This work aimed to investigate the effect of different shim techniques, voxel sizes, and repetition time (TR) on using theT2 and T2* sequences to determine their optimum settings to investigate the quantification of iron in transfused dependent sickle cell patients. The effect of each of these parameters was investigated on phantoms of different Gadolinium (Gd) concentrations, on 10 volunteers and 25 patients using a1 5T MRI Philips scanner. No significant difference between the three shim techniques was noticed in either T2 or T2* sequence measurements. Pixel sizes of 1 × 1 and 2 × 2 mm provided optimum results for T2 measurements. At 1 × 1 mm pixel size the T2* measurements experienced less error in measurements than the size of 2.5 × 2.5 mm used in the literature. Even though the slice thickness variation did not provide any changes in T2 measurements, the 12 mm provided optimum T2* measurements. TR variation did not yield significant changes on either T2 or T2* measurements. These results indicate that both T2 and T2* sequences can be further improved by providing more reliable measurements and reducing acquisition time. The number of cases of this disease reached 30% among pastoral tribes in western Sudan. Up to 16% was found in immigrant tribes in the area4.In Africa, sickle cell disease is raising great health concerns, particularly in the western part of Sudan among the Baggara (Misseriya tribe). Archibald5. Their life expectancy is < 20 years old6, and patients younger than 5 years are at high risk of death.The prevalence of patients with SCA in Sub-Saharan Africa ranges between 5 and 40%Blood transfusions in sickle cell patients could lead to iron overload particularly in the liver. Iron overload promotes the formation of toxic oxygen radicals that can cause cell damage. Therefore, the knowledge of iron levels in these patients is important to mitigate the health consequences of iron overload.7.The levels of iron in blood-transfusion patients are often monitored using the serum ferritin method. This method known to be an unreliable marker for assessing iron in organs such as the heart and liver9. It is therefore, expected that the serum ferritin and invasive biopsy methods will be replaced by the MRI methods, however, there is limited data in the literature that systematically compared T2 and T2* sequences in sickle cell anemia (SCA)10. For the quantification of iron using MRI techniques, the literature highlighted that MR signal measurements could be affected by sequence protocol14. Nevertheless, many of these studies were limited to narrow investigations of parameter effects on T2 and T2* measurements. Researchers stated that T2 techniques are not affected by the size or shape of the imaging voxel15 or shimming techniques16, and commented that T2* methods were affected by voxel size17, shimming technique and TR.The use of magnetic resonance imaging (MRI) techniques involving transverse relaxation times such as the T2 and T2* have shown promising results in estimating iron concentration in transfusion-dependent patients18. While the literature highlighted some guidelines for use of protocols for T2* measurements for cardiovascular image19, different acquisition approaches were implemented for T2 sequences and hence lead to variations in T2 values20. It was also suggested that changing T2* sequence parameters may particularly be significant at high liver concentrations9.The empirical effects of shimming techniques, range of voxel sizes, and TRs were not been sufficiently investigated. There is also a lack of understanding of how these changes in parameters affect T2 or T2* measurements. Reported T2 and T2* values in healthy subjects showed large variation between centres which could be explained due to the acquisition standardisationGradient echo sequence (T2*), and Ferriscan (T2 sequences) have been used for evaluating iron in patients with iron overload, however, Ferriscan is not widely available in Africa.21. The T2 sequence that is available in most scanners is the Fast Spin Echo Sequence or Turbo Spin Echo (TSE) sequence, and has been suggested to be used for iron quantification in transfusion-dependent patients22.The T2 sequence is currently a validated sequence for quantification of iron, on the other hand it is technically difficult to implement and requires additional costs and delay for data analysisHerein we thought to investigate the effect of different shim techniques, voxel sizes, and repetition times (TR) on the quantification of iron in transfusion-dependent sickle cell patients and examining optimum settings for appropriate assessment of patients.The present study was built on the experimental hypothesis in changing settings and optimizing parameters that may lead to improving the quality of the images produced, which leads to the appropriate evaluation transfusion dependent patients.The study was conducted at Dar-Alateeba Hospital, a private hospital located in Khartoum State, Sudan. The measurements involved the use of a 1.5 T whole-body Philips-MRI scanner. The scanner was equipped with high performance gradients with a maximum strength of 40 mT/m and a maximum slew rate of 200 T/m/s. A four-element torso phased array coil was used for all the scans. The research work explored the best settings that can be used in patients’ measurement via investigations conducted first on a phantom, on healthy volunteers and finally on patients as described in the following subsections.25. Researchers reported that the increase in gadolinium concentrations led to a significant decrease on the T2 and T2* relaxation27.Phantom was used in the study to simulate the relaxation properties of tissues with different concentrations of iron. It consisted of a Plexiglas holder containing eight plastic bottles, each with a volume of 17 ml. Seven bottles contain gadolinium (Gd) at concentration of 0.5, 1, 2, 3, 4, 5 and 20%. One of the bottles contained pure water for reference. The effect of the paramagnetic gadolinium on the signal intensity measurements using T1, T2 and T2* sequences has been previously investigated in number of studiesThe phantom was initially scanned with a balance fast field echo (FFE) sequence to localise the best plane for analysis. Following this a Turbo Spin Echo (or T2 sequences) and a Gradient Echo (or T2* sequence) were run on the phantom first for calibration using the following parameters: shim = default, pixel size = 2 × 2 mm, slice thickness = 10 mm, TE/ES = 4.4/4.4 and TR = 400 ms, which gives an acquisition time of 27.2 s. For T2* sequence the settings were: shim = default, pixel size = 2 × 2 mm, slice thickness = 10 mm, TE/ES = 2.5/1.1 ms, and TR = 200 ms and this gives an acquisition time of 7.8 s. The number of echoes for each of the T2 and T2* sequences were 20 and 15 respectively. The scan for each of the two calibration protocols was repeated 3 times. Their mean and standard deviation (SD) of the repeat measurements were obtained.Following this, optimization protocols were carried out for both the T2 and T2* sequences and it included the effects of the calibration parameters as well as the effects of the remaining: the shim techniques, four pixel sizes, two slice thicknesses and four TR values. For each of the imaging parameters, the scan is repeated three times on which also the mean and SD were calculated for the two sequences.The results obtained from the phantom study were tested on 10 volunteers and 25 patients. The volunteers were healthy, with no known previous diseases. Initially, serum ferritin measurements were performed for all patients and volunteers. The studied subjects were scanned for the following parameters: Shim default, auto and volume for both T2 and T2* sequence. Pixel sizes were 2 × 2, 2.5 × 2.5, 3.28 × 3.28 and 4 × 4 mm for T2 and 1 × 1, 2 × 2, 2.5 × 2.5 and 3.28 × 3.28 mm for T2*. TR values were 245, 330, 400, and 500 ms for T2, and 100,160, 200, and 230 ms for T2* sequence. Slice thickness of 8, 10, and 12 mm was also investigated on the phantom for both T2 and T2* sequences.The patients’ study was conducted at the optimum settings obtained from both the phantom and volunteers’ studies using both T2 and T2* sequences. These were then compared to the calibration/standard settings, which was implemented before the incremental changes. The settings for the optimised sequence for T2 were: shim = auto, pixel size = 2 × 2 mm, slice thickness = 10 mm, TE/ES = 4.4/4.4 ms, and TR = 245 ms, with an acquisition time = 16.9 s. The optimised settings for the T2* sequence were as follow: shim = default, pixel size = 1 × 1 mm, slice thickness = 12 mm, TE/ES = 3.7/1.7 ms and TR = 100 ms-with acquisition time = 5.8 s.For paediatric patients not able to breath-hold, the sequence was implemented during free breathing using respiratory triggering.28  using Matlab code (version 2015b). For the phantom study, the ROI was chosen around each of the eight bottles. As for the volunteers and patients, regions away from the vascular structure were chosen to avoid the contribution of artefacts from the blood. The pixel intensities of each of the selected region were averaged together and this region is propagated to other images with longer echo times (TE). The signals were then plotted versus their corresponding TE values using Levenberg–Marquardt algorithm of non-linear curve fitting. Data from T2 and T2* were fitted using a simple exponential decay formula29 and proven to provide more accurate measurements than the offset and baseline subtraction methods9.All data points at noise level were removed using the truncation method as they are currently widely usedt-test was calculated. A p value less than 0.05 was considered to be significant. Image analysis were carried out using a personally written programming code (Matlab 2015b).All Statistical analysis was performed using EXCEL spreadsheets. To evaluate the differences between the two data sets, a paired Student’s Ethical approval was obtained from the Health Research Council-National Research Ethics Committee . The committee was established to review ethical issues in health research proposals submitted for implementation, in the country, and review its results in accordance with regulations that adopt international guidelines. Written informed consent was obtained from each individual for carrying out the studies.2, which determines the associated strength between two variables. All results are presented in in Figs. The effects of tested parameters were studied in terms of three performance indices: (i) The exponential decay curves of both T2 and T2*; (ii) the magnitude measurements of T2 or T2* values using Eq. The results of the phantom and volunteers measurements, are presented in Tables The results of serum ferritin for the volunteers ranged between 5.5 and 86.8 ng/ml. For the patients, the serum measurements ranged between 179 and 2000 ng/ml. T2 decay curves of standard TR 400 ms) versus optimised (TR 245 ms) of a sickle cell patient with iron overload are shown in Fig. 00 ms verThe mean magnitudes of the standard and optimised sequences for T2 were 41.72 ± 11.82 ms and 41.10 ± 11.31 ms, and for T2* they were 5.11 ± 3.39 and 5.25 ± 3.49 ms respectively.Figure It was observed that all decay curves of the phantom studies appeared with offset at the first two data points of the curve. The T2* curves experience slight