Heart failure (HF) does not only reduce the life expectancy in patients, but their life is also often limited by HF symptoms leading to a reduced quality of life (QoL) and a diminished exercise capacity. Novel parameters in cardiac imaging, including both global and regional myocardial strain imaging, promise to contribute to better patient characterization and ultimately to better patient management. However, many of these methods are not part of clinical routine yet, their associations with clinical parameters have been poorly studied. An imaging parameters that also indicate the clinical symptom burden of HF patients would make cardiac imaging more robust toward incomplete clinical information and support the clinical decision process.n = 56, including HF with reduced ejection fraction (HFrEF), HF with mid-range ejection fraction (HFmrEF), and HF with preserved ejection fraction (HFpEF)] and a control cohort (n = 19). Parameters assessed included measures for external myocardial function, for example, cardiac index and myocardial deformation measurements by cardiovascular magnetic resonance imaging, left ventricular global longitudinal strain (GLS), the global circumferential strain (GCS), and the regional distribution of segment deformation within the LV myocardium, as well as basic phenotypical characteristics including the Minnesota Living with Heart Failure Questionnaire (MLHFQ) and the 6-minute walk test (6MWT). If less than 80% of the LV segments are preserved in their deformation capacity the functional capacity by 6MWT  as well as the symptom burden are significantly impaired . Differences were also observed in the perceived exertion assessed by on the Borg scale  as well as quality of life measures –while these differences were not significant.This prospective study conducted at two centers in Germany between 2017 and 2018 enrolled stable outpatient subjects with HF [The share of LV segments with preserved myocardial contraction promises to discriminate between symptomatic and asymptomatic subjects based on the imaging findings, even when the LV ejection fraction is preserved. This finding is promising to make imaging studies more robust toward incomplete clinical information. Patients with heart failure (HF) are at high risk for mortality and hospitalization and have a high burden of symptoms that alter their function and health-related quality of life (QoL) –5. QoL aVarious dimensions including physical capacity influence QoL. Routine measures to assess physical capacities include the semi-objective 6-minute walk tests and the subjective New York Heart Association (NYHA) functional class, often used in clinical trials but rarely in daily routine .per se and the distribution of its impairment assessed by strain measurements characterizes HF patients in more detail (Cardiovascular magnetic resonance imaging (CMR) is a comprehensive technique, increasingly accessible and providing not only a high resolution of information on functional cardiac parameters but also information of tissue characteristics. Measurements of cardiac contractility and the assessment of myocardial deformation by strain analyses are an emerging and promising tool to better characterize patients compared to traditional parameters, e.g., left ventricular ejection fraction (LVEF) . While Le detail . The adde detail –12. The e detail . It has e detail . Variouse detail –16.We hypothesize that the better characterization of cardiac deformation in HF patients provides information on QoL and functional capacity. Therefore, we aim to evaluate the association of cardiac deformation assessed by the MyoHealth score and parameters for QoL and functional capacity in this analysis.This study was a prospective study conducted at two centers in Berlin, Germany, the Charité—University Medicine Berlin and the German Heart Centre Berlin, between 2017 and 2018. Its rationale and design have been previously described , 17–20.Briefly, subjects were screened for diagnosed HF and an age of at least 45 years. The initial diagnosis of HF should have been older than 30 days; the patients were required to be in a stable state with no changes in their HF medication and no HF hospitalization within the previous 7 days. HFrEF was defined as diagnosis of HF, increased N terminal pro brain natriuretic peptide (NT-proBNP) (>220 pg/mL) and LVEF < 40%, HFmrEF as the diagnosis of HF, increased NT-proBNP (>220 pg/mL) and 40% ≥ LVEF < 50% as well as HFpEF as diagnosis of HF, increased NT-proBNP (>220 pg/mL) and LVEF ≥ 50% at the time of study inclusion. We did not distinguish between the causes for HF for recruiting patients .Additionally, we recruited subjects without HF or advanced cardiovascular (CV) diseases as