers.t-test and a one-way analysis of variance with the Bonferoni post-hoc test. The Mann-Whitney U test and the Kruskal-Wallis test with Dunnet’s post-hoc test were used for the non-normally distributed continuous variables. The receiver operating characteristic (ROC) curve analysis was performed to assess the predictive value of TAPSE and TAPSE/PASP regarding RVEF < 35%, RVEDVI < 100 mL/m2 and NT-proBNP < 1000 pg/mL. A two-tailed p value < 0.05 was considered to indicate statistical significance. Statistical analysis was performed using R software and SPSS Version 25.0.0 .Continuous variables are presented as mean ± standard deviation (SD) or median with 25th to 75th interquartile range, (IQR), as appropriate. Categorical variables are expressed as numbers and percentages. Parametric distribution was assessed with the Shapiro–Wilk test. Normally-distributed continuous variables were compared using the Welch two-sample n = 111) are shown in The baseline characteristics of the imaging cohort  in the intermediate and 50% (p < 0.001) in the high tertile . In terms of clinical characteristics, there were no significant differences between these three groups . However tertile A. Conver tertile . In term tertile .The RV function reflected by RV long-axis global longitudinal strain was reduced in the lowest TAPSE/PASP tertile A. NativeNT-proBNP showed also differences in concentrations according to TAPSE/PASP tertiles with the lowest tertile having the highest NT-proBNP values B.To present the data of the TAPSE/PASP ratio in the context of the established echocardiographic RV parameter TAPSE alone, we also analyzed the cohort according to TAPSE tertiles . These analyses showed similar results in terms of right ventricular function and structure as compared to TAPSE/PASP tertiles. RVEF was reduced and the volumes RVEDVI and RVESVI were higher in the lowest TAPSE tertile . Global p for AUCTAPSE/PASP vs. AUCTAPSE = 0.2, 2, TAPSE/PASP was superior to TAPSE alone with an AUC of 0.78 vs. 0.68  are shown as n = 89). The TASPE/PASP ratio was lower in non-survivors compared to survivors  in non-survivors. In terms of the established echocardiographic parameter TAPSE, no significant difference, only a trend, between survivors and non-survivors was observed (p = 0.12). The baseline characteristics of the validation cohort (p = 0.01) in the univariate analysis. Apart from TAPSE/PASP, higher LVEDd, higher age, lower LVEF, lower eGFR, prior PCI and diabetes were also associated with all-cause mortality in the univariate analysis and, therefore, were analyzed together with either TAPSE/PASP or PASP as predictors of mortality in a multivariable regression model. Here, only TAPSE/PASP, LVEDd and prior PCI remained independent predictors of mortality  was also associated with all-cause mortality Low TAPSE/PASP (cut-off 0.38 mm/mmHg) and a low TAPSE (cut-off 16 mm) are both associated with RV dysfunction, RV dilation and higher NT-proBNP levels;(2)TAPSE/PASP, but not TAPSE alone, shows an association with LV dysfunction, LV dilation and fibrosis in the ventricular septum and RV insertion points;(3)TAPSE/PASP < 0.38 mm/mmHg is associated with a significantly increased mortality and TAPSE/PASP is an independent predictor of mortality.The main findings of the study are: By providing high spatial resolution and 3D volumetric data, CMR allows accurate quantification of cardiac function and dimensions. This is especially important in RV assessment because of its distinctive geometry ,21. FurtExisting evidence shows that CMR assessment of RV function and structure does provide valid information for the risk stratification of patients with ischemic and non-ischemic cardiomyopathy. In a study of 250 patients with non-ischemic dilated cardiomyopathy, a CMR derived RVEF of < 45% was an independent predictor of cardiovascular death or transplantation . FurtherThese robust and available data on CMR, which is an established method to stratify RV-mediated risk, motivated us to use CMR as a reference method for the assessment of prognostically-relevant RV and LV maladaptive remodeling via echocardiographic imaging parameters. The measurement of TAPSE during echocardiography is already an established parameter to estimate RV function. It is a simple and cost-effective method for the measurement of RV systolic function and a threshold of 16 mm is recommended by the current guidelines  as a proThe TAPSE/PASP ratio was proposed as a novel echocardiographic parameter that is not as load-dependent as TAPSE; thus, it might define RV-PA coupling in a non-invasive way . MeasuriHowever, a recent study showed a good correlation for both TAPSE and TAPSE/PASP with Ees/Eea in HFrEF patients and both parameters were independent predictors of mortality . These fThe novel aspect of our study is that it analyzes the role of TAPSE and TAPSE/PASP for RV and LV remodeling using CMR imaging. The results from our imaging cohort showed a similar correlation of TAPSE and TAPSE/PASP with RVEF, RVESVI and RVEDVI. Tertile analysis further showed that TAPSE/PASP < 0.38 mm/mmHg and TAPSE < 16 mm are both associated with significantly worse RVEF and RV long-axis global longitudinal strain and RV dilation, making these thresholds the potential cut-off values for RV maladaptation in patients with cardiomyopathies. Both parameters were also good predictors of RVEF < 35% with TAPSE/PASP better predicting a mild dilation in the ROC analysis. Hence, our study supports that TAPSE/PASP and TAPSE might provide comparable information in assessing RV systolic dysfunction and dilation via standard 2D echocardiography. Beyond systolic RV dysfunction and dilation, the amount of fibrosis also appears to be an important prognostic sign of RV maladaptation. Histological and cardiac imaging studies show a significant increase in RV fibrosis in patients with PH and right heart failure as compared to healthy controls ,33,34. ROur study could not show a correlation of TAPSE alone with CMR derived parameters of fibrosis, whereas lower TAPSE/PASP showed a significant association with increased fibrosis in the septum and at the RV insertion points as measured by T1 relaxation time. Several studies already have shown that elevated T1 relaxation times at the insertion points could be early markers of disease progression in PH that occur before the deterioration of RV function ,38. InseThe most common cause for secondary PH in patients with LV pathologies is an elevated filling pressure due to functional and structural LV alterations . TherefoHence, compared to previous studies, our analysis provides a detailed assessment of the associations between TAPSE, TAPSE/PASP and important parameters of RV and LV remodeling. In our second cohort, TAPSE/PASP was an independent predictor for mortality. The defined TAPSE/PASP cut-off (0.38 mm/mmHg) for prognostically-relevant RV dysfunction that stemmed from the imaging cohort was also associated with an increased mortality in cardiomyopathy patients in this independent cohort. Interestingly, TAPSE/PASP below a threshold of 0.38 mm/mmHg was also identified as a mortality cut-off in the study comparing TAPSE/PASP with invasive PV loop measurements in HFrEF patients . In HFpEIn contrast to TAPSE/PASP, the parameter TAPSE alone did not independently predict mortality in our cohort of cardiomyopathy patients. A potential reason for this somewhat-unexpected finding could be the heterogenous nature of our cohort that was without focus on patients with RV alterations. TAPSE/PASP seems to be related to a broader spectrum of RV and LV pathologies than TAPSE, which could explain this difference to TAPSE regarding mortality.As a potentially-limiting aspect, it must be acknowledged that the clinical data are derived from two prospective observational studies of relatively small sample sizes, which could limit the validity of our findings. Our analysis validates the role of TAPSE/PASP and its cut-off of 0.38 mm/mmHg as echocardiographic parameters of maladaptive RV remodeling that are also associated with mortality. In comparison to TAPSE alone, it shows additional associations to RV fibrosis and maladaptive LV remodeling, which seems to increase its prognostic value in a heterogenous population of patients with ischemic and non-ischemic cardiomyopathy.