oscillation. The presence of field inhomogeneities probably caused this oscillation. In Fig. 30. The scattering of data points were noticed to be specifically higher at pixel sizes of 3.28 × 3.28 and 4 × 4 mm, especially for T2* measurements. The trend of the decay curves for the different slice thickness for T2 appeared the same. However, the signal intensity measurements for T2* were noticed to be the highest at 12 mm.Results for volunteers, as shown in Fig. 2) ranging from 0.98 to 0.99 for the three shim techniques. However, the 1% Gd concentration experienced different T2* measurements since it recorded the highest magnitude measurement with the lowest (SD). On the other hand, the increase in pixel sizes resulted in a steady increase in magnitude measurements. The 20% concentration recorded the lowest R2 and highest SD, especially at smaller pixel sizes. This is probably because low T2 measurements cannot be measured accurately due to the limitation of the short echo time and echo spacing used (5.9/5.9 ms). For T2* measurements, the 1 × 1 mm recorded the lowest magnitude measurements with low SD for the whole range of Gd concentrations. Measurements fluctuations can be observed at 4–20% Gd concentrations and the magnitude values increased by nearly twice as much when using pixel sizes 3.28 × 3.28 mm or 4 × 4 mm compared to the 1 × 1 mm pixel. R2 values ranged between 0.514 and 0.997 for all Gd concentrations using these pixel sizes, with the optimum obtained at 1 × 1 mm.Tables 2 ranging 0.975–0.997at p < 0.01. Moreover, TR values had small effects on T2 measurements while 1–2% Gd concentration demonstrated a slight increase in measurements with TR. It was also observed that TR has a minor effect on T2* measurements with the lowest fluctuations of measurements found for concentrations of 3–20% with R2 range between 0.98 and 0.996.The slice thickness study on the 1% and 2% Gd using T2* sequence demonstrated higher magnitude measurements at 8 mm, while the 12 mm thickness showed low SD for all the concentrations with R33. We also observed that the average magnitude measurement using the default shim was less than the measurements recorded with auto and volume shim techniques by approximately 0.1 and 0.2%, respectively. The default shim recorded high SD values, while the low fluctuation of measurements was recorded using the auto-shim technique. The overall T2* measurements recorded from the volunteers fell between 30 and 45 ms (average 36 ± 5 ms) comparable with literature34. The T2 magnitude measurements were presented with a slight increase for pixel sizes larger than 2.5 × 2.5 mm.Tables The T2* magnitude measurements at different pixel sizes showed similarity to the magnitude measurement obtained for the 1% Gd concentration. The lowest measurement was recorded at 1 × 1 mm. Larger pixel sizes provided T2* measurements of up-to 20% than that of the 1 × 1 mm. It is also observed that the SD values became higher with pixel size (reaching up to 50% for pixel size of 4 × 4 mm).35. Larger pixel sizes have caused the measurements to become less reliable. Similar to the T2 measurements the utilization of higher receiver bandwidth in this study incorporated more noise on the acquired images, and subsequently caused scattering in signal intensity measurements. This led to wide fluctuations of measurements especially in the case of high pixel sizes of 3.28 × 3.28 mm and 4 × 4 mm (R2 ~ 0.614). The T2 sequence results showed no significant differences between the magnitude measurements for the slice thicknesses of 8, 10, and 12 mm. As for T2*, the 12 mm thickness was associated with the highest magnitude measurements and lowest fluctuations of the measurements.In comparison with the literature, our study found that the increase of pixel size resulted in an increase in the sensitivity of the magnitude measurements2 range 0.95–0.99).Mean magnitude measurements of T2 for the range of studied TR witnessed no significant difference in their values. T2* measurements at TR values of 100-160 ms, recorded low mean magnitude of measurements (by ~ 30%) compare to those at 200-230 ms. Long T2* components, like those found in healthy volunteers, require long TR values for accurate measurements. It is observed that long TRs of 200–230 ms provides consistent results . The correlation coefficient for the standard sequence ranged between 0.942–0.99, while for the optimised (0.945–1.0) at p-value < 0.01.Our studies on the effects of these parameters were for the first time investigated on the livers of transfusion-dependent paediatric patients using both T2 and T2* sequence. Our investigations showed a room for further improvement in the T2* sequence by adopting the optimised sequence instead of the conventional sequence. Another advantage of this optimisation is that the acquisition time for the T2 sequence was reduced by almost 38% and for T2* by 25%. We also noticed that the measurements' reliability has dramatically improved.This study has some limitations to generalize its outcomes for a number of reasons: (i) the number of samples is relatively small (10 volunteers + 25 patients). (ii) To get the optimum pixel size and keep the Hz/pixel fixed, this requires a change in both the field of view (FOV) and the matrix size. This type of modification affects the routine of work in the hospital so we had to keep the FOV and the size of the matrix constant throughout the study period.The aim of this study was to investigate the effect of different shim techniques, voxel sizes, and repetition time (TR) on T2 and T2* sequences and to determine optimum settings for the evaluation of the amount of iron in the livers of transfusion dependent sickle cell patients. Phantom with different concentrations of Gd (1–20%), and ten volunteers were used to define these settings, which were then investigated on 25 patients. The optimized protocols resulted in a reduction of acquisition time by 38% and 25% for T2 and T2*, respectively. In addition, the quality of images were not compromised as compared to the conventional sequences. The outcomes of this study could be particularly beneficial for young adults who cannot tolerate MRI scans for long periods of time. The research results indicated that T2 and T2* sequences can be further refined to provide more reliable measurements and on transfusion dependent-sickle cell patients.


Pre-determined controlling factors were sex, age, body mass index (BMI), COPD-assessment test, forced expiratory volume in one second in percent of the predicted value (FEV1pred), and distance walked on the 6-minute walk test. Eighty-one patients with COPD  were included. Small to moderate bivariate correlations  were found between quadriceps function and measures of PA. The best multiple linear regression models explained 38–49% of the variance in the data. Isotonic endurance was the only muscle contributor that improved all PA models; daily steps (ΔR2 = .04 [relative improvement 13%] p = .026), daily sedentary time  and MVPA-minutes . Isotonic endurance was also independently associated with most PA variables, even when controlling for strength, power or isometric-isokinetic endurance properties of the muscle . In contrast, neither strength, power, isometric-or isokinetic endurance properties of the muscle was independently associated with PA measures when controlling for isotonic endurance . To conclude, strength, power, and endurance properties of the quadriceps were low to moderately associated with PA in patients with COPD. Isotonic quadriceps endurance was the only quadriceps property that was independently associated with the different measures of PA after controlling for a basic set of known determinants of PA, quadriceps strength or power, or isometric or isokinetic quadriceps endurance. Future longitudinal studies should investigate its potential as a modifiable determinant of PA.Knowledge about modifiable determinants of daily physical activity (PA) in patients with chronic obstructive pulmonary disease (COPD) is crucial to design effective PA interventions. The present study aimed to determine the contribution of quadriceps strength, power and endurance to daily PA in COPD. Additionally, for quadriceps endurance, we also aimed to determine to what extent the association varies according to the mode of movement . Using a multicentre cross-sectional trial design we determined the contribution of quadriceps function to daily PA  using bivariate and partial Pearson correlation analysis (r) and multiple linear regression models (ΔR Importantly, PA levels can potentially be improved1, and over recent years, several modifiable determinants of PA in COPD have been identified3. Even so, there is still limited and inconsistent evidence on the effectiveness of interventions to enhance PA in COPD1. Considering that knowledge about determinants of PA in patients with COPD is crucial to design effective PA interventions6, these findings highlighting that other modifiable determinants of PA likely exists, even though they have yet to be identified3.Physical activity (PA) is recognized as an essential feature in patients with chronic obstructive pulmonary disease (COPD)8. Even though improving quadriceps function often is an integrated aim of exercise interventions11, information on the potential role of quadriceps function as a determinant of PA in COPD is sparse.Quadriceps dysfunction, defined by reduced strength, power or endurance properties of the quadriceps is a common extrapulmonary manifestation of the disease, evident in over a third of the COPD-population14, there is today limited knowledge on the impact of other potentially modifiable properties of the quadriceps on PA in COPD. Recently, quadriceps power has emerged as a more important predictor of PA than quadriceps strength, being positively associated with active time per day as well as light intensity PA in COPD13. However, to our knowledge, the role of quadriceps power to PA has only been investigated in this single study in which the sample size was small, and the study included only older men, highlighting a need for further investigation13.Other than quadriceps strength, shown not to be linked to PA in several different studies15 indicates a similarity in PA task requirements based on the repetitive nature of quadriceps use in everyday daily activities such as walking. For example, quadriceps endurance has previously been found to be independently associated with walking distance on the 6-minute walk test (6MWT) even after controlling for quadriceps strength16. Considering the existing link between 6MWT and PA in COPD17, these findings indicate that quadriceps endurance could also be more closely associated with PA than other aspects of quadriceps function.Another potentially modifiable determinant of PA is quadriceps endurance. The endurance capacity of the quadriceps may be of particular interest to PA, considering that the muscle's ability to repeat a specific task over time18. Thus, a secondary objective was to determine to what extent the association varies according to the mode of movement . Amongst the quadriceps muscle properties examined, the main hypothesis was that quadriceps muscle endurance would show the strongest association and contribution to the physical activity measures.The primary aim of the present study was, therefore, to determine and to