controls.All studies included complied with the Declaration of Helsinki, the protocols were approved by the responsible ethics committees, and all patients gave written informed consent. It was registered at the German Clinical Trials Register . The detailed inclusion and exclusion criteria are listed on the webpage of the DRKS.As previously described, all CMR images were acquired using a 1.5 T  magnetic resonance imaging (MRI) scanner with a five-channel cardiac surface coil in a supine position. All study participants were scanned using the identical comprehensive imaging protocol. The study protocol included initial scouts to determine cardiac imaging planes. Cine images were acquired using a retrospectively gated cine-CMR in cardiac short-axis, vertical long-axis, and horizontal long-axis orientations using a steady-state free precession sequence for volumetry , 20. The® Suite MR  for voluinterme measurements and the software MyoStrain  for fast-SENC strain measurements.All images were analyzed offline using commercially available software in accordance with the recent consensus document for quantification of LV function using CMR . In the n = 37), described as MyoHealth score  key parameters as well as the New York Heart Association (NYHA) functional classification.Patients were instructed to cover the maximum distance in 6 min  at a self-graded walking speed, pausing to rest when needed. The test was supervised by the same study staff to minimize the variability. The 6MWD as well as the level of perceived exertion indicated as specific level on the Borg score were recorded. The functional capacities indicated by the New York Heart Association (NYHA) functional classification were also part of the baseline information collected.In accordance with the study protocol, study participants completed a QoL questionnaire, the Minnesota Living with Heart Failure Questionnaire (MLHFQ) .Statistical analysis was carried out with R version 3.5.1 .P-value was obtained using one-way ANOVA, the group means were examined by the Holm–Bonferroni method. Values of P < 0.05 were considered statistically significant. For the comparison of categorical variables between the groups were used the χ2 test.Normality of variables was assessed by visual assessment of normality curves and the Shapiro–Wilk test. Comparison between groups for continuous variables was performed with a one-way ANOVA for normally distributed data. When a significant 2 = 5.21, p = 0.157, n = 71) in The ratio of non-altered myocardial deformation was assessed in 71 patients. The baseline characteristics of these patients have been previously reported, in brief the details are presented in p-value: 0.03). The 6MWD was significantly different across groups separated by the MyoHealth score .p-value: 0.15).p-value < 0.01).In this study, aiming to better characterize HF patients and imaging parameters indicating their symptom burden, we found that the proportion of myocardial segments with preserved myocardial deformation indicates better functional capacity. Furthermore, this exploratory analysis suggests an association of the MyoHealth score with quality of life surrogate parameters in larger study population.per se represents the proportion of segments with preserved strain values.Our observational study of consecutive patients with HF as well as control subjects was carefully designed to better characterize myocardial contraction. After focusing on the contraction pattern and describing the onset of changes in HF in interventricular septal segments, we sought to highlight that CMR scans in HF are not only relevant to characterize HF but to better phenotype patients with regards to parameters limiting their lives on a daily basis .Given the high prevalence of HF and a nearly half of these patients showing nearly normal values with regards to traditional HF parameters, e.g., LVEF, there is an unmet need for innovative tools to diagnose patients and identify those at risk . In thisThe MyoHealth score allows for the estimation of the clinical condition when functional capacity data is not available. If the signal with regards to the QoL assessed by the MLHFQ prove feasible and the differences are significantly different in a larger study population, this might lead to fewer resources than assessing the symptom burden systematically aside from the image acquisition, e.g., by conducting a 6MWT or questionnaires for QoL.Impaired functional capacity, often assessed by 6MWT, is the main symptom in patients with HF, regardless of LVEF –28. WithWhile there is some evidence indicating a worse prognosis based on CMR characteristics in HFpEF, the association with the symptom burden remains to be further explored –31.The HFA-PEFF algorithm