It remains to be established to what extent physical activity (PA) levels among individuals are independently associated with deviations from the “optimal” state of the arterial system. Accelerometers have been proposed as means to obtain reliable, objective, and more comprehensive data of PA. Decisions at the time of data collection/processing could influence the association between accelerometry-derived indices and arterial properties.(i) To identify to what extent the strength of association between arterial properties and accelerometer-derived indices depend on the recording site and/or the epoch length; (ii) to determine whether some arterial characteristics  or regions  have higher levels of association with accelerometry-derived indices.n = 1,688; age: 2–84 years; female: 51.2%) to evaluate at which degree each parameter deviates from the “optimal” value.Physical activity (PA), cardiovascular risk factors (CRFs), and cardiovascular properties were evaluated in 60 volunteers . PA was measured daily for 7 days  and raw data was converted at epoch lengths of 1, 5, 10, 30, and 60-s. PA-related energy expenditure, daily time in moderate-to-vigorous PA, steps/minute, and counts-per-minute for vector magnitude were calculated. The cardiovascular evaluation included hemodynamic , structural (diameters and intima-media thickness), and functional  parameters of carotids, femoral, and brachial arteries, and carotid-femoral and carotid-radial pathways. Arterial z-scores were obtained using age-related equations derived from healthy participants not exposed to CRFs  than structural variables and with central than peripheral arteries.Regardless of the PA index, there were independent associations with central artery characteristics, which reinforces that these territories would be the most related to PA levels. Differences in data acquisition and processing could lead to differences in conclusions when addressing the association between accelerometer-derived indices and the cardiovascular system. Physical activity (PA) is associated with a reduced burden of atherosclerotic cardiovascular disease (CVD). However, it is to note that many of the studies on this topic have shown limitations related to objectively assessing the participants' PA volume , which refers to the interval of time over which the units of accelerometer measures (“counts”) are summed . Although a hip-mounted accelerometer has been traditionally used to measure PA, the use of wrist-worn devices has gained popularity  hemodynamic , structural , or functional  characteristics, or with the status of (ii) a particular histological arterial type   to identify whether levels of accelerometer-derived PA indices depend on the recording site (hip vs. wrist) and/or the epoch length; (ii) to identify whether the levels of association between PA indices and arterial properties depend on the recording site or the epoch length; (iii) to assess to what extent the association between arterial properties and PA indices depend on the parameter  or territory evaluated ; (iv) to evaluate whether associations between PA indices and arterial properties are independent of other participants' characteristics. We analyzed both (i) the data obtained directly from the participants, and (ii) the data representing the deviation (z-score) of each arterial parameter from the expected value considering the age and sex of the participant  and was allowed to determine, for each cardiovascular variable, the expected value in healthy participants  project  described later. A family history of CVD was defined by the presence of at least one first-degree relative with early CVD . Body weight  and body height  were measured with the participants wearing light clothing and no shoes. BMI was calculated as a BW-to-squared BH ratio.Participants were asked to avoid exercise, tobacco, alcohol, caffeine, and food intake 4 h prior to evaluation. Measurements were performed in a temperature-controlled environment (21–23°C), with the participant in the supine position and resting for at least 10–15 min. The cardiovascular evaluation included assessing hemodynamic, structural, and functional parameters. In this study, we focused on BP, beat-to-beat arterial diameter and wall thickness, and arterial stiffness parameters.Heart rate, peripheral  systolic BP (baSBP), and diastolic BP (baDBP) were recorded  immediately before, simultaneously, and/or after each non-invasive ultrasonographic and tonometric arterial measurement. Pulse pressure  and mean BP  were calculated.Central (aortic) systolic and diastolic BP  levels were non-invasively obtained by applanation tonometry   and carotid-femoral pulse wave velocity  were obtained by tonometry  and right (R-) common carotid (CCA), common femoral (CFA), and left brachial (BA) arteries were analyzed using ultrasound . Sequences of images  were stored for offline analysis. Diameter waveforms were obtained using border detection software . Peak systolic diameter (SysD), end-diastolic diameter (DD), and intima-media thickness  values were obtained by averaging at least 20 beats. CCA diameter and IMT were measured a centimeter proximal to the bulb, CFA diameter was measured in a straight segment in the penultimate centimeter proximal to the bifurcation. BA measurements were acquired at the elbow level in a straight segment of at least one centimeter long  and Beta Index (β). EM relates BP and diameter changes: EM = (SBP – DBP)/[(SysD – DD)/DD]. To minimize the impact of BP level on arterial stiffness, β was quantified: β = Ln(SBP/DBP)/[(SysD – DD)/DD]. Brachial BP was used to quantify CFA and BA EM and β, while aortic BP was used to quantify CCA EM and β .Physical activity (PA) raw data was collected by ActiGraph accelerometers , which measure accelerations in three axes  at a frequency of 100 Hz, with a dynamic range of ±8 units of gravity ]. To be included in the data analysis, the participant needed to have at least 6 valid days, defined as those with ≥ 18 h of valid monitoring.Anthropomorphic data (BH and BW), body location (hip or wrist), sex, race, and age of the participant were entered into the ActiLife software  , then the “Williams Work-Energy ('98)” formula is applied. The “Williams Work-Energy ('98)” formula utilizes the physics equivalent of energy: EE  = CPM*0.0000191*BW, where kcals are “total calories for a single epoch.” In turn, PA intensity was classified into 4 categories based on VM CPM, according to the “Freedson Adult VM3 (2011)” algorithm -related EE was determined by the “Freedson VM3 Combination 2011)” algorithm, which combines (i) “Freedson VM3 ('11) formula” with (ii) “Williams Work-Energy ('98) equation” . “Freedson VM3 ('11)” equation uses all three axes to estimate EE. VM calculation is only valid if the epoch CPM exceeds the Scale × 2,453 CPM. Consequently, if VM > 2,453 CPM, then EE  = 0.001064” algorit*WC; (ii) WC range: 645–1,272, HEC = 1.7133758*WC – 759.414013; (iii) WC range: 1,273–3,806, HEC = 0.3997632*WC + 911.501184; and (iv) WC range: 3,807 to infinity, HEC = 0.0128995*WC + 2383.904505  were calculated for hip and wrist records. Similar to previous studies, according to the manufacturer's recommendations, for wrist-worm data, the “Worn on wrist” option (ActiLife software) was selected during data scoring   and SD were obtained. We implemented parametric regression methods based on several models   . A z-scor interpretation: <0.20, very weak; 0.20–0.39, weak; 0.40–0.59, moderate; 0.60–0.79, strong; ≥0.80, very strong  analyses were done to quantify the association between accelerometry-derived indices and cardiovascular parameters, expressed both as un-standardized and standardized (z-scores) variables . Evans'sg Evans, .r = 0.35–0.50 , the number of participants included was higher than the minimum sample size required, both to construct the RG (sample size required: 377), and to perform agreement and association analyses (sample size required: 29–60). Analyses were done using SPSS Software , MedCalc , and NCSS 2020 . A p < 0.05 was considered statistically significant.According to the central limit theorem, a normal distribution was considered   and z-baDBP (r: −0.405 to −0.439) (r: −0.353 to −0.373) was observed only after adjustments were made (r: −0.419) and z-baDBP (r: −0.446)  . Similarere made . In turn −0.446) .r: 0.341–0.458), z-Left CCA DD (r: 0.377–0.486), Right CCA DD (r: 0.451–0.434), and z-Right CCA DD (r: 0.398–0.472) remained significant  showed positive associations (mostly “moderate to strong”) with CCA and CFA diameters. In addition, EE from wrist-recordings was positively associated with BA DD . After anificant . On the nificant .p between 0.05 and 0.10) for positive associations with Left CCA DD and z-CCA DD  analysis (hip-recordings) supports the existence of positive independent relationships between PA and central arteries diameters since both before and after adjustment there were trends  showed “moderate” negative associations with Right CCA and Right and Left CFA stiffness . After aRegional stiffness and PWV ratio showed no independent associations with EE or MVPA% (hip and wrist recordings). Neither before nor after the adjustment for cofactors of the VM CPM data from hip or wrist-recordings were associated with regional stiffness or stiffness gradient (PWV Ratio).p between 0.05 and 0.10) toward negative associations with z-cfPWV, PWV Ratio, and z-PWV Ratio  . RegardlThere were accelerometer-derived PA indices associated with arterial parameters of more than one arterial territory. EE and MVPA% recorded at the hip were associated with both CFA and CCA local stiffness. On the contrary, other indices only showed association with functional properties of a single arterial territory  .Some PA indices and arterial characteristics were independently associated with disregard of the accelerometer location , whereas other associations depended on the recording site considered . Compared to indices derived from wrist recordings, those obtained from hip measurements showed a higher number of statistically significant independent associations with arterial parameters  .Regardless of the PA index considered, there were always several statistically significant independent associations when hip recordings and central artery parameters were considered. In contrast, wrist recordings only showed associations with CCA when considering steps/min and VM CPM.In some cases, the variation in the epoch length resulted in(significant) changes in the levels of association between an accelerometry-derived PA index and an arterial parameter. For instance, in partial correlations, the associations between EE data obtained from hip-recording and Left or Right CCA DD decreased (from “moderate” to “weak”) as the epoch length increased  Supplem. In turnIn contrast, when considering steps/min and VM CPM, the association strengths were shown to be unchanged as epoch length was varied .Our findings are in agreement with previous studies in which using the same devices (ActiGraph GT3X+) and processing option provided by the software (“Worn-to-wrist”), it was observed that compared to data derived from wrist-recordings, those obtained from hip records showed lower (i) PA-related EE . The authors found that light PA, bouts of MVPA, and sedentary behavior increased with longer epochs. Besides, total MVPA decreased using longer epochs  which is in agreement with the findings of this study  (The epoch length-related differences observed in this study are consistent with previous data obtained in children and adolescents using the same accelerometers (hip or waist recordings)  are offered, highlighting that the device can be used to evaluate the same parameters  regardless of the accelerometer location  and found participants to be “more active” based on wrist data, it could be said that wrist correction would not make data from different locations alike. Consequently, it could be proposed that, despite using the “Worn to wrist” option, hip and wrist-derived PA and epoch length-derived indices (with the exception of steps/min and VM CPM) would not provide similar values and would not be equivalent , 3. Hip In line with the above, when evaluating the association between PA indices and arterial parameters, it was necessary to separately analyze PA data obtained from different locations and epoch lengths. To our knowledge, there are no previous studies analyzing the associations of different arterial parameters, types, and regions with accelerometry-derived parameters.p between 0.05 and 0.10) to be negatively associated with baDBP (wrist and hip recordings) and z-baDBP (wrist recordings). In turn, VM CPM data from wrist-recordings were negatively and independently associated with baDBP and z-baDBP. The above, obtained for steps/min and VM CPM, indices that do not require considering “cut-off values” and/or equations that include variables related to individual characteristics , reinforces that in healthy participants from the general population, higher “movement” is associated with lower baDBP .As was