compare the contribution of quadriceps strength, power and endurance to PA in patients with COPD. Furthermore, in recent studies, static (isometric) and dynamic  endurance protocols have been found to reflect different aspects of quadriceps function in COPD19 controlled through medical records. Exclusion criteria’s consisted of recent COPD exacerbation (within 3 months), muscular-, rheumatic-, or cardiac disorders affecting testing procedures, and a daily dose of prednisone >10mg within 3 months, also controlled through medical records, and self-reported regular quadriceps strengthening exercises.The present study was a multicentre cross-sectional study conducted in Sweden, Canada, and the Netherlands. Participants in this prospective study were continuously enrolled with convince sampling at each centre. Participants were included in every month of the year, thereby covering all seasons. Inclusion criteria were at least 40 years of age, and a confirmed diagnosis of mild to very severe COPD according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria20, spirometry21, and an isometric quadriceps strength test performed. The second visit included the assessment of isokinetic quadriceps power as well as isometric, isokinetic and isotonic quadriceps endurance22 , and symptoms on the COPD assessment test (CAT) collected. After that were a 6MWT22. Quadriceps strength was measured during a maximal voluntary contraction (MVC) using an isometric (static) protocol at a 90° knee angle22, performed in line with international recommendations and reported in Newton-meters (Nm)7. Quadriceps power, equivalent to energy output per unit of time, was obtained from the average power developed during 30 maximal isokinetic contractions; results were expressed in watt24.Quadriceps strength, power and endurance were measured with a computerized dynamometer  using test procedures that have been described in detail elsewhere22, all performed with similar (1) starting position , (2) direction of movement (restricted by the lever arm), and (3) duration of the test (~ 60 s). The three protocols differed regarding the mode of contraction/movement . The two dynamic protocols had identical range-of-motion , while the static protocol was performed at a 90° knee angle22. Standardized verbal encouragements were given in all tests.Quadriceps endurance was assessed with three reliable protocols22. The isokinetic endurance protocol consisted of 30 maximal dynamic contractions at a fixed pace of 90°/s 22. The isotonic endurance test protocol consisted of the maximal amount of dynamic leg extensions throughout the full range of motion, performed using a resistance of 30% of isometric MVC maintaining an externally set pace by a metronome at 60 beats per minute  22.The isometric protocol consisted of a static contraction at 60% of MVC at 90° knee angle using visual feedback 25 and is a small, light ambulant measurement device  worn with an elastic belt on the lower back. Since the sensors measure gravity (g) in static situations, the acceleration signal is expressed relative to g. The participants were instructed to wear the accelerometer for seven consecutive days, including a weekend day. The minimum wearing criteria was ≥ 4 days, with ≥ 8 h wearing time each day27. Daily steps, daily sedentary time in minutes, and daily time spent in moderate to very vigorous activity (MVPA) were selected as these are the three most commonly used measures of PA in COPD intervention studies1 and were considered to display different aspects of PA. PA measures were summarized for valid days by the manufacturer software. Thresholds for describing time spent at different intensity levels were; sedentary time < 1.5 metabolic equivalents (METs), and time spent in moderate to very vigorous activity ≥ 3 METs, as proposed by the American College of Sports Medicine28. To define each individual’s average value during the physical activity measurement was the median from valid days used in the main analysis. To compare levels of PA between week- and weekend days, the individual’s median value during the valid week and weekend days was used.A tri-axial accelerometer  was used to measure PA. The accelerometer is considered valid for patients with COPDp value of < .05 was considered to indicate statistical significance. Contribution of quadriceps function to PA  was determined through Pearson’s bivariate and partial correlations, and multiple linear regression analyses. Levels of PA between week- and weekend was compared using paired t-tests and Pearson’s bivariate correlations. For bivariate analysis were correlation coefficients (r) values in the range of < .1 considered trivial, .1–.3 small, .3–.5 moderate, .5–.7 large, .7–.9 very large, and > .9 extremely large29. Partial correlations analyses were used to examine the correlation between PA and one quadriceps property while controlling for another quadriceps property . In the multiple linear regression analysis, daily steps, daily sedentary time, and daily MVPA-minutes represented dependant variables. Based on previous literature13 and basic clinical characteristics7 were sex, age in years, BMI, CAT score, FEV1pred and 6MWT in meters selected as pre-determined independent variables and constituted the basic model31. A minimum of 75 participants was aimed to be included based on the general rule that 10 to 15 subjects per predictor are needed for a reliable equation32. To determine the contribution of various quadriceps properties to PA in COPD, isometric strength, isokinetic power, as well as isotonic, isometric and isokinetic quadriceps endurance measurements were entered independently to the basic model. The models were then again applied to the three dependent PA variables. Outcomes to evaluate the contribution to PA included the standardized estimated effect of included variables, the predicting ability of the model using R2, and absolute change (ΔR2) between the first and second models. Multicollinearity was evaluated with the tolerance and variance inflation factor (VIF) statistics with tolerance value > .1 and VIF < 10. The quality of the linear regression models was assessed using the Akaike information criterion (AIC) 33.A statistical software package was used for all calculations , a The study was conducted in accordance with the declaration of Helsinki and was approved by the respective local ethical boards  region Arnhem-Nijmegen: CMO: NL59926.091.16), all participants received written and verbal information about the study and gave their written informed consent before the study commenced.2, and ΔR2 of each multiple linear regression model, while Table Eighty-one participants with COPD were included in the analysis, 4 participants were excluded from the analysis, either missing a valid isometric quadriceps muscle endurance measurement n = 3) or isotonic quadriceps muscle endurance measurement n = 1). The PA measurement covered both weekdays and weekends for all participants. Eighty participants had at least one valid weekend day. Table . The PA  or isotop = .07) when controlling for quadriceps power. In contrast, neither strength nor quadriceps power was independently associated with PA measures when controlling for isotonic endurance. Similarly, other than daily steps when controlling for isokinetic endurance , isotonic quadriceps endurance was also independently associated with PA measures when controlling for isometric and isokinetic endurance. At the same time, no significant associations were seen between PA measures and isometric and isokinetic endurance when controlling for isotonic endurance  were found between different quadriceps function properties and all PA measures. Partial correlation analyses on strength, power and endurance properties of the quadriceps revealed that isotonic quadriceps endurance was independently associated with all PA measures after controlling for quadriceps strength as well as independently associated with sedentary time and MVPA-minutes but not daily steps . Isotonic quadriceps endurance was included in the best model to additionally explain variability of daily steps (ΔR2 = .04 [relative improvement of the model = 13%] p = .026), daily sedentary time  and MVPA-minutes , resulting in 38–49% of the variance in PA being explained . The MVPA model also improved by isokinetic endurance  , sedentary time was not different . The correlations between weekday and weekend PA were very large .Group means of the individual’s average value using medians for valid week- and weekend days separately show higher daily steps and daily MVPA-minutes during weekdays than during weekends  quadriceps strength was not a significant contributor to any of the models. These findings are in line with previous research34. However, considering the known link between BMI and quadriceps strength in COPD35, it should be noted that the lack of added predictive value of quadriceps strength to the basic set of variables, may, at least partly, be explained by that BMI was one of the basic variables. Furthermore, quadriceps power was recently found to be positively associated with light intensity PA, and active time per day (r = .37 to .51), but not daily steps in older men with COPD 13. In the present study, active time per day and light intensity PA was not explicitly investigated but isokinetic quadriceps power was associated with all included aspects of PA, even daily steps . About the latter, considering the similarity in the coefficient of correlation in the present study (r = .313) and in the study of Hernandez et al. (r = .300), the lack of statistical significance in the latter study was likely due to the lower sample size (n = 44 vs. n = 81)13. Nevertheless, even though quadriceps power has been highlighted as a more important predictor of PA than maximum strength13, the results from the present study indicate that it does not seem to add additional value when added to already known determinants of PA in COPD, or when compared to the endurance capacity of the quadriceps. It should be noted that the recognised link between isokinetic power and distance walked on the 6MWT18 likely contributed to why the basic models were not further improved by isokinetic power. However, in contrast, the endurance capacity of the quadriceps improved PA models when added to the basic models despite the known link to distance walked on the 6MWT36. Our observed findings are further supported by the results from the partial correlation analysis in which neither quadriceps strength nor power was independently associated with PA when controlling for isotonic quadriceps endurance. In contrast, isotonic quadriceps endurance was, except for steps per day when controlling for quadriceps power, independently associated with daily steps, sedentary time and MVPA-minutes even after controlling for strength and power properties of the quadriceps. Similarly, isotonic quadriceps endurance was independently associated with most PA measures even after controlling for isometric or isokinetic quadriceps endurance measurements.Quadriceps strength was associated with all PA measures, however, when added to a basic set of known determinants of PA . Isotonic quadriceps endurance was also independently associated with PA in COPD even after controlling for strength/power or other modes (isometric/isokinetic). In contrast, neither strength/power nor