introduced imaging parameters to diagnose HFpEF, e.g., E/e’, tricuspid regurgitation velocity, left atrial volume index, and LV wall thickness . In brieHFA-PEFF parameters as well as other HFpEF criteria have been often analyzed for a prognostic value regarding survival, but only recently a few studies focused on functional capacity , 34, 35.With regards to the QoL the greatest difference could be observed between the group with preserved MyoHealth score and the impaired groups, as illustrated in S1, indicating that this parameter indicates QoL. While many patients with HF suffer from depression, QoL was only recently used as a clinical trial outcome parameter in HF—very rarely in cardiac imaging and CMR studies –40.The main limitation of our study is that we cannot provide prognostic information of the subjects and patients examined. Nonetheless, the main objective of this analysis was to evaluate the predictive value of regional myocardial deformation on functional capacity as well as the quality of life in HF patients, especially HFpEF.post hoc subject sex or age matched analysis, as it would lead to even smaller numbers of subgroup subjects.However, our explorative analyses to better understand the differences between the study subgroups are limited due to the smaller subgroup sizes the more fragmented they become. Comparing HF entities from different subgroups against each other within our analyses –4 will iThe small numbers also limit some of our analyses where we see quantitative difference, which do not reach the level of statistical significance, e.g., the assessment of QoL by the MLHFQ. Revisiting this analysis in a larger study population would lead to results that are more reliable. However, we believe that these not significant results are a signal to further analyses.The results of this study promise an association between regional LV strain impairment and the symptom burden of HF patients with regards to functional capacity and quality of life, especially relevant in patients with a preserved LVEF that requires future prospective validation.The original contributions presented in this study are included in this article/The studies involving human participants were reviewed and approved by Ethikkommission der Charité – Universitätsmedizin Berlin. The patients/participants provided their written informed consent to participate in this study.DH, HDD, FE, and SK: conception and design of the study and literature review. DH, MB, and SK: analysis and interpretation of the data. DH: drafting of the manuscript. DH, PD, and MB: data collection. All authors revising and editing the manuscript and approved the submitted version.


Except for NT pro BNP (p = 0.059), all parameters served to distinguish between severe and mild-moderate cases of OSA. 3D STE may be a reliable and accurate method for predicting OSA. Consequently, 3D RV GLS is a good tool of assessing the RV global function in OSA, because it correlates well with other established measurements of RV systolic function. Furthermore, 3D RV GLS was a precise parameter in identifying severe cases of OSA, while NT pro BNP showed no association.There is a consistent relationship between obstructive sleep apnea (OSA) and cardiovascular diseases. It is already recognized that OSA may influence the geometry and function of the right ventricle (RV). This has encouraged the development of echocardiographic evaluation for screening of OSA and its severity. Three-dimensional speckle tracking echocardiography (3D STE) is in assumption better, compared with 2D STE, because it overcomes the standard 2D echo limitations. Thus, the purpose of our study is to evaluate whether 3D STE measurements, could predict the positive diagnosis and severity of OSA. We enrolled 69 patients with OSA and 37 healthy volunteers who underwent a cardiorespiratory sleep study. 2DE was performed in all patients. RVEF and 3D RVGLS were measured by 3DSTE. NT pro BNP plasma level was also assessed in all participants. 3D RV GLS (− 13.5% vs. − 22.3%,  It is characterized by repeated partial or complete obstructive events, leading to intermittent hypoxia, sleep fragmentation, snoring and daytime somnolence, even with an acceptable duration of sleep3. Obesity or anatomic features have traditionally been implicated as the primary factors driving the pathogenesis of OSA. Despite this, OSA can occur without obesity or clinically evident structural compromise of the upper airway. As a result, the pathogenesis of OSA varies from individual to individual. Physiologic studies of upper airway function in OSA have recognized several mechanisms of sleep-related upper airway instability. Among the key mechanisms underlying sleep-induced narrowing and