mentioned, statistically significant negative associations between wrist-derived EE data and baDBP and z-baDBP were only observed after adjusting for cofactors. Then, regardless of age, sex, and exposure to CRFs, higher EE (obtained from wrist recordings) was associated with lower baDBP  and lower baDBP with respect to the expected  for age-matched healthy participants not exposed to CRFs. As was described, EE calculus  considers the relationship between the VM (or CPM) and BW (Kg) of a participant. At least in theory, when adjusting  for participant's characteristics , VM (or CPM) would become the variable that governs the relationship between EE and baDBP, making it evident that the higher the PA detected in the wrist, the lower the baDBP . In contrast, when no adjustments are made (simple bivariate correlations), the participant's anthropomorphic characteristics would “hide and reverse” the association, making EE positively associated with aoSBP   could have the disadvantage of integrating into a single index—variables that have inverse relationships with BP. In this regard, the use of indices whose determinants do not include BW or BMI  could be more useful for identifying the beneficial negative relationship between PA and BP, minimizing the impact of confounding factors.p between 0.05 and 0.10) in both before and after adjustment for positive relationships with Left CCA DD and z-CCA DD. In contrast, in general terms, after adjustment, the positive association between EE (wrist-records) and arterial diameters was no longer significant. In turn, MVPA% data from wrist measurements did not show significant associations (or trends to) with carotid, femoral, or brachial structural parameters. Therefore, indices from wrist recordings would not be independently associated with characteristics of arteries that are the main determinants of arterial impedance and left ventricular load.The PA-related EE determined from hip-recordings would be positively and independently associated, mainly with central (carotid) arteries diameters . Since tThese results show that the structural characteristics of central arteries  would be the most sensitive to structural variations associated with variations in the accelerometry-derived indices EE and MVPA%. Therefore, the analysis of central  rather than peripheral  arteries would be the most valuable for monitoring structural arterial variations associated with PA levels (determined by accelerometry-derived indices).After adjusting for confounders, EE (wrist-records) was no longer associated with local stiffness, whereas EE levels obtained from hip-recordings showed “moderate” negative associations with CCA and CFA local stiffness . In lineThen higher PA levels obtained from hip-recordings (but not from wrist-measurements) would be (or tend to) independently associated with lower levels of femoral and carotid stiffness (which would certainly indicate a PA-related benefit for the cardiovascular system). The above reinforces the value of hip-recordings to assess the association between PA and arterial characteristics.Each arterial segment fulfills two different but interrelated “biomechanical” functions: to deliver an adequate blood supply to organs and tissues (“conduit function”), and to smooth the pressure and flow pulsation resulting from the intermittent left ventricular ejection so as to transform the oscillatory (highly pulsatile) hemodynamic into a continuous low-pulsatile one (“buffering or cushioning function”). Both functions are mainly determined by the cross-sectional area of the arterial segment and by the arterial wall stiffness. Arteries with a larger diameter and lower stiffness interpose less resistance to blood flow  while performing greater filtering (a more efficient “buffering function”) of blood flow and pressure pulsatility. In this context, our results showed that accelerometer-derived indices assessed at the hip  would be related to the levels of arterial diameter and stiffness, which would mean that they would be independently associated with the two main determinants of the arterial biomechanical functions.Regional stiffness and PWV ratio showed no independent associations with EE, MVPA%, or VM CPM data obtained from hip and wrist recordings. However, after the adjustment for cofactors, steps/min data obtained from hip-recordings showed a trend toward negative associations with z-cfPWV, PWV Ratio, and z-PWV Ratio. Accordingly, higher PA levels measured in terms of steps/min would tend to be associated with lower regional aortic  stiffness and “central stiffness/peripheral stiffness” ratio . Reduced aortic stiffness levels would be beneficial to the cardiovascular system as they result in lower levels of ventricular afterload (cardiac effects) and increased buffering capacity. In turn, a reduced PWV ratio would protect the microcirculation and contribute to ensuring an adequate capillary-tissue exchange, reducing the amount of pulsed energy accessing the exchange system ], Andersson et al. . Whereas, after adjusting for cofactors, BP no longer showed a positive association with some PA indices but became negatively associated (wrist data) with EE and MVPA% (which would be related to the proposed benefits of PA on BP). CCA diameters and stiffness continued to show, respectively, positive and negative associations with PA, reinforcing that the relationship between these variables would not depend on participant's characteristics or exposure to other CRFs . AccordiSince accelerometer-derived PA indices showed a major independent association with central elastic  than with peripheral arteries , the former would be preferentially “affected” or would be more “sensitive” to the PA effects . This obOn the other hand, after adjustment for cofactors, regardless of the recording site or epoch length considered, the highest levels of association were observed for functional  rather than hemodynamic or structural arterial parameters . The aboRegardless of epoch length, there were accelerometer-derived PA indices associated with the arterial parameters of more than one arterial territory. On the contrary, other indices only showed association with functional properties of a single territory. This could have a practical impact on the selection of accelerometry indices to be used in studies  that attempt to identify associations between PA levels and the cardiovascular system. The selection of indices associated with more than one characteristic and/or arterial pathway could increase the depth and scope of the study approach, whereas selecting indices without an association could lead to wrong conclusions . The above reinforces the idea that PA does not impact homogeneously the arterial system, but rather differentially affects the arterial territories and characteristics. Regarding the latter, local stiffness indices  would be more sensitive than regional parameters (cfPWV or crPWV) in showing associations with accelerometry-derived indices. Consequently, when analyzing and discussing the impact of PA on “arterial stiffness” or “arterial diameter,” it is necessary to specify the territory and parameter evaluated.Our results indicated that compared to wrist-derived indices, those obtained from hip measurements showed a greater number of statistically significant associations with arterial parameters. In theory, this could be evidence that the “acceleration” recorded at the hip would be more closely related to PA levels that are biologically linked to structural and functional characteristics of the arterial system. As an example, when walking, running, bending down, or climbing stairs, the aerobic PA associated with benefits on the cardiovascular system could be more accurately recorded with an accelerometer placed on the hip. As discussed, although the software used “counts” measured at the wrist and after converting them to hip equivalents (conversion equations) and calculated PA parameters that attempt to be similar to those from hip-recordings, these clearly did not outperform the data obtained directly from hips in terms of levels of association with arterial characteristics. Anyway, whether the observed differences between hip and wrist data  are such as to recommend the use of hip recordings over wrist should be further analyzed in prospective studies.Unfortunately, there are no previous studies comparatively analyzing the associations between accelerometer-derived indices (hip and wrist) and arterial variables. We only found one manuscript. In this regard, our findings agree with Cooke et al. who described that the association between step counts and cfPWV was only observed when the accelerometer was attached to the hip   could improve the usefulness of accelerometry-derived variables in the analysis of the relationship between PA and the status of the cardiovascular system.In practical terms, the selected “epoch length” could determine the association between PA levels and cardiovascular health markers. As was mentioned, Aadland et al. , 2020 foThis study has strengths and limitations that should be considered. First, our study included a comprehensive non-invasive evaluation of cardiovascular properties. Second, the definition of an RG made it possible to determine inter-individual cardiovascular variations (z-scores). Since the RG included Uruguayan adults non-exposed to CRFs, at the time of identifying in the 60 participants the degree of deviation from the expected or optimal values, we avoided using bibliographic data obtained non-Uruguayan participants who do not necessarily have characteristics similar to those of the Uruguayan population. Third, in this study, central and peripheral SBP and DBP were used to quantify central and peripheral arterial stiffness levels.We are aware that our research may have limitations. First, it is a cross-sectional study, so participants were not followed and the temporal profiles of the cardiovascular properties and/or the time spent on PA components and subcomponents were unknown. Second, the accelerometers do not allow capturing some PA . Third, an obvious limitation was the lack of a criterion measure, such as direct observation, which precluded comparing and determining which epoch length would be the most accurate to assess PA. It should be noted that in addition to the mentioned  and used in this study, there are other analysis and classification methodologies  proposed to determine PA behaviors from tri-axial wrist and hip acceleration raw data which allow the development of models  . Second, the EE and MVPA% levels obtained from wrist and hip change in the opposite way when varying the epoch length. As the epoch length increased, EE and MVPA% levels decreased when considering hip recordings, but the opposite was observed for wrist-derived data. Steps/min and VM CPM values did not vary in association with variations in the epoch length considered. Hip and wrist-derived PA indices and indices obtained considering different epoch lengths would not provide similar data and would not be considered equivalent. Then, hip and wrist data should not be used interchangeably. In turn, the epoch length should be selected in advance according to the proposed aims or analysis . Third, mostly central arteries (CCA) characteristics and mainly the functional ones  were associated with accelerometry-derived indices . Then, central territories would be those mainly related to PA levels assessed by accelerometry. Whatever the index considered , there was an association with central arteries (CCA). Fourth, hip records (with respect to wrist records) showed the highest level of association with arterial characteristics. In general, PA indices obtained by hip recordings outperformed those obtained from wrist measurements in terms of association with arterial parameters. Fifth, variations in the epoch length considered resulted in variations in the strength of association between arterial characteristics and EE and MVPA% levels (but not steps/min and VM CPM), although there was no clear trend enabling to define whether a certain epoch length would be “of choice.”The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Comité de Ética del Hospital de Clínicas, Comité de Ética del Centro Hospitalario Pereira-Rossell y Comité de Ética del Instituto Superior de Educación Física. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.MG-G, DB, and YZ contributed to the conception and design of the study, performed the accelerometry and cardiovascular non-invasive recordings, constructed and organized the database, and performed the statistical analysis. MG-G, JT, DB, and YZ wrote the first draft and final version of the manuscript, contributed to manuscript revision, read, and approved the submitted version. All authors contributed to the article and approved the submitted version.This research was funded by Agencia Nacional de Investigación e Innovación (ANII), grant number PRSCT–008–020 and FSPI_X_2015_1_108484, and extra budgetary funds provided by DB, YZ, and CUiiDARTE Center.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.