other modes of quadriceps endurance was associated with any of the included PA measures when controlling for isotonic endurance. A possible explanation for these findings is that isotonic endurance measurements, in a similar way as many daily physical activities, e.g., going for a brief daily walk, consists of dynamic submaximal movements/contractions. In contrast, isometric measurements are static  while isokinetic power and endurance measurements consist of maximal, and not submaximal contractions24.As previously reported, FEV37, if all other factors remain constant. For the 6MWT, the corresponding change for a similar improvement in isotonic quadriceps endurance based on our data would be 63 m. Even though these estimations should be interpreted cautiously due to the cross-sectional nature of the data which prevent concluding on cause and effect, other research groups have found that trials with significant improvement in PA have also demonstrated considerable improvements in distance walked on the 6MWT (47 to 79 m)40. One of the studies also reports improvements of isometric quadriceps endurance of ~ 35% and isometric quadriceps strength of ~ 14% after an intervention with high-intensity interval training on stationary bicycles with significant improvements in several PA measures40. To our knowledge, isotonic quadriceps endurance has not been evaluated in trials that have demonstrated significant improvements in PA. Still, isotonic quadriceps endurance is repeatedly shown to be highly adaptable (+ 50 to 97%) by exercise interventions42.The relevance of the association of isotonic quadriceps endurance when estimating PA can be extrapolated to a clinical example. Based on the predictive models, an improvement of roughly 37% in isotonic quadriceps endurance would be needed to achieve a clinically relevant 600-daily step improvement in PATaken together with the observation that isotonic endurance also was independently associated with most PA measures even when controlling for strength, power, or isometric- and isokinetic endurance properties of the quadriceps, our results indicate that isotonic quadriceps endurance seems to be more closely associated with PA than other aspects of quadriceps function. Nevertheless, and as further described in the strengths and limitations of the study, only about half or less of the variation in PA is explained in our models, despite including a wide range of known determinants of PA among patients with COPD, and bivariate and partial correlations mainly demonstrated low to moderate associations for quadriceps muscle properties and PA in COPD.45. Thus, we cannot be certain that the results would have been similar if other strategies were also used. Nevertheless, isometric MVC was chosen as a measure of quadriceps strength since it, to date, is the recommended approach to assess quadriceps strength in COPD7. For quadriceps power, no such specific assessment recommendation exist44. However, other strategies such as the stair climb power test46, sit to stand47 or isotonic measures of power24 exist and may have provided other information, even though this needs to be further investigated. Furthermore, even though several different PA measures exist3, daily steps, sedentary time and MVPA-minutes were selected as these are the three most commonly used outcomes of PA in intervention studies targeting PA in COPD1. Steps and MVPA-minutes were lower during the weekend than during weekdays (− 476 steps/day and − 5.8 MVPA-minutes), but with very large correlations, as shown previously in COPD48. Inclusion of both week and weekend days resulted in more valid days in the main analysis, and the associations, therefore, reflect an average of valid days and not any specific part of the week. Lastly, an important notion is that only about half or less of the variation in PA is explained in our models, despite including known determinants of PA among patients with COPD3. The explanatory degree in the present study may have been further improved by the inclusion of more known factors than those selected50.The international multicentre design with continuous data collection, the broad spectrum of disease severity and the direct comparison of several different aspects of quadriceps function are key strengths of the current study, increasing generalizability and facilitating the interpretation of the role of quadriceps function to PA in COPD. However, in line with the findings from the present study, it should be noted that strength, power and endurance properties of the quadriceps could be measured in various ways50. However, movement intensity was not used as a dependent variable in this study, and movement intensity and movement amount (steps and time in activity) might reflect different aspects of PA48.Firstly, have limitations in chest wall volume measurements, and central hemodynamic and peripheral muscle oxygenation been investigated and show that quadriceps muscle oxygen saturation and inspiratory reserve chest wall volume as the significant best contributors, explaining 77.7% of the variance in daily movement intensity51. And thirdly, testing also other muscle groups, such as the calf-muscles, could also provide additional value considering the know link between the calf-muscles and walking ability in COPD52. Nevertheless, we do believe that this basic set of factors was sufficient for the present study's aim, that is, to determine and compare the association between different aspects of quadriceps function and PA in COPD.Secondly, in combination with the notion that included participants, even though representative in all GOLD stages, had a relatively well-preserved functional exercise capacity . Factors other than pure physiological factors, such as motivation, social participation, meaningful interpersonal interactions, readiness to change and self-efficacy may have provided additional value and should be considered in future studiesIn conclusion, this study found that strength, power and endurance properties of the quadriceps were low to moderately associated with PA in patients with COPD, but that isotonic quadriceps endurance was the best, and the only quadriceps property that was associated with all the different measures of PA  even after controlling for a basic set of known determinants of PA or when controlling for strength or power properties of the muscle. Thus, altogether these findings highlight that the endurance capacity of the quadriceps seems to be a new potentially modifiable determinant of PA in COPD that may be considered if the goal is to optimize the role of exercise training as a mean to improve PA in COPD, even though this needs to be confirmed in future longitudinal studies. Furthermore, when examining quadriceps endurance, the mode of movement seems to be important as isotonic quadriceps endurance was independently associated with most PA measures even when controlling for isometric and isokinetic endurance properties of the quadriceps.


PWV was correlated to passive atrial emptying volume even if only the > 35-year-old were considered . Total peripheral resistance demonstrated similar correlations as PWV, but in a regression analysis only the total aorta PWV was related to left atrial (LA) passive emptying volume. Via impaired ventriculo-arterial coupling, the increased aortic PWV seen with normal ageing hence affects atrio-ventricular coupling, before increased aortic PWV is associated with significantly increased arterial blood pressure or LV hypertrophic remodelling. Our findings reinforce the existence of atrio-ventriculo-arterial coupling and suggest aortic distensibility should be considered an early therapeutic target to avoid diastolic dysfunction of the LV.As part of normal ageing, conductance arteries lose their cushion function, left ventricle (LV) filling and also left atrial emptying are impaired. The relation between conductance artery stiffness and LV diastolic function is normally explained by arterial hypertension and LV hypertrophy as needed intermediaries. We examined whether age-related aortic stiffening may influence LV diastolic function in normal healthy subjects. Aortic distensibility and pulse wave velocity (PWV) were related to LV emptying and filling parameters and left atrial emptying parameters as determined by magnetic resonance imaging in 36 healthy young (< 35 years) and 16 healthy middle-aged and elderly (> 35 years) with normal arterial blood pressure and myocardial mass. In the overall cohort, total aorta PWV correlated to a decrease in LV peak-emptying volume (r = 0.43), LV peak-filling (r = 0.47), passive atrial emptying volume (r = 0.66), and an increase in active atrial emptying volume (r = 0.47) (all  In their milder forms, increased PWV as well as increased LA emptying problems are both part of normal ageing. Thus, with age conductance arteries loose distensibility5 and also the left ventricle (LV) develops early signs of diastolic dysfunction6. The impact on the heart of an increased PWV is explained by the pulse wave of stiff conductance arteries being reflected back from the periphery towards the heart, hence adding to LV myocardial stress during end-systole8. Indices of impaired ventriculo-arterial coupling is present in patients with LV hypertrophy and diastolic dysfunction in patients with heart failure with preserved ejection fraction (HFpEF)10. In this setting, LV diastolic dysfunction with impaired LA emptying and enlargement is seen and is explained by myocardial hypertrophic remodelling or ischemic heart disease as intermediaries via an eventual increase in blood pressure preceded by the stiffening of conductance arteries10. A correlation of high aortic PWV and signs of LV diastolic dysfunction in patients with hypertrophy have indeed been noted earlier14.Increased aortic pulse wave velocity 14, aortic PWV and distensibility was determined in healthy young and middle-aged and elderly subjects with normal LV myocardial mass, without arterial hypertension or other known risk factors for atherosclerosis, in order to correlate PWV with early signs of LV diastolic dysfunction and impaired atrio-ventricular coupling. We aimed at an equal number of men and female gender as lower values for PWV are seen in women16 and controlled for variables associated with flow including hemoglobin18. We hypothesized that stiffening of the aorta with age is related to CMR indices of impaired LV filling and impaired LA function without the need for an increase in arterial pressure or LV hypertrophy to act as needed intermediaries 19. If this were so this would add to thinking about a stiff aorta as an early therapeutic target to avoid later in life heart failure with preserved ejection fraction.If aortic distensibility can be demonstrated to impact on LV diastolic mechanics without LV myocardial hypertrophy or signs of atherosclerosis as needed intermediaries to produce LV diastolic dysfunction, this will support the hypothesis that aortic distensibility is considered an important early therapeutic target for HFpEF1c and hemoglobin concentration were measured in venous plasma, and left brachial artery systolic (SAP) and diastolic (DAP) blood pressures was measured in the resting supine state by a sphygmomanometer . Pulse pressure (PP) was calculated as the difference between SAP and DAP, and the mean arterial pressure (MAP) was determined