The aim of this study was to examine the effect of dapagliflozin on the incidence of ventricular arrhythmias and sudden death in patients with heart failure and reduced ejection fraction (HFrEF).post hoc analysis of DAPA-HF, we examined serious adverse event reports related to ventricular arrhythmias or cardiac arrest, in addition to adjudicated sudden death. The effect of dapagliflozin, compared with placebo, on the composite of the first occurrence of any serious ventricular arrhythmia, resuscitated cardiac arrest, or sudden death was examined using Cox proportional hazards models. A serious ventricular arrhythmia was reported in 115 (2.4%) of the 4744 patients in DAPA-HF . A total of 206 (41%) of the 500 cardiovascular deaths occurred suddenly. Eight patients survived resuscitation from cardiac arrest. Independent predictors of the composite outcome , ranked by chi-square value, were log-transformed N-terminal pro-B-type natriuretic peptide, history of ventricular arrhythmia, left ventricular ejection fraction, systolic blood pressure, history of myocardial infarction, male sex, body mass index, serum sodium concentration, non-white race, treatment with dapagliflozin, and cardiac resynchronization therapy. Of participants assigned to dapagliflozin, 140/2373 patients (5.9%) experienced the composite outcome compared with 175/2371 patients (7.4%) in the placebo group , and the effect was consistent across each of the components of the composite outcome.In a Dapagliflozin reduced the risk of any serious ventricular arrhythmia, cardiac arrest, or sudden death when added to conventional therapy in patients with HFrEF. ClinicalTrials.gov unique identifier: NCT03036124 (DAPA-HF).  Various proposed actions of SGLT2 inhibitors raise the hypothesis that these agents might reduce the risk of ventricular arrhythmias. Potential antiarrhythmic actions include favourable effects on left ventricular loading conditions and remodelling, autonomic nervous system activity, serum electrolytes, the cardiac sodium channel current  reports of ventricular arrhythmias, resuscitated cardiac arrest, and sudden death according to randomized assignment to dapagliflozin or placebo.Therefore, to investigate the hypothesis that SGLT2 inhibition reduces the incidence of ventricular arrhythmias, we undertook a , , DAPA-HF was a randomized, double-blind, controlled trial in patients with HFrEF, which evaluated the efficacy and safety of dapagliflozin 10 mg once daily, compared with matching placebo, added to standard care. The design, baseline characteristics, and primary results of the trial are published.2 , type 1 diabetes mellitus, and another condition likely to prevent patient participation in the trial or greatly limit life expectancy. A full list of exclusion criteria is provided in the design paper.Men and women aged ≥18 years with heart failure were eligible if they were in New York Heart Association (NYHA) functional class II–IV, had a left ventricular ejection fraction (LVEF) ≤40%, and were optimally treated with pharmacological and device therapy for HFrEF. Participants were also required to have an elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration. Key exclusion criteria included: symptoms of hypotension or systolic blood pressure <95 mmHg, estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 mAfter the provision of informed consent, visit 1 started a 14-day screening period during which the trial inclusion and exclusion criteria were checked, and baseline information was collected. Visit 2 was the randomization visit and after randomization, follow-up visits took place at 14 and 60 days, and then at 120, 240, and 360 days and every 4 months thereafter.The primary outcome in DAPA-HF was the composite of an episode of worsening heart failure or cardiovascular death, whichever occurred first. Secondary endpoints included the composite of the occurrence of heart failure hospitalization or cardiovascular death and all-cause death. The primary composite outcome in the present analysis was the time-to-first occurrence of any ‘serious’ ventricular arrhythmia, resuscitated cardiac arrest, or sudden death, as discussed in more detail below.All deaths were adjudicated according to prespecified criteria and subclassified as due to a cardiovascular cause, a non-cardiovascular cause, or an undetermined cause. Cardiovascular deaths were further subclassified into the following categories: sudden death, heart failure or cardiogenic shock (‘pump failure’), acute myocardial infarction, stroke, and others (e.g. procedure-related). Sudden death included: (i) witnessed and instantaneous death without new or worsening symptoms, (ii) death witnessed within 60 min of the onset of new or worsening cardiac symptoms, (iii) death witnessed and attributed to an identified arrhythmia, e.g. captured on an electrocardiographic recording or witnessed on a monitor, or unwitnessed but found on ICD review, (iv) death after unsuccessful resuscitation from cardiac arrest or a patient successfully resuscitated from cardiac arrest but who died within 24 h without identification of a non-cardiac aetiology, (v) death >1 day after a patient has been successfully resuscitated from cardiac arrest and without identification of a non-cardiovascular aetiology, and (vi) unwitnessed death in a subject seen alive and clinically stable ≤24 h before being found dead without any evidence supporting a specific non-cardiovascular cause of death.Because of the extensive safety information on dapagliflozin and SGLT2 inhibitors, selective adverse event reporting was employed in DAPA-HF. While all SAEs were collected, only non-SAEs associated with discontinuation of trial treatment and prespecified ‘non-SAEs of interest’  were collected.Serious adverse events were examined for any report of any ventricular arrhythmia. The adverse events were identified using the Medical Dictionary for Regulatory Activities (MedDRA) preferred terms ‘ventricular tachycardia’ (VT) (including sustained and non-sustained VT), ‘ventricular fibrillation’ (VF), ‘torsade de pointes’, ‘ventricular tachyarrhythmia’, and ‘ventricular arrhythmia’.The primary outcome in the present analysis was the time-to-first occurrence of any ‘serious’ ventricular arrhythmia, resuscitated cardiac arrest, or sudden death. For this analysis, a ‘serious’ ventricular arrhythmia was defined as VT, VF, torsade de pointes, ventricular tachyarrhythmia and ventricular arrhythmia (reflecting MedDRA preferred terms used for reporting SAEs). Premature ventricular ectopic beats were not included in this analysis. For participants who experienced more than one type of ventricular arrhythmia, only the first event reported was included in the analysis of the composite endpoint.Serious adverse event reports of cardiac arrest were also examined and patients who were resuscitated from cardiac arrest were included in this analysis if the cardiac arrest was adjudicated as being non-fatal.Baseline characteristics were compared for patients experiencing any component of the composite outcome of any serious ventricular arrhythmia, resuscitated cardiac arrest, or sudden death and patients who did not. Categorical variables are reported as whole numbers with percentages. Continuous variables are reported by their mean value with standard deviations or median value plus interquartile ranges depending on a respective normal or skewed distribution. The effect of dapagliflozin compared with placebo was examined in a time-to-first event analysis using Cox proportional hazards regression models. The primary models included factors for randomized treatment group assignment and history of heart failure hospitalization and the randomization stratification variable of diabetes status. In addition, we examined the effect of dapagliflozin, compared with placebo, on the narrower composite of VT, VF, or torsade de pointes (i.e. excluding the MedDRA preferred terms ‘ventricular tachyarrhythmia’ and ‘ventricular arrhythmia’). In sensitivity analyses, we excluded non-sustained VT from both the primary composite outcome and the narrower composite. Event rates per 100 person-years were calculated and are presented with 95% confidence intervals (CIs). The cumulative incidences of outcomes are presented graphically using the Kaplan–Meier method. The effect of randomized treatment was examined in Cox proportional hazards regression models, and the interaction with randomized therapy tested in several subgroups: patients with an ischaemic or non-ischaemic aetiology for heart failure, patients with or without an implanted defibrillating device [ICD or cardiac resynchronization therapy with a defibrillator (CRT-D)] at baseline, patients treated with or not treated with a mineralocorticoid receptor antagonist (MRA), patients with or without diabetes, patients with or without a history of ventricular arrhythmia, patients with a diagnosis of heart failure within 1 year or for >1 year before randomization, and patients who were in NYHA class II or III/IV. Baseline LVEF, NT-proBNP, and systolic blood pressure subgroups were analysed both as a categorical variable (divided at the median) and a continuous variable . These variables were chosen because: (i) patients with an ischaemic aetiology are at greater risk of sudden death than those with a non-ischaemic aetiology and there seems to be an interaction between aetiology and the effectiveness of an ICD. (ii) We wanted to examine the effectiveness of dapagliflozin added to other treatments reducing the risk of ventricular arrhythmias/sudden death. The only pharmacological treatment subgroup reasonable to do this was MRA therapy (∼70% yes/30% no); the other relevant therapies had too many (≥94% on a renin-angiotensin system blocker and a beta-blocker) or too few receiving the treatment [angiotensin receptor-neprilysin inhibitor (ARNI) 11%]. (iii) The ICD/CRT-D subgroup was chosen for the same reason as (ii) and we wondered if dapagliflozin might have more effect in patients without an ICD/CRT-D. (iv) NYHA class, NT-proBNP, systolic blood pressure, and time from diagnosis of heart failure were all chosen as recognized markers of severity of heart failure; ICDs are not indicated in patients with more severe heart failure symptoms because of the relatively higher competing risk of pump-failure death and we were interested to see whether dapagliflozin was less effective in reducing ventricular arrhythmias/sudden death in patients with evidence of more severe/advanced heart failure. (v) LVEF is a well-known predictor of sudden death and arrhythmias and the primary determinant of whether there is an indication for an ICD. (vi) Patients with a previous ventricular arrhythmia were a subset at high risk of the events of interest. (vii) Diabetes mellitus—this was included because HFrEF patients with diabetes have a higher risk of sudden death than those without diabetes and ICDs seem to be less effective in patients with diabetes. To account for the fact that death precludes the future occurrence of ventricular arrhythmias, a proportional hazards competing-risk regression model was used as a sensitivity analysis.2-transformed values), adjusted for baseline NT-proBNP, and the incidence of serious ventricular arrhythmia, resuscitated cardiac arrest, or sudden death was examined using Cox proportional hazards linear models. For this analysis, only events occurring after 8 months were included. The association between baseline LVEF and NT-proBNP as continuous variables and the primary composite outcome were examined in linear models and reported graphically.The association between relative change in NT-proBNP from baseline to 8 months  total symptom score, history of ventricular arrhythmia, hypertension, diabetes, atrial fibrillation, chronic obstructive pulmonary disease, myocardial infarction, stroke, percutaneous coronary intervention or coronary bypass grafting, ICD, CRT, and anaemia. Randomized treatment and prior heart failure hospitalization were fixed factors in the model. Odds ratios with 95% CIs are presented. The effect of individual variables on the logistic regression model was examined and a χ 2 value calculated using a post-estimation test. Randomization treatment and a history of heart failure hospitalization were forced into the model.A backward stepwise logistic regression multivariable model was constructed with a P-value of <0.05 was considered statistically significant. Statistical analyses were performed using Stata 17 .A At least one episode of a serious ventricular arrhythmia was reported in 115 (2.4%) of the 4744 patients in DAPA-HF. The events reported were VT in 87 patients (86 as a first event), VF in 16 patients (15 as a first event), torsade de pointes in 2 patients (2 as a first event), a ‘ventricular tachyarrhythmia’ in 1 patient (1 as a first event), and a ‘ventricular arrhythmia’ in 13 patients (11 as a first event). Among patients experiencing VT, 7 patients reported to have a ‘non-sustained VT’ event (6 as a first event) and 4 reported a ‘paroxysmal VT’ event (3 as a first event), identified by MedDRA low-level terms. Of the 500 cardiovascular deaths, 206 (41%) were adjudicated as sudden death. Overall, 23 patients (0.5%) had a documented cardiac arrest, of whom 8 (35%) survived. A total of 315 patients (6.6%) experienced the composite of a serious ventricular arrhythmia (104 as the first event in the composite), resuscitated cardiac arrest (8 as the first event), or sudden death (203 as the first event). A total of 8 patients had the same time to the occurrence of a serious ventricular arrhythmia and sudden death and were counted as sudden death in the analysis of the composite outcome. Similarly, one patient who had the same time to the occurrence of a serious ventricular arrhythmia and resuscitated cardiac arrest was counted as a resuscitated cardiac arrest in the analysis of the primary composite outcome.Table 1 shows the baseline characteristics of patients who did and did not experience the primary composite outcome in this analysis . Compared to patients who did not experience the composite outcome, patients who did were more likely to be male, have a history of ischaemic heart disease and ventricular arrhythmia, and had a lower LVEF, higher NT-proBNP, longer duration of heart failure, worse renal function, a broader QRS, and greater symptom burden at baseline . More patients who experienced a composite event were treated with an MRA and had an ICD at baseline. Background treatment with beta-blockers was high in both groups, although slightly fewer patients who experienced the composite outcome were taking a beta-blocker at baseline. The baseline characteristics of patients with any serious ventricular arrhythmia or sudden death, separately, are shown in χ 2 value, were log-transformed NT-proBNP, history of ventricular arrhythmia, LVEF, systolic blood pressure, history of myocardial infarction, male sex, body mass index, serum sodium concentration, non-white race, treatment with dapagliflozin, and CRT (Table 2).Independent predictors of the composite outcome, ranked by S2).When modelled continuously , higher NT-proBNP was associated with a greater risk of a primary composite event and baseline values below the median were associated with a lower risk. An inverse relationship was observed between baseline LVEF, modelled continuously, and the primary composite outcome  0.79 (95% CI 0.63–0.99), P = 0.037] . We conducted a sensitivity analysis including only VT, VF, and torsade de pointes as the ventricular arrhythmia component of the composite (i.e. excluding events reported as ‘ventricular tachyarrhythmia’ and ‘ventricular arrhythmia’). This analysis of VT, VF, torsade de pointes, resuscitated cardiac arrest, or sudden death also occurred less frequently in patients treated with dapagliflozin compared to placebo . The effect of dapagliflozin compared to placebo on the incidence of any ‘serious’ ventricular arrhythmia [HR 0.76 (95% CI 0.53–1.10)]; VT, VF, or torsade de pointes [HR 0.72 (95% CI 0.49–1.07)]; and sudden death [HR 0.81 (95% CI 0.62–1.07)] was consistent with the effect on the primary composite outcome. In further sensitivity analyses, we excluded non-sustained VT from both the primary composite outcome and the narrower composite of VT, VF, torsade de pointes, resuscitated cardiac arrest, or sudden death; the findings of these analyses were consistent with the analyses reported above (Table 3). Although there were numerically more resuscitated cardiac arrests in the dapagliflozin group (5 vs. 3 in the placebo group), the overall number of