as DAP + 1/3 of the PP.36 healthy young  and 16 healthy middle-aged subjects  were included. Exclusion criteria included pregnancy, a history of cardiovascular disease, hypertension , diabetes mellitus, coronary or peripheral artery disease, reduced kidney function, a history of systemic or connective tissue disease. Patients with known general inflammatory disease and immune-mediated disease were also excluded and disease states were screened for as all patients had normal C reactive protein. The study adhered to the principles of the Helsinki declaration. The study has been approved by the Regional Committees on Health Research Ethics in the Capital Region of Denmark (protocol: H-3-2012-074). All subjects gave written informed consent. Lipids , HbACMR images were acquired on a 1.5-Tesla MRI scanner  equipped with a 16-channel coil (retrospective ECG gating). Following scout imaging, steady-state free precession (SSFP) cine images were acquired corresponding to 2-, 3-, and 4-chamber followed by a short axis stack including atria as well as ventricles  with parallel imaging technique . Images were required during 8–10 s expiratory breath-holds with 25 phases of the cardiac cycle . For aortic distensibility, two additional SSFP sequences were acquired in the transverse plane at the level of the pulmonary artery perpendicularly cross-cutting the ascending and descending aorta, and at the level of the abdominal aorta immediately below the diaphragm and above the renal arteries. If the abdominal aorta was not parallel to the long axis of the subject, the scanning plane was tilted so the abdominal aorta could be imaged perpendicularly. Through-plane flow sequences  were acquired in the ascending, descending, and abdominal aorta with the same scan planes as used for distensibility measurements. For determination of distance between scanned areas of the aorta, a sagittal SSFP-sequence image of the aorta was acquired covering its full course in the thorax and abdomen (‘candy cane’).p) and peak-filling (FRp) rates for the LV were automatically calculated by the software as the maximal down- and early up-ward slopes of the LV time-volume curve and indexed to LVEDV. ERp and FRp were further indexed to BSA as ERp(i) and FRp(i). The fraction of the cardiac cycle duration for end-systole was determined to ascertain if end-systole occurred at the same time point in all, and LV stroke work  was determined as the LVSV indexed to body surface area multiplied by mean LV systolic pressure from the formula LVSW = LV mean systolic pressure * LVSV(i) * 0.0136. The LV mean systolic pressure was determined as 0.9 * SAP20.CMR analysis was performed using dedicated software . LV volumes were measured throughout the cardiac cycle from the short axis cine images using semi-automated edge detection, with the volume of each ventricular slice determined by drawing the endocardial contour (including papillary muscles in the myocardium) in all 25 phases. The volume of each slice was calculated as luminal area times slice thickness, and the sum of all slice volumes was used to obtain LV volumes. The LV stroke volume (SV) was the difference between the LV end-diastolic volume (EDV) and the LV end-systolic volume (ESV). LV ejection fraction (EF) was the LVSV divided by LVEDV. Cardiac output (CO) was calculated as the product of LVSV and heart rate (HR). LV peak-ejection , distensibility is calculated as (Amax-Amin) * 100%/(Amin * PP) (in %/mmHg)21. Aortic PWV was calculated from the flow images by measuring the time delay, Δt, for the arterial waveform to pass a given length, Δx, between two aortic points, i.e. PWV = Δx/Δt22. The arrival of the aortic pulse wave was determined as the intersection of the tangent of the upslope of the flow curve to the time axis, as tangents were determined by the least-squares method of the three points surrounding the half-maximal flow. ∆t was determined as the difference between time-axis intersections of the ascending, descending, and abdominal aorta flow curves, respectively. PWV was calculated for the aortic arch, and for the total aorta. There is good agreement between PWV measured invasively and by CMR23.Arterial distensibility is the relative change in luminal cross-sectional area for a given change in PP and was calculated in the ascending, descending, and abdominal aortic lumen, respectively. With Amax) and minimal volume (LAmin) were determined from the short axis cine images. The LA mid-diastolic volume (LAmdv) and the LA volume immediately before atrial contraction (LAlav) were determined, and from these the LA passive emptying volume (LApev) was determined as LAmax-LAmdv. The LApev is a measure of the volume of blood flowing into the LV immediately after opening of the mitral valve as a consequence of LV early diastolic filling. The LA active emptying volume (LAaev) was LAlav-LAmin, as a measure of the volume of blood flowing into the LV during late ventricular diastole as a consequence of the active systole of the LA . LA conduit volume (LAcv), a measure of the blood that flows through the LA passively during LV diastasis, was calculated as LVSV-(LApev + LAaev). LA reservoir volume (LArv) was calculated as LApev + LAaev. LA passive emptying fraction (LApef) was calculated as LApev/LAmax. LA active emptying fraction (LAaef) was calculated as LAaev/LAlav. LA reservoir emptying fraction (LAref) was calculated as (LAmax-LAmin)/LAmax.LA maximal  was calculated as MAP divided by CO. Data were tested visually for normal distribution. Normal distributed data were analyzed using ANOVA, and if significant the Tukey post-hoc test was used to identify which group means differed. Correlations were evaluated with Pearson’s r. Independent influence of variables on FRp(i) and LAPEV was evaluated with least square multiple variable regression analysis. Age, sex, and MAP were considered as independent variables, however, age and sex highly influenced both TPR and PWVTotal and MAP was highly correlated with TPR and were therefore excluded as independent variables. Statistical significances were indicated by a p ≤ 0.05. Statistical analysis was performed using the SPSS software package .Normally distributed data are expressed as mean ± SD, and non-normally distributed data are expressed as median with range. LV and LA volumes were indexed to body surface area (Mosteller)Male subjects had a higher BSA than females, and BSA increased with age, but besides BSA no significant differences were noted between genders and age groups for HR, SAP, DAP, PP or any of the blood chemistry parameters Table . All basp and FRp decreased with age in both genders , FRp (i), and LAPEV, and myocardial mass correlated with ERp(i) and LAmax  even if only the > 35 years were included.TPR correlated with ERax Table . Distensax Table , Fig. 1.Total, both independently affected PFR/BSA , can affect LV function as has recently been suggested for blood pressure27, and has been shown for athletes using anabolic steroids28. Increased afterload, impacted by stiff conductance arteries, early impacts entire atrio-ventricular-arterial coupling cascade, and does not need to wait years for an increase in PP or LV hypertrophy to become manifest. In cohort studies of patients with HFpEF, high PWV is already noted to be prevalent, but these patients also have increased PP and LV hypertrophy to account for LV diastolic dysfunction and signs of heart failure14, and therefore from these studies it is less obvious that PWV is of independent direct importance for the atrio-ventriculo-arterial coupling cascade. In different disease models, a negative correlation between PWV and left atrial strain has been shown30. With all important variables measured on precise quantitative scales, our study now establish that now only is PWV in subjects were FRp, LApev and LAaev are affected, but PWV is in fact correlated with not only peak LV ejection rate but also LV relaxation with consequent LA emptying changes well before LV hypertrophy or PP increments. Hence age-related changes on impaired LV relaxation with lowered FRp and impaired LAPEV reported in normal materials of young and elderly subjects is partly explained by stiffening of the conductance arteries. With a stiff aorta demonstrably impacting on the entire atrio-ventriculo-arterial coupling sequence even in normal young and elderly. We cannot say by what mechanism increased aortic stiffness impinges on the LV filling rate. We speculate that part of the mechanism is by LV myocardial ATP-depletion (and if so it would be immediately correctable), part by induction of LV myocardial diffuse fibroses (and if so it would be more important to avoid in good time)31.Conductance arteries ideally transform the pulsatile LV outflow into a smooth continuous flow in the peripheral capillaries, as during systole aorta distends and thereby stores energy generated (“Windkessel”). The pulse wave, however, travels forward quickly, and theory suggests the pulse wave is reflected back from the periphery towards the heart against the forward moving blood. With distensible conductance arteries, PWV is low, and pulse wave reflection therefore will be small and will arrive after the aortic valve has closed hence not affecting LV. With stiffer conductance arteries, PWV increases, and the reflected wave returns before the aortic valve has closed and thus help increase late-systolic arterial blood pressure and afterload for the LV. Thus, whereas the TPR reflects hydraulic opposition to LV outflow during early LV systole, the reflected pulse wave becomes an added burden to the LV during late systole. In normal subjects, aortic distensibility decreases already in the 3th–4th decade, followed by an increase in aortic PWV and the DAP and PP beyond the 6th decade33. It is a limitation that our study is cross-sectional. In theory, it may therefore be that aortic stiffness, ERp(i) and FRp(i) and LAPEV co-vary not because of causality, but because they were affected by the same overarching variable. Atherosclerosis would be a candidate for such an overarching variable. However, no subject had signs of or risk factors for ischemic heart disease, and such would have to be significant to lower FRp that in our study was comparable to FRp recorded in other normal materials. Further studies are warranted to investigate the relation between diastolic function and diffuse myocardial fibrosis by T1 mapping in healthy as this was not performed in the present study. To the best of our knowledge healthy subjects – in opposition to for example patients with HFPEF, hypertension or diabetes – are not known to have significant myocardial fibrosis35.It is a strength of our study that we only invited healthy subjects without hypertension or LV myocardial hypertrophy. Also, it is a strength that we applied CMR, the reference standard for non-invasive flow and cardiac volumes, to determine parameters of importance on the same study day. CMR also provides excellent reproducibility of peak filling and peak emptying rateIncreased aortic stiffening and pulse wave velocity impairs atrio-ventriculo-arterial coupling before manifest arterial hypertension or left ventricular hypertrophic remodelling is seen. Our findings provide physiological rational for designing randomized studies to target aortic distensibility as an early therapeutic target to avoid later in life HFpEF.