events was small. Analysis modelling all-cause mortality as a competing risk also gave similar results  implanted at baseline, 102 (8.2%) experienced at least one ventricular arrhythmia. Among the 3502 participants without a defibrillating device, 213 (6.1%) experienced either a serious ventricular arrhythmia, resuscitated cardiac arrest, or sudden death. The HR for the effect of dapagliflozin, compared with placebo, on this composite outcome in patients with an ICD/CRT-D was 0.99 (95% CI 0.67–1.45), compared with 0.71 (95% CI 0.54–0.93) in those without such a device. Despite the apparently smaller effect in patients with a defibrillating device, the P-value for interaction was not significant (=0.174).The effect of dapagliflozin on the composite outcome in key subgroups is shown in P-value for interaction was 0.032 (Table 4). When the interaction was tested using NT-proBNP modelled as a continuous variable, the P-value for interaction was 0.056.Of the 2372 patients with a baseline NT-proBNP at or below the median, 121 (5.1%) experienced the primary composite event. A total of 194 of 2370 (8.2%) patients with a baseline NT-proBNP above the median experienced one of the composite events. The HR for the effect of dapagliflozin, compared with placebo, on the composite outcome in patients with an NT-proBNP at or below the median was 0.58 (0.40–0.84) compared with 0.96 (0.72–1.27) in those with an NT-proBNP above the median. The Appendix Figure S4).Change in NT-proBNP between baseline and 8 months was analysed in 4222 patients (89.0%). An increase in NT-proBNP, adjusted for baseline value, was associated with a higher risk of any serious ventricular arrhythmia, resuscitated cardiac arrest or sudden death , whereas a decrease in NT-proBNP was associated with a lower risk  (P = 0.002). The corresponding adjusted HR was 2.09 (95% CI 1.26–3.45) (P = 0.004).When the occurrence of a serious ventricular arrhythmia was modelled as a time-varying covariate, there was a strong association with mortality. For a serious ventricular arrhythmia, the unadjusted HR for subsequent death from any causes was 2.16 (95% CI 1.31–3.56) .The main finding of this analysis was that dapagliflozin reduced the risk of the composite outcome of an investigator-reported serious ventricular arrhythmia, resuscitated cardiac arrest, or sudden death in patients with HFrEF  and the rates of appropriate ICD therapy reported in generally similar patient populations are broadly in keeping with the rates of ‘serious’ ventricular arrhythmias in DAPA-HF and PARADIGM-HF, accounting for background therapy and other differences.P-value for the interaction between the effect of dapagliflozin and baseline device status was non-significant and the device subgroup was of modest size and had relatively few events. However, it is plausible that dapagliflozin might be less likely to reduce sudden death in patients with an ICD/CRT-D compared to those without such a device. The effect of dapagliflozin on a ventricular arrhythmia or sudden death seemed to be more consistent regarding aetiology (non-ischaemic vs. ischaemic) and baseline MRA therapy .The risk of any ventricular arrhythmia, resuscitated cardiac arrest, or sudden death was decreased by 21% when dapagliflozin was added to other treatments previously shown to reduce ventricular arrhythmias and sudden death, including beta-blockers, MRAs, and sacubitril/valsartan., I Na) in cardiomyocytes from mice with heart failure and in cardiac Nav1.5 sodium channels containing the long QT syndrome 3 mutations.+/H+) exchanger-1 (NHE-1), although this has not been confirmed by all investigators.We do not know of any other reports of the effect of SGLT2 inhibitors on ventricular arrhythmias in this patient group, although empagliflozin has been shown to reduce the incidence of VF related to ischaemia/reperfusion in Langendorff-perfused rabbit hearts.Our study had several limitations. First, this analysis was not prespecified. As a result, our findings should be regarded as hypothesis generating and require confirmation, although a recent meta-analysis of 22 trials involving 52 115 patients with a variety of conditions  found that the use of an SGLT2 inhibitor was associated with a lower risk of VT reported as an adverse event .post hoc analysis, dapagliflozin, compared with placebo, reduced the incidence of investigator-reported (but not adjudicated) ventricular arrhythmias in patients with HFrEF, most of whom were treated with a renin–angiotensin system blocker, beta-blocker, and an MRA as well.In summary, in this European Heart Journal online.The DAPA-HF trial was funded by AstraZeneca. J.J.V.M. and M.C.P. are supported by a British Heart Foundation Centre of Research Excellence Grant (RE/18/6/34217).Conflict of interest: J.P.C. has no disclosures. K.F.D.’s employer, the University of Glasgow, has been remunerated by AstraZeneca for working on the DAPA-HF trial. P.S.J.’s employer, the University of Glasgow, has been remunerated by AstraZeneca for working on the DAPA-HF trial (Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure) and the DELIVER trial  and speakers and advisory board fees from AstraZeneca. Speakers and advisory board fees from Novartis and advisory board fees and grants from Boehringer Ingelheim. M.C.P. reports receiving lecture fees from AstraZeneca and Eli Lilly during the conduct of the study and personal fees from Novo Nordisk, AstraZeneca, NAPP Pharmaceuticals, Takeda Pharmaceutical, Alnylam, Bayer, Resverlogix, and Cardiorentis, and grants and personal fees from Boehringer Ingelheim and Novartis. S.E.I. reports personal fees and nonfinancial support from AstraZeneca, Boehringer Ingelheim, Sanofi/Lexicon, Merck, VTV Therapeutics, and Abbott/Alere, and personal fees from AstraZeneca and Zafgen, as well. L.K. reports other support from AstraZeneca and personal fees from Novartis and Bristol Myers Squibb as a speaker. M.N.K. reports personal fees from AstraZeneca and Vifor Pharma; grants, personal fees, and other from AstraZeneca; grants and personal fees from Boehringer Ingelheim; and personal fees from Sanofi, Amgen, Novo Nordisk, Merck (Diabetes and Cardiovascular), Janssen, Bayer, Applied Therapeutics, and Eli Lilly. F.A.M. reports personal fees from AstraZeneca. M.S.S. reports grants from Bayer, Daiichi Sankyo, Eisai, GlaxoSmithKline, Pfizer, Poxel, Quark Pharmaceuticals, and Takeda; grants and personal fees from Amgen, AstraZeneca, Intarcia, Janssen Research and Development, The Medicines Company, MedImmune, Merck, and Novartis; and personal fees from Anthos Therapeutics, Bristol Myers Squibb, CVS Caremark, DalCor, Dyrnamix, Esperion, IFM Therapeutics, and Ionis. P.P. reports personal fees and other from AstraZeneca, Boehringer Ingelheim, Bayer, BMS, Cibiem, Novartis, and RenalGuard; personal fees from Pfizer, Servier, Respicardia, and Berlin-Chemie; other from Amgen; and grants, personal fees, and other from Vifor Pharma. M.S.S. is a member of the TIMI Study Group, which has also received institutional research grant support through Brigham and Women’s Hospital from Abbott, Aralez, Roche, and Zora Biosciences. O.B., A.M.L., and M.S. are employees of AstraZeneca. S.D.S. has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, BMS, Celladon, Cytokinetics, Eidos, Gilead, GSK, Ionis, Lilly, Lone Star Heart, Mesoblast, MyoKardia, NIH/NHLBI, NeuroTronik, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Theracos, and has consulted for Abbott, Action Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi Sankyo, Gilead, GSK, Ironwood, Lilly, Merck, Myokardia, Novartis, Roche, Takeda, Theracos, Quantum Genetics, Cardurion, AoBiome, Janssen, Cardiac Dimensions, Tenaya, Sanofi Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, and American Regent. J..J.V.M.’s employer, the University of Glasgow, has been remunerated by AstraZeneca for working on the DAPA-HF and DELIVER trial, Cardiorentis, Amgen, Oxford University/Bayer, Theracos, Abbvie, Novartis, Glaxo Smith Kline, Vifor-Fresenius, Kidney Research UK, and Novartis, and other support from Bayer, DalCor, Pfizer, Merck, Bristol Myers, and Squibb, as well.The data that support the findings of this study are available from the corresponding author on reasonable request.ehab560_Supplementary_DataClick here for additional data file.


Far from being historically considered a primary healthcare problem, tricuspid regurgitation (TR) has recently gained much attention from the scientific community. In fact, in the last years, robust evidence has emerged regarding the epidemiological impact of TR, whose prevalence seems to be similar to that of other valvulopathies, such as aortic stenosis, with an estimated up to 4% of people >75 years affected by at least moderate TR in the United States, and up to 23% among patients suffering from heart failure with reduced ejection fraction. This recurrent coexistence of left ventricular systolic dysfunction (LVSD) and TR is not surprising, considered the multiple etiologies of tricuspid valve disease. TR can complicate heart failure mostly as a functional disease, because of pulmonary hypertension (PH), subsequent to elevated left ventricular end-diastolic pressure, leading to right ventricular dilatation, and valve tethering. Moreover, the so-called “functional isolated” TR can occur, in the absence of PH, as a result of right atrial dilatation associated with atrial fibrillation, a common finding in patients with LVSD. Finally, TR can result as a iatrogenic consequence of transvalvular lead insertion, another frequent scenario in this cohort of patients. Nonetheless, despite the significant coincidence of these two conditions, their mutual relation, and the independent prognostic role of TR is still a matter of debate. Whether significant TR is just a marker for advanced left-heart disease, or a crucial potential therapeutical target, remains unclear. Aim of the authors in this review is to present an update concerning the epidemiological features and the clinical burden of TR in the context of LVSD, its prognostic value, and the potential benefit for early tricuspid intervention in patients affected by contemporary TR and LVSD. The long-time accepted idea that tricuspid regurgitation (TR) is a benign valvular condition has been deeply rebutted by almost one decade of insights into its epidemiological and clinical implication. While trivial TR is a common finding during routine echocardiography examination of asymptomatic subjects and is considered almost a physiological condition , most reThe current review analyzes the prevalence, the morphological types of TR, and its prognostic value in the context of LVSD.p < 0.01) and strongly linked to age (p < 0.0001), reaching up to 4% in people older than 75; interestingly, LVSD accounted for 12.9% of all TR causes. The prevalence of significant  TR was 10.2% among 2,054 consecutive patients with different types of cardiac pathologies evaluated over a 3-month period ; p = 0.012], and heart transplantation  , 35, sevIt is mandatory to underline that functional TR can persist or even progress despite appropriate pharmacological treatment or interventional resolution of the concomitant left-heart disease , 46, 47.Considering the extreme heterogeneity of the “TR population” and the natural progressive history of this disease, a correct evaluation of the morphologic type of TR, focusing on the annular dimensions, the subvalvular apparatus, the tenting area, and the RV function and dimension, is pivotal at the time of TR diagnosis. Moreover, we should even aim to assess the independent impact on the outcome of each subtype of TR, as different subtypes and different stages of significant TR may imply different treatment options, varying from isolated TR surgery, and transcatheter options to palliative procedures only in selected patients.Although the question concerning the prognostic role of TR in the natural history of LVSD has been debated for decades, only in the recent years we have gained a significant amount of evidences, with well-designed studies across most of the various clinical scenarios , that could help dealing with our initial dilemma: does TR represent just a marker for advanced myocardial disease, or is it an independent cause of the adverse outcome and a potential therapeutic target? The answer may not be univocal. Indeed, various features associated with a greater severity of TR, such as LVSD, PH, and AF, are all independently associated with a decreased long-term survival; nonetheless, in case of LVSD, different plausible mechanisms could directly and indirectly relate TR to a poor outcome.First, albeit volume overload is initially well-tolerated by the RV, compared to pressure-overload , if sustNotably, hemodynamically relevant TR is a primary effector mechanism for the increase in central venous pressure (CVP). Systemic venous congestion is a main determinant of reduced renal blood flow and, subsequently, of the decline of glomerular filtration rate and of the exhaustion of renal autoregulatory capacity –54. A paHepatic failure, resulting from both hepatic congestion and reduced hepatic perfusion, is crucially combined to TR severity . As RV pIn summary, several TR-induced mechanisms can affect the prognosis of these patients by both reducing left-ventricle pump function and leading to multiple organs dysfunction in the context of right-heart failure . We mustDespite different pathophysiological implications by which TR, both itself and indirectly, can contribute to a poor prognosis, uncertainty has long persisted regarding its independent association with negative outcomes in patients with LVSD. Four main issues need to be addressed to evaluate the role of TR in LVSD. First, the hypothesis of severe functional TR as a marker of end-stage myocardial disease is strongly supported by the pathophysiological implications of LVSD, particularly if corroborated by left-valvular disease, PH and AF, and by the amount of evidence emerged regarding the poor prognosis of these patients. Second, although it is unanimously accepted that, in the vicious cycle of a damaged left ventricle affected by systolic dysfunction, leading to PH and RV maladaptive remodeling, the appearance of relevant TR warrants a state of poor long-term survival, to demonstrate its prognostic role regardless of the multiple co-existing cardiac comorbidities can be extremely challenging. Third, one could argue that the impact of TR in this context may depend upon its grade or the severity of LVSD and PH: this has a therapeutical relevance, since we lack knowledge on the appropriate timing of intervention, and different subgroups of patients would benefit more than others from invasive treatment of TR. In particular, invasive hemodynamic assessment through right heart catheterization provide us fundamental and often underestimated parameters, such as cardiac index, pulmonary wedge pressure, the subgroup of PH and its eventual reversibility, that may indeed help us to correctly identify the candidate patient that would benefit most from TR invasive treatment .Finally, if considered a therapeutical target, we eagerly await for randomized prospective studies demonstrating a safety and beneficial effect of isolated TR correction in patients with LVSD, in order to definitely clarify its clinical role.In the recent years the growing interest from the scientific community has led to a “Copernican Revolution” on the vision of TR-related poor outcome and on the need for an appropriate therapeutical management, a reappraisal that could bring us at least closer to an answer for our initial question see .p < 0.0001 for all), confirming its role as a marker of advanced myocardial disease.Benfari et al. , in thei2) resulted in an increased mortality , and cardiac events  , both after comprehensive adjustment for age, sex, comorbidity index, LVEF > moderate right ventricular dysfunction, renal dysfunction, AF, left atrium size, and right ventricular systolic pressure. Again, there was a significant link (p < 0.001) between TR severity and patients in NYHA class III–IV and with right heart failure.In a cohort of patients with LVSD and FTR assessed quantitatively by Topilsky et al. , severe p < 0.001). At least moderate TR was associated with an increased overall mortality in the proportional hazard methods  adjusted for age, gender, major comorbidities, and echocardiographic parameters . Ejection fraction and cardiac output were progressively reduced along with the increase of TR severity (p < 0.001).Chorin et al.  have evap = 0.0125) but not in those with severe LVSD (ejection fraction < 35%).Whether the impact of TR depends on the degree of LVSD is a current matter of debate and was evaluated by Neuhold et al. . The autp = 0.005) and NT-proBNP levels (p < 0.001), surprisingly the thresholds of TR quantitative parameters associated with an increased mortality (p < 0.001) were congruent with moderate TR as defined by the present guidelines  and of overall mortality  in 373 consecutive patients with at least mild functional MR regardless of age, PH, RV function or ejection fraction.The prognostic role of TR in the context of functional MR and LVSD has been investigated by Agricola et al. . ModeratIt's noteworthy that recent data from the COAPT trial , which eHoke et al.  evaluateIndeed, this significant number of studies enlightening the prognostic role of TR seems to justify the changing face of our attention to TR in case of concomitant LVSD. Whether these studies enforce the call for an early intervention is still unclear. In particular, the results provided by Neuhold et al.  and BartAt last, it is mandatory to underline that TR is a dynamic entity, whose natural course requires a close follow-up, as non-severe TR progression conveys a significant risk of worsening PH, valvular and ventricular remodeling, and long-term augmented mortality , 77. In In patients with TR and LVSD, the pharmacological therapy aims at two targets: the LV and the hemodynamic consequences of TR. Guidelines medical therapies, such as angiotensin-converting enzyme inhibitors, beta blockers and angiotensin receptor neprilysin inhibitor, may reduce TR, particularly in its early stage, by improving LV systolic and diastolic dysfunction , 79. LooIn the last years, transcatheter strategies, despite being in their initial phase yet, have emerged as a potential therapeutic option. This interventional strategy is of particular interest and need, considering the high-surgical risk typical of the population affected by TR and LVSD. Current treatments include annuloplasty, improved leaflet co-aptation, edge-to edge repair, reduction of the reflux in the vena cava, and percutaneous valve replacement –86. The Up until now, the ideal candidate seems to be a patient with FTR and partially preserved leaflets co-aptation, in the absence of significant apical valve tethering, RV dysfunction and PH , 92; in Despite being historically recognized only as a surrogate of advanced heart disease, latest studies have clearly demonstrated that at least moderate TR, in combination with LVSD, is a frequent condition, with different etiologies, and associated with independent excess mortality that increases with the degree of TR, highly suggesting of a causal effect that relies on different direct and indirect pathological mechanisms. While we look forward to randomized trials of transcatheter tricuspid devices in a selected population with LVSD, we must continue to improve our awareness of the role of TR in the context of left and right ventricular disease, in order to comprehend whether to consider it a surrogate of advanced myocardial disease or, if a potential target, the most appropriate timing for intervention.All the authors have contributed, read, and approved the final 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.