Cirrhotic cardiomyopathy (CCM) is a relatively new medical term. The constant development of novel diagnostic and clinical tools continuously delivers new data and findings about this broad disorder. The purpose of this review is to summarize current facts about CCM, identify gaps of knowledge, and indicate the direction in which to prepare an updated definition of CCM. We performed a review of the literature using scientific data sources with an emphasis on the latest findings. CCM is a clinical manifestation of disorders in the circulatory system in the course of portal hypertension. It is characterized by impaired left ventricular systolic and diastolic dysfunction, and electrophysiological abnormalities, especially QT interval prolongation. However, signs and symptoms reported by patients are non-specific and include reduced exercise tolerance, fatigue, peripheral oedema, and ascites. The disease usually remains asymptomatic with almost normal heart function, unless patients are exposed to stress or exertion. Unfortunately, due to the subclinical course, CCM is rarely recognized. Orthotopic liver transplantation (OLTx) seems to improve circulatory function although there is no consensus about its positive effect, with reported cases of heart failure onset after transplantation. Researchers indicate a careful pre-, peri-, and post-transplant cardiac assessment as a crucial point in detecting CCM and improving patients’ prognosis. There is also an urgent need to update the CCM definition and establish a diagnostic algorithm for early diagnosis of CCM as well as a specific treatment of this condition. Cirrhotic cardiomyopathy (CCM) is a relatively new medical term. It was first described in 2005 during the World Congress of Gastroenterology in Montreal as characteristic changes in the circulatory system in patients with alcoholic liver cirrhosis. Initially, it was suspected that the toxic effect of alcohol was responsible for the pathogenesis of these changes. Subsequent studies have shown that the same haemodynamic abnormalities also occur in cirrhosis with a different aetiology ,2.Cirrhotic cardiomyopathy is a clinical manifestation of disorders in the circulatory system in the course of portal hypertension. It is characterized by impaired left ventricular systolic and diastolic dysfunction and electrophysiological abnormalities, especially QT interval prolongation. Unfortunately, due to the subclinical course, these irregularities are rarely recognized. The disease usually remains asymptomatic with almost normal heart function, unless patients are exposed to stress. Decompensation of the circulatory system may occur during liver transplantation, which is responsible for increased perioperative mortality due to cardiovascular causes ,4.In this review, we summarize the most important facts concerning cirrhotic cardiomyopathy and indicate the direction for further research.We performed a review of the literature. The search was carried out using PubMed and ScienceDirect as data sources. We searched classical articles and clinical trials. The following keywords were used: “cirrhotic cardiomyopathy”. The inclusion criteria included articles that reported upon cirrhotic cardiomyopathy written in the years 1953–2021. Non-English articles were excluded.The incidence of cirrhotic cardiomyopathy is not clearly defined. There was no correlation between the aetiology of liver failure and the incidence of cirrhotic cardiomyopathy. However, it has been proven that the prevalence of CCM depends on the severity of liver cirrhosis. Based on the Child–Pugh classification of hepatic insufficiency, the majority of CCM diagnoses are found in patients in Class C ,6.At the 2005 World Congress of Gastroenterology in Montreal, diagnostic and supportive criteria were proposed for cirrhotic cardiomyopathy. According to this definition, CCM symptoms include: systolic dysfunction , diastolic dysfunction , supportive criteria: electrophysiological abnormalities, abnormal chronotropic response, electromechanical dyssynchrony, prolonged QTc interval, enlarged left atrium, increased myocardial mass, increased brain natriuretic peptide and pro-BNP, increased Tn I.Since 2005, the progress in cardiac diagnostics greatly changed the concept of ventricular dysfunction and made the criteria out of date. In 2019, a multidisciplinary group consisting of cardiologists, hepatologist, and anaesthesiologists formed the Cirrhotic Cardiomyopathy Consortium and presented novel proposed criteria of CCM ,8. TheseDue to the fact that the disease is usually asymptomatic, data on the prevalence of cirrhotic cardiomyopathy are very limited. Symptoms of hemodynamic cardiac dysfunction may occur when patients are exposed to stress. Some authors have shown that 50% of patients undergoing liver transplantation have developed some symptoms of heart dysfunction. However, about 7–21% of patients died of heart failure in the period after liver transplantation ,10,11.Pathomechanisms underlying cirrhotic cardiomyopathy are complex and not clearly understood. Moreover, their prevalence in the course of disease is also hard to determine. Cirrhotic cardiomyopathy is characterized by an impaired cardiac response to stress, which results from a combination of autonomic dysfunction, alterations in cell membrane composition, ion channel defects, and an overproduction of cardio depressant factors. A more detailed pathomechanism is presented in the following sections, and a diagram is presented in One of the most common alterations in CCM is activation of the RAA system  and enhaAn increased sympathetic tone accompanied by prolonged cardiomyocyte exposure to noradrenalin may result in myocardial injury, desensitization, and down-regulation of the ß-adrenalin receptor .+/K+ ATPase, Na+/Ca2+ exchanger, and Ca2+ ATPase [2+ and K+, may play an important role in inducing heart electrical abnormalities [Another important element in the pathophysiology of CCM is alterations in cell membrane structure. Decreased membrane fluidity and permeability along with an elevated level of membrane cholesterol may be caused by an increased serum concentration of cholesterol and a decreased concertation of lecithin-cholesterol acyltransferase (LCAT) . These c+ ATPase ,20. Altemalities . Moreovemalities .Inflammation and its complications could trigger cardiac dysfunction, particularly in patients with decompensated cirrhosis. Several possible factors inducing inflammation are postulated, such as impaired intestinal permeability, delayed lymphocyte recruitment in mesenteric lymph nodes, and bacterial translocation leading to constant stimulation of the immune system ,24. In rEndocannabinoids are bioactive signaling particles, increased serum concentration of which is observed in patients with cirrhosis, probably as a result of inflammation . Their bAnother negative inotropic agent is nitric oxygen (NO)  and its In the course of cirrhosis there is up-regulation in haem oxygenase, an enzyme producing carbon monoxide (CO), whose elevated serum concentration leads to blunted papillary muscle contractility .Prolonged cardiomyocyte exposure to humoral agents such as CO, NO, endocannabinoids, and impaired intracellular calcium homeostasis may result in activation of cell apoptosis ,31.CCM is mainly a subclinical syndrome. Signs and symptoms reported by patients are non-specific and include reduced exercise tolerance, fatigue, peripheral oedema, and ascites. Some of these features may not be easily distinguished from those of the underlying diseases .Due to the splanchnic vasodilatation associated with cirrhosis, CCM is rarely manifested by symptomatic heart failure, although most patients with advanced liver disease are affected by the cardiomyopathy . HoweverIn the course of CCM there are several abnormalities associated with the systolic, diastolic, and electrical function of the myocardium.-LA dilatation and increased LA volumes;-Increased LV diameters (but not volumes);-Increased thickness of the posterior wall of the LV and the interventricular septum;-Prolonged isovolumetric relaxation time (IVRT > 80 ms);-Prolonged deceleration time (DT > 200 ms);-E/A ratio < 1 (after age correction).Diastolic dysfunction is presumably the initial manifestation of CCM and precedes systolic dysfunction . The mecIt is worth noting that current guidelines of the European Society of Cardiology (ESC) and the American Society of Echocardiography (ASE) propose more complex algorithms for diastolic dysfunction using a wider range of echocardiographic parameters than those mentioned above. This shows that the working definition of CCM has become much simpler and outdated .2 [Conventional pulse-wave doppler technique had limitations in patients with CCM  . In addi2 .There are contradictory results in the case of a correlation between the diastolic dysfunction grade and liver failure stage. Some papers confirmed the significance of this correlation ,39,40, wSystolic dysfunction in cirrhotic patients is mostly latent, owing to low peripheral resistances and hyperdynamic circulation. Their cardiac pressures remain within normal limits at rest due to decreased afterload, as well as increased cardiac output and normal ejection fraction (EF) . AlthougIn the course of CCM dysfunction in the electrical activity of the myocardium may occur, manifesting as a prolonged QT interval, electromechanical uncoupling, and chronotropic incompetence.1/3) or a formula dedicated for cirrhotic patients (QTC = 453.65 × RR1/3.02). In recent research, the total number of identified QTc interval prolongation was 19% decreased by using Fridericia [QT interval prolongation is an integral part of the CCM definition. QT interval prolongation  is observed in 40–55% of patients with liver diseases . Some stElectromechanical uncoupling in CCM patients leads to dyssynchrony between electrical and mechanical systole. There is a correlation between electromechanical uncoupling and QT interval prolongation, which increases the latency difference of electrical and mechanical contraction . HoweverChronotropic incompetence is defined as an inability to proportionally increase HR as a response to increased metabolic demand, i.e., physical exertion or after dobutamine infusion. In early stages of cirrhosis the chronotropic incompetence may not be fully pronounced, probably due to desensitization and down-regulation of the ß-adrenergic receptor in cardiomyocyte .Natriuretic peptides—atrial (ANP), brain (BNP), and its prohormone (NT-proBNP)—are sensitive markers of myocardial injury, and their higher serum concentrations are associated with an advanced stage of cirrhosis, greater LV systolic dysfunction, myocardial hypertrophy and a poor prognosis .ANP serum levels are elevated in patients with cirrhosis and ascites due to LA enlargement related to an increase in circulating blood volume .BNP and NT-proBNP serum concentrations correspond to the liver failure stage, and it is highest in patients with class C in the Child–Pugh score and a high MELD score ,48. An eTroponins (Tn) are specific markers of myocardial necrosis, especially cTnT, if its area is limited. In some papers, it was found that higher cTnT serum concentrations in cirrhotic patients are correlated with an advanced stage of liver disease and higher mortality . In our The TnI serum level is often elevated in patients with alcoholic liver cirrhotic and corresponds to impaired systolic function, although it is not related to an advanced stage of cirrhosis and portal hypertension .Galectin-3 is a novel biomarker associated with cardiac diastolic  and systThe mechanisms of haemodynamic changes also include an imbalance between an overproduction of circulating vasodilators ) and a reduction in levels of vasoconstrictors (endothelin-1 (ET-1)) .Histologic changes of myocardial cells in cirrhotic cardiomyopathy are non-specific; they may be similar to those that are observed in alcoholic cardiomyopathy. They could look like