We report a new pulmonary circulation model during cardiopulmonary bypass that is able to cause pulmonary congestion but without left heart failure. This kind of congestion is characterized by right and left heart output mismatching. The pathophysiological mechanism, clinical manifestations, diagnosis, differential diagnosis, and treatment of this pulmonary congestion are reviewed and discussed in the following article. A 74-year-old female patient who had mitral valve regurgitation (MR) was admitted to our hospital because of progressive dyspnea for 6 years, and her illness worsened during the previous 2 months. Her body weight and height were 56 kg and 152 cm, respectively. She had been diagnosed with MR for 2 years and had received diuretic and inotropic therapy for a couple of months. After a preoperative physical examination, a systolic murmur (grade 4/6) was identified by cardiac auscultation at the heart apex, and the boundary of heart dullness was found to expand to the left. Transthoracic echocardiography (TTE) revealed a posterior mitral valve leaf prolapse with severe MR. In addition, the patient still had mild-to-moderate tricuspid valve regurgitation, and the pressure gradient was estimated to be 67 mmHg according to the Bernoulli equation. The left ventricular diameter was 52 mm at the section of papillary muscles, and the ejection fraction (EF) value was 74.5%. An electrocardiogram (ECG) showed sinus rhythm with a heart rate (HR) of 73 beats per minute (bpm). A chest computed tomography (CT) scan did not reveal any obvious abnormalities except for a sign of heart shadow enlargement. The patient denied any previous disease history and did not take any medication before this illness. Preoperative anesthetic assessments indicated that she was classified as American Society of Anesthesiologists III status (ASA III) and the surgical risk score was 6 (EuroSCORE of 6). The surgeons decided to replace her mitral valve under cardiopulmonary bypass (CPB).2) value was 94% at room air. After induction of anesthesia with 4 mg midazolam, 50 mg propofol, 0.5 mg fentanyl, and 16 mg vecuronium bromide, the patient underwent tracheal intubation with an ID 7.0 mm tube and was then connected to an anesthetic machine for ventilation. At first, the tidal volume was 450 ml and the respiratory rate was 10 bpm. The inspiratory to expiratory ratio was set at 1:2 without an inspiratory pause. The peak airway pressure was 20 cmH2O with the presence of a positive end-expiratory pressure (PEEP) of 5 cmH2O. End-tidal carbon dioxide (ETCO2) was maintained between 35 and 45 mmHg by subsequently adjusting the ventilation frequency. The patient’s hemodynamics, SpO2, and ETCO2 were stable and were maintained in the normal range during anesthesia induction. After placement of a transesophageal echocardiography (TEE) probe and a Swan-Ganz catheter, the central venous pressure (CVP), pulmonary artery pressure (PAP), and cardiac output were monitored. The baseline PAP was 56/22 mmHg after Swan-Ganz catheter placement. Anesthesia was maintained with sevoflurane, cis-atracurium, intermittent fentanyl, and the bispectral index (BIS) value was maintained at 40–60 during most time of the surgical procedure.Before anesthesia induction, the invasive blood pressure (IBP) was 138/62 mmHg after left radial artery A-line establishment. The ECG demonstrated sinus rhythm and the HR was 62 bpm. The pulse oxygen saturation (SpO2O after resuming ventilation under the previous ventilator settings. The PAP was not high (10 mmHg) because the patient was still dependent on the CPB machine. The anesthesiologist excluded an inadequate anesthesia depth, airway circuit obstruction, anesthetic machine problems, pleural cavity, or mediastinal abnormalities for a short period of time. Fibrotic bronchoscopy did not reveal bronchus intubation or any obvious secretions. Bronchospasm was initially diagnosed and bronchial dilators together with sevoflurane were administered, but without any obvious effect to relieve the airway pressure. Because bronchospasm usually happens in light anesthetic state and what is more, volatile anesthetics can dilate bronchus directly. Even if it was difficult to listen to breath sound because of aseptic towel, we tried to obtain the breath sound in the two lungs. As pulmonary auscultation did not indicate obvious wet or dry rales and ETCO2 waveform did not indicate small airway obstruction, the anesthesiologist began to consider cardiogenic factors. At that time, the IBP was 75/65 mmHg and HR was 90 bpm.After about 60 min of mitral valve replacement, the heart began to re-beat successfully after releasing the aortic clamp. The heart contractility seemed good with the help of dobutamine administered at a rate of 5 μg/kg/min. The anesthesiologist found that the peak airway pressure increased gradually from 20 to 38 cmHLVOT)2 . DLVOT was 0.97 cm and VTI was 5.38 cm. Therefore the stroke volume of left ventricle was almost 4 ml, but the right heart stroke volume was 12 ml through Swan-Ganz catcher measurement. The surgeons confirmed that the left atrial suction tube was working well and excluded an increase of left atrial pressure or left ventricular distension. Due to pulmonary artery blood supply and pulmonary venous return mismatching  blood flow volume and the left atrial suction rate. Through echo measurements and calculation, we can get the left ventricle output according to the formula VTI × π × 2 2 . DLVOT wdilators . They weIn healthy human heart and lungs, the right heart cardiac output is nearly equal to that of the left heart, except for a tiny anatomic shunt from the right to the left, which will cause a slight difference between right heart and left heart cardiac output .In some congenital heart disease patients, such as atrial septal defect (ASD) or ventricular septal defect (VSD) patients, there will be a mismatching between the right and left heart cardiac output . HoweverThe following changes may have a potential and temporary effect on the pulmonary compliance and airway resistance: (1) the heart stops beating and the pulsatile PAP is missing during CPB, hence the main pulmonary blood driving force will be generated form non-pulsatile bronchial arteries; (2) there will be air filling the pulmonary vein or venules after the left heart opens and then this air will hold part of the pulmonary blood drainage to the left atrium or the CPB machine ; (3) pul2 waveform, especially during CPB. Also, this type of bronchospasm is unresponsive to regular bronchodilators, corticosteroids, or inotropic drugs. Left atrial pressure measurement or TEE examination may exclude left heart volume overload or contractile dysfunction. Pulmonary ultrasound and echocardiography are very useful, non-invasive, and effective to diagnose pulmonary congestion and cardiac dysfunction in these patients (We should differentiate this type of pulmonary congestion from bronchospasm, heart failure, allergic reactions, airway secretions, pleural or mediastinal problems, post-CPB lung injury, anesthetic machine malfunction, and protamine adverse effects, etc. . It is rpatients , 2019. Fpatients . Echocarpatients . Anotherpatients , yet cheThe pulmonary circulation during hypothermic CPB may not be the same as normal circulation during conscious state, so that it is worth while to pay attention to it and calculate specific parameters . AccordiPulmonary congestion due to right/left heart output mismatching will not happen in every CPB patient and pulmonary tissues are not easily obtained to do histological examination. As a result, there is a barrier to get direct evidence to confirm our hypothesis. However, we have to be cautious about this pathophysiological change to avoid excessive prolonging CPB time when we encounter similar patients. Further studies are needed to confirm our postulate and clarify the specific pathophysiological mechanism in greater detail.JY and YL wrote the manuscript. JS did this anesthesia case, made a thorough analysis of the pathophysiological changes, and finalized the manuscript. All authors contributed to the article and approved the submitted version.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.


Clinical interest continues in identifying heart failure patients who will improve with cardiac resynchronization therapy (CRT). Since the advent of applying phase analysis to measure the synchronicity of the regional LV onset of mechanical contractionThe purpose of this report is to describe the technical considerations undertaken in this trial to assure valid results and the algorithms in ECTb4 used to measure synchronicity-pertinent LV parameters. Some of the descriptions below are specific to using ECTb4. The quality control, the processing technical tips and algorithms descriptions are universal to technologists, physicians and industries interested in assessing LV mechanical dyssynchrony (LVdys).The SPECT scans are performed approximately 30 minutes post rest injection using 740-1110 MBq (20-30 mCi) of 99mTc-sestamibi or tetrofosmin. SPECT images are usually acquired on dual-headed cameras with high-resolution low energy collimators, using 180° orbits and a standard resting protocol.Gating errors can cause errors in the measurement of LV dyssynchrony,Either 8 or 16 frames per cardiac cycle are used for ECG gating. Since the measurement of phase is count sensitive, i.e., the more counts the more accurate the dyssynchrony measurement, the choice of number of frames is dictated by the number of counts per pixel in the gated LV myocardium  and the magnitude of intraventricular dyssynchrony (PSD > 43° by ECTb4The identification of the last contracting viable segment(s) by ECTb4 is used to identify the target region in the LV to place the CRT lead via venous access.LVEF and ESV were measured by ECTb4 in the conventional way. The amount of LVdys is measured as the PSD.The automatic determination of the last viable segment(s) to contract were determined as previously reported.This report presents helpful tips used in the VISION-CRT trial intending to explain and guide the correct gMPI acquisition, processing and parametrization of synchrony-pertinent LV functional parameters that may assist in the identification of patients who respond to CRT and in the evaluation of the treatment. The procedures described in this report were used by the nuclear cardiology core laboratory at Emory University to generate the trial’s results and each of the individual trial sites independently followed this guidance to generate the site’s results. By following these procedures applied to the automated algorithms described here should ensure widespread use of reproducible dyssynchrony measurement techniques that overcome the disagreements reported in the PROSPECT trial when using echocardiographic techniques for the same purpose.Electronic supplementary material 1 (OPUS 373 kb)Electronic supplementary material 2 (PDF 1219 kb)Below is the link to the electronic supplementary material.