areas of fibrosis, subendocardial edema. or vacuolation of the nucleus and cytoplasm .As many studies have shown, liver failure significantly interferes with cardiovascular function. As a result, it may lead to hyperkinetic circulation, which results in cirrhotic cardiomyopathy. Therefore, it is extremely important to find an appropriate diagnostic algorithm for early diagnosis of CCM.The first examination that should be performed by each patient is an electrocardiogram (ECG). In the group of patients suspected of hepatic cardiomyopathy, we are mainly looking for abnormalities in the form of a prolonged QT interval . HoweverAnother necessary examination is echocardiography. This is the basic method of detecting systolic and diastolic dysfunction of the heart muscle, which is essential for the diagnosis of CCM ,55,56. PIn patients with cirrhosis we should determine the basic biomarkers, i.e., NT-proBNP and TnI ,60,61. EThe Cardiopulmonary Exercise Test (CPET) is based on the analysis of respiratory gases during increasing exercise. It is a very good test in the assessment of physical capacity, as it enables the assessment of the maximum oxygen absorption at the peak of the exercise (VO2peak). Patients with liver failure are characterized by reduced physical capacity, and reduced oxygen absorption at the peak of the effort may result from many complications of the disease, including the presence of sarcopenia or CCM. A decrease in peak VO2 correlates with the severity of cirrhosis assessed by MELD and Child–Pugh scoring ,63,64.Magnetic resonance imaging (MRI) allows for both morphological and functional evaluation of the heart muscle. It is a valuable addition to echocardiography, especially when it is limited by difficult technical conditions. MRI also assesses myocardial swelling and fibrosis in CCM. Observation of the entire cardiac cycle enables a precise functional analysis of the heart, including the assessment of left ventricular contractility disorders. It can therefore detect subclinical changes before manifest heart failure occurs. Unfortunately, the prevalence of diagnostics using this method is limited by its low availability and high cost ,7,59,65.Substantial blood volume relocation from splanchnic vessels to the central circulation associated with the transjugular intrahepatic portosystemic shunt (TIPS) procedure may lead to rapid preload increase, aggravation of hyperdynamic circulation, and hemodynamic deterioration. There are several adjustments to the circulatory function after shunt establishment—increases in EDV, CO and pulmonary pressures. All of them normally resolve within 6–12 months after the procedure. Nevertheless, these alterations may become symptoms of progressive diastolic dysfunction in the course of CCM. Occurrence of symptomatic diastolic failure after a TIPS procedure is associated with worse ascites mobilization and poor prognosis . HoweverOrthotopic liver transplantation is a major stress factor for the circulatory system owing to significant alterations in both preload and afterload, as well as a massive release of mediators of inflammation and vasoactive agents ,67,68. CThe perioperative deviations in preload, afterload, and peripheral vascular resistance may reveal impaired myocardial contractile responsiveness . More thThe role of diastolic dysfunction in predicting or determining the prognosis of patients with cirrhosis remains unclear. Three independent studies revealed significant diastolic dysfunction in patients after OLTx ,35,77, aLiver transplantation also impacts electrical heart activity. Amelioration of electrophysiological dysfunction displayed by a decline of the QTc interval prolongation occurred in 55–72% of the patient population after OLTx ,42.Unfortunately, to date no guidelines for CCM management have been developed. Despite their limitations, studies consistently indicate an improvement in cardiovascular performance after liver transplantation, therefore establishing that transplantation may be a causal treatment of CCM ,68. HoweAs there is no specific treatment for this disease, the therapy should focus on symptomatic treatment of congestive heart failure. Diuretics are mainly recommended. It is also recommended to use beta-blockers to reduce the risk of bleeding from esophageal varices, as it is a frequent complication of cirrhosis and portal hypertension. In addition, administration of a single dose of beta-blockers improves the QT interval in cirrhosis. However, chronic administration of non-selective beta-blockers is effective in shortening the QT interval only in patients with an initially prolonged QT interval .Drugs from the group of angiotensin-converting enzyme inhibitors are contraindicated due to a further decrease in peripheral resistance, which adversely affects the haemodynamic state in patients with CCM. However, angiotensin II receptor blockers (ARBs) may show beneficial effects due to reducing the left ventricular dimension, reducing myocardial hypertrophy, and improving diastolic function .The most important issue is to update the definition of hepatic cardiomyopathy and the criteria for diagnosis. In addition, the diagnostic methods in the CCM should be evaluated and harmonized. Better understanding of the pathogenesis and pathology of cirrhotic cardiomyopathy is crucial in developing more accurate diagnostic tools and specific treatments for this condition. Another important point for further research is the prevalence of CCM—the impact of the aetiology of liver cirrhosis is still unknown. There are also limited data on the association between CCM and hepatopulmonary syndrome as well as other specific liver cirrhosis complications.We should also consider methods for the early diagnosis of cardiovascular dysfunction in patients with cirrhosis. Earlier diagnosis may have prognostic significance for patients, and it may be associated with lower risk of irreversible cardiovascular dysfunction and complications and with longer survival.Rules for treatment in patients with CCM should be developed. Liver transplantation is currently the only effective method of treatment of liver cardiomyopathy and prolonged survival. Since the operation itself involves a very high cardiovascular risk, a detailed cardiological evaluation of patients and their proper qualification and preparation for liver transplantation should be developed. After liver transplantation, we should also include patients in special post-operative care due to their general condition and increased risk of complications. It is also important to provide an individual rehabilitation plan after the operation, in cooperation with physiotherapists. There is a demand to assess novel biomarkers indicating specific changes in cirrhotic patients’ circulation and include their evaluation in therapeutic routines and risk stratification.Since liver cardiomyopathy is usually asymptomatic, and any symptoms are very unspecific and may overlap with the symptoms of the underlying disease, we should observe and evaluate patients particularly carefully for cardiovascular abnormalities. Clinical understanding of CCM in end-stage liver disease is the best way to avoid life-threatening consequences in patients undergoing special procedures (TIPS or OLT).The pathophysiology and importance of CCM have been of interest to many scientists over the past decades. However, not all issues concerning CCM have been clarified to this day, so further research is needed on this condition.Despite newly proposed diagnostic criteria there still are many additional criteria that are not fully understood. Moreover, there is a demand to find new diagnostic tools for further CCM investigations, such as novel biomarkers or new cardiac imaging methods.Additionally, the new CAR-OLT score should be evaluated in a higher number of patients undergoing OLTx. A multidisciplinary approach to CCM is crucial for understating its clinical impact on patients with ESLD and undergoing transplantation.Taking into account the abovementioned problems, preparing new scientific papers remains very necessary and urgent for the verification and organization of knowledge concerning CCM.


Background: Pulmonary hypertension (PH) is a life-threatening disease in dogs characterized by an increase in pulmonary arterial pressure (PAP) and/or pulmonary vascular resistance. Right ventricle adapts to its pressure overload through various right ventricular (RV) compensative mechanisms: adaptive and maladaptive remodeling. The former is characterized by concentric hypertrophy and increased compensatory myocardial contractility, whereas the latter is distinguished by eccentric hypertrophy associated with impaired myocardial function.Objectives: To evaluate the RV adaptation associated with the increase of PAP using two-dimensional speckle tracking echocardiography.Animals: Seven experimentally induced PH models.Methods: Dogs were anesthetized and then a pulmonary artery catheter was placed via the right jugular vein. Canine models of PH were induced by the repeated injection of microspheres through the catheter and monitored pulmonary artery pressure. Dogs were performed echocardiography and hemodynamic measurements in a conscious state when baseline and systolic PAP (sPAP) rose to 30, 40, 50 mmHg, and chronic phase. The chronic phase was defined that the sPAP was maintained at 50 mmHg or more for 4 weeks without injection of microspheres.Results: Pulmonary artery to aortic diameter ratio, RV area, end-diastolic RV wall thickness, and RV myocardial performance index were significantly increased in the chronic phase compared with that in the baseline. Tricuspid annular plane systolic excursion was significantly decreased in the chronic phase compared with that in the baseline. The RV longitudinal strain was significantly decreased in the sPAP30 phase, increased in the sPAP40 and sPAP50 phases, and decreased in the chronic phase.Conclusions: Changes in two-dimensional speckle tracking echocardiography-derived RV longitudinal strain might reflect the intrinsic RV myocardial contractility during the PH progression, which could not be detected by conventional echocardiographic parameters. Pulmonary hypertension (PH), a life-threatening disease in dogs, is characterized by increased pulmonary arterial pressure  and/or pulmonary vascular resistance , 4. ConsCurrently, various echocardiographic variables are used as clinical, non-invasive tools to assess RV function in veterinary medicine; specifically, two-dimensional speckle tracking echocardiography (2D-STE) enables quantitative, non-invasive assessment of the intrinsic RV myocardial function –12. HoweWe hypothesized that 2D-STE indices would reflect the changes in RV function associated with RV adaptation, and there would be differences in RV function between the acute and chronic phase of RV pressure overload. This study aimed to assess RV morphology and function associated with the increase in PAP during the process of creating model dogs with chronic PH.Our prospective, experimental study consisted of procedures that were performed in accordance with the Guide for Institutional Laboratory Animal Care and Use in Nippon Veterinary and Life Science University and was approved by the ethical committee for laboratory animal use of the Nippon Veterinary and Life Science University, Japan .Seven laboratory male beagles  were used in this study. All dogs were determined to be healthy based on a complete physical examination, blood tests, thoracic and abdominal radiography, transthoracic and abdominal ultrasonography, and oscillometric method-derived blood pressure measurement.The study dogs were administered butorphanol tartrate  , midazolam hydrochloride  , heparin sodium  , and cefazolin sodium hydrate   as pre-anesthetic medication. They were then anesthetized intravenously with propofol , maintained with 1.5–2.0% isoflurane  mixed with 100% oxygen. The end-tidal partial pressure of carbon dioxide was monitored and maintained between 35 and 45 mmHg by manual ventilation at a rate of 8–12 breaths per minute. The anesthetized dogs were placed in left lateral recumbency and the right lateral neck region was clipped, prepared aseptically, and draped. An ~5.0-cm surgical cutdown was performed over the right jugular furrow to exteriorize the right jugular vein. Then an 8-Fr multipurpose catheter  was placed in the main pulmonary artery under fluoroscopic guidance. The right side of the neck was sutured, and all the dogs completely recovered from anesthesia through the conventional method .The PAP was measured using circulatory function analysis software . The conscious dogs were restrained in the most stable position, and the PAP  was measured invasively by calibrating with the atmospheric pressure. The average value of PAP calculated from nine consecutive cardiac cycles was considered as “baseline” data and used for the statistical analysis. After baseline PAP measurements were taken, microspheres measuring between 150 and 300 μm in diameter  were injected repeatedly and the peripheral pulmonary artery was embolized via the prepared catheter , 17. TheEchocardiography was performed in all dogs on the same day as the hemodynamic measurements were taken at all time points. Conventional 2D and Doppler examinations were performed by a single investigator (RS) using a Vivid 7 or Vivid E95 echocardiographic system  and a 3.5–6.9 MHz transducer. A lead II electrocardiogram was recorded simultaneously and the images were displayed. Data obtained from at least five consecutive cardiac cycles in sinus rhythm from the dogs that were manually restrained in right and left lateral recumbency were stored. The images were analyzed using an offline workstation  by a single observer (YY).For studying the right heart morphology, the end-diastolic and end-systolic RV areas (RVEDA and RVESA) along with the end-diastolic RV wall thickness (RVWTd) were measured using the left apical four-chamber view optimized for the right heart (RV focus view), as described previously –20. EachThe RVWTd was measured as the largest diameter of the RV free wall at end-diastole using the B-mode method. Additionally, the ratio of pulmonary artery to aortic diameter (PA:Ao) was obtained from the right parasternal short-axis view at the level of the pulmonary artery, as described previously .Tricuspid annular plane systolic excursion (TAPSE), RV fractional area change, peak systolic change (RV FAC), tissue Doppler imaging-derived peak systolic myocardial velocity of lateral tricuspid annulus (RV s'), RV myocardial performance index (RV MPI), RV stroke volume (RV SV), and RV cardiac output (RV CO) were measured as indicators of RV systolic function, as described previously , 20, 22.The RV MPI was obtained from the tissue Doppler imaging-derived lateral tricuspid annular motion wave using the following formula:where a is the duration of the systolic tricuspid annular motion wave, and b is the interval from the end of the late diastolic tricuspid annular motion wave to the onset of the early diastolic tricuspid annular motion wave . The RV If the dogs had tricuspid valve or pulmonary valve regurgitation, we classified these severities as mild, moderate, or severe using color Doppler and continuous wave Doppler methods, as described previously , 28.3seg) and strain rate (RV-SrL3seg) , and strain rate (RV-SrL6seg)  . Right vSrL6seg) . Manual SrL6seg) , 30. TheSrL6seg) .Intra-observer measurement of variability was performed by a single observer who performed all the echocardiographic and radiographic measurements (YY). The baseline RV morphological and functional indices were obtained from the seven dogs. All measurements were performed on two different days at >7-day intervals using the same cardiogram and cardiac cycles. A second blinded observer (HK) measured the same indices for the determination of inter-observer variability using the same echocardiogram and heart cycles.All statistical analyses were performed using the commercially available EZR software, version 1.41  . All cont-test for normally distributed data or Friedman rank sum test with subsequent pairwise comparisons using the Bonferroni-adjusted Wilcoxon signed rank sum test for non-normally distributed data.The normality of data was tested using the Shapiro–Wilk test. Continuous variables were compared between each timepoint by means of repeated measures analysis of variance with subsequent pairwise comparisons using the Bonferroni-adjusted paired Variability of intra- and inter-observer measurements was quantified by the coefficient of variation (CV), which was calculated using the following formula:P <0.050.Intra- and inter-class correlation coefficients (ICC) were also used to evaluate the measurement variability. Low measurement variability was defined as CV <10.0 and ICC > 0.7. Statistical significance was set at The dogs were administered repeated microsphere infusions for 2.2 ± 1.0, 6.9 ± 3.8, 14.9 ± 5.7, and 50.9 ± 13.1 weeks to meet the definition of sPAP30, sPAP40, sPAP50, and chronic, respectively. The median total dose of microspheres was 1.24 mg/kg (range: 0.93–1.37). There was no significant change in body weight. Two dogs required sedation with butorphanol tartrate and midazolam hydrochloride to perform echocardiography and for taking PAP measurements at each timepoint. None of the dogs showed any clinical symptoms associated with PH, including syncope, dyspnea, lethargy, ascites, and pleural effusion throughout this study protocol.P = 0.012, P = 0.018, P <0.001, and P = 0.021, respectively) parameters. The diastolic PAP was significantly increased in the sPAP50 and chronic phases compared with the baseline and sPAP30 values . There were no significant changes in systolic, mean, and diastolic systemic arterial pressure and heart rate with increased sPAP.The hemodynamic data obtained from all seven model dogs were included in the statistical analysis. In this study, the echocardiographic data obtained from all seven model dogs were included in the statistical analysis. All the dogs had mild pulmonary valve regurgitation at baseline, sPAP30, and sPAP40 phases, and that was progressed to moderate at sPAP50 and chronic phases in four dogs (57%). Additionally, three dogs (43%) had mild tricuspid valve regurgitation at each timepoint.P = 0.034 and P = 0.038, respectively). This value was also significantly elevated in the chronic phase compared with those in the baseline, sPAP30, and sPAP40 phases . The RVEDA index and RVESA index were significantly increased in the chronic phase compared with those in the sPAP30 phase . The RVWTd was significantly higher in the sPAP50 phase compared with that in baseline phase (P = 0.042). This value was also significantly elevated in the chronic phase compared with those in the baseline and sPAP30 phases . The TAPSEn and RV MPI were significantly worse in the chronic phase compared with the baseline values . The RV SV was significantly higher in the chronic phase compared with that in the sPAP30 phase (P = 0.016), whereas, RV FACn, RV s', and RV CO showed no significant changes with increased sPAP.3seg and RV-SL6seg were significantly decreased in the sPAP30 phase compared with the baseline values . Additionally, RV-SL3seg was significantly lower in the chronic phase compared with those in the baseline, sPAP40, and sPAP50 phases    (The results of 2D-STE indices are summarized in ctively) . Howeverctively) . The RV-ctively) .The results of intra- and inter-observer measurement variability for the echocardiographic indices assessed in this study are summarized in We created model dogs with chronic pre-capillary PH with moderately increased PAP and substantial right heart remodeling and compared the changes in RV function associated with increased PAP that was measured invasively in conscious dogs. In the acute phase, 2D-STE-derived RV systolic function was temporarily decreased due to the acute rise in PAP; however, it improved with RV hypertrophy; this may be a sign of RV adaptive remodeling. In contrast to the acute phase, RV systolic dysfunction assessed by RV-SL and RV dilatation were observed in the chronic phase of PH, which could be because of RV maladaptive remodeling and myocardial dysfunction.In this study, certain conventional echocardiographic indices, such as TAPSEn and RV MPI, did not significantly change with increased PAP in the acute phase, although these indices were significantly worse in the chronic phase of PH. Nonetheless, 2D-STE indices showed substantial changes in the acute phase as well as in the chronic phase of PH. Previous studies reported that these conventional echocardiographic indices are affected by angle- and load-dependent limitations –36. FurtIn the acute phase, RV-SL was significantly reduced in the sPAP30 phase and gradually increased in the sPAP40 and sPAP50 phases. In the sPAP30 phase, all the dogs did not have RV remodeling; therefore, the acute rise in PAP might have induced the imbalance between RV contractility and RV pressure overload . However, RV-SL gradually increased with PAP and RVWTd, which indicates RV adaptive remodeling. In human medicine, RV adaptation remodeling was induced in PH patients through various mechanisms such as neurological activation, inflammation, and altered bioenergetics , 37, 38.There was a significant difference between the 2D-STE-derived RV systolic functional indices of the sPAP50 and the chronic phases, although there was no significant difference in the RV loading condition (sPAP was stable at 50 mmHg). In general, chronic RV pressure overload increases myocardial wall stress, which in turn increases RV wall thickness and contractility to maintain RV CO –9. HowevIn this study, RV-SL changed more drastically in 3seg than in 6seg in the acute phase, although both indices were significantly decreased in the chronic phase. Considering the interventricular septum when evaluating RV function is a matter of controversy , 42. A pOur study has several limitations. First, the results were obtained from dogs with PH that was experimentally induced by microsphere infusion, which may vary in actual clinical settings or dogs with PH. Additionally, our findings may not be applicable in dogs with PH because of other causes such as left heart disease owing to its different pathophysiology that can increase PAP. Further studies are warranted to evaluate the relationship between echocardiographic indices and invasive PAP in dogs with spontaneous PH. Second, two of the seven dogs were sedated using butorphanol tartrate and midazolam hydrochloride. However, sedation with these agents have minimal effect on cardiovascular function . FurtherIn conclusion, our study found that 2D-STE-derived RV-SL was significantly decreased in the sPAP30 phase compared with that in the baseline phase; it gradually increased in the sPAP40 and sPAP50 phases compared with that in the sPAP30 phase and decreased in the chronic phase compared with the baseline and sPAP50 phases. These results suggest that this non-invasive echocardiographic variable may reflect the RV compensative mechanism against PH pathophysiology, which could not be detected by conventional echocardiographic indices for RV function.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The animal study was reviewed and approved by Ethical committee for laboratory animal use of the Nippon Veterinary and Life Science University.YY performed the concept/design, data analysis/interpretation, drafting article, and critical revision of article. RS performed the concept/design, data analysis/interpretation, critical revision of article, and approved the article. HK performed the data analysis as the second observer. TT, HM, and HK performed data interpretation, critically revised the manuscript, and approved the article. All authors contributed to the article and approved the submitted version.HK received a grant from Toray Industries, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.