occlusion of the upper airways are: the capacity of the upper airway dilator muscles to respond to respiratory challenge during sleep, upper airway anatomy, the tendency to wake from increased respiratory drive during sleep and the stability of the respiratory control system4.Obstructive sleep apnea (OSA) is one of the most common forms of sleep disorders, affecting approximately one billion people around the world6. OSA patients are mainly clinically supervised by sleep physicians with work experience in respiratory medicine. Nevertheless, many patients are asymptomatic from their apneas, seeing a cardiologist when having arterial hypertension, atrial fibrillation, stroke, coronary artery disease or heart failure7.Initial reports of OSA were of severe apnea in obese male patients, however it is now known that women account for one third of OSA patients and a normal body mass index (BMI) is frequently associated9. Such an association is largely due to autonomic, inflammatory, hemodynamic and metabolic consequences of this obstructive sleep pattern. The effects may also contribute to the pathogenesis of a variety of cardiovascular diseases. Repetitive apneas expose cardiovascular system to cycles of hypoxia and excessive negative intrathoracic pressure. These mechanisms can, sequentially, depress myocardial contractility and parasympathetic activity, activate the sympathetic nervous system, raise blood pressure, heart rate, myocardial wall stress, induce oxidative stress, systemic inflammation, activate platelets and damage vascular endothelial function10. As has been demonstrated, OSA is a condition, that has the potential for negative feedback, because it worsens conditions that could in turn aggravate OSA11.Observational studies have shown a consistent relationship between OSA and cardiovascular diseases (CVD)12. However, OSA is extensively underdiagnosed; up to 95% of people from population surveys with clinically notable OSA reveal no previous OSA diagnosis13. In a published statement, the U.S Preventive Services Task Force (USPSTF) concluded that the current evidence is insufficient to assess the balance of benefits and harms of screening for OSA in asymptomatic adults14. Despite this statement, the high cardiovascular (CV) morbidity and mortality associated with this disease, alongside with significant improvements in quality of life, mood and social life with OSA treatment, provide solid grounds for OSA screening.The suspicion of OSA is based on symptoms and confirmed with diagnostic testing. Polysomnography is the “gold standard” to diagnose and characterize the severity of OSA15.Screening for OSA is usually performed using questionnaires, typically having high sensitivity but low specificity, which limits their value as screening tools16. RV has a complex structure, makingconventional two-dimensional (2D) echocardiography techniques insufficient for accurate assessment17. Lately, 2D speckle tracking echocardiography (STE), which detects subclinical RV dysfunction, has shown to be a reliable and feasible quantitative technique for the assessment of RV function19. Furthermore, there is evidence suggesting that RV longitudinal strain of free wall (RV FWLS) derived from 2D STE offers prognostic information over common RV parameters in different clinical scenarios, including patients with pulmonary hypertension (PHT), heart failure (HF) or coronavirus-19 disease21. This is however a technique with limitations, the main ones being the fact that it only evaluates deformation in a 2D plane, the views can be foreshortened, and geometric modeling is difficult. Moreover, 2D STE assessment is only obtainable in the apical four chamber view (A4C), thus excluding the evaluation of RV outflow sections22. Three-dimensional (3D) STE appears to be better, compared with 2D STE, because it assesses deformation in 3 orthogonal planes from one analysis, overcoming the previously mentioned limitations23.OSA may affect the function and geometry of the heart chamber, especially that of the right ventricle (RV). This has stimulated the interest in the development of echocardiographic methods for screening for OSA and assessing its severity24. Results from a single study demonstrate the prognostic utility of 3DSTE of the RV (using a software designed for the LV) to predict mortality among patients with PHT25. The value of this novel technique for RV assessment in OSA patients has not yet been established.Evaluation of RV strain using 3D STE has been shown to be feasibleThe aim of this study is to investigate whether 3D STE measurements, compared with standard RV 2DE parameters, could predict the positive diagnosis and severity of OSA.Between January 2020 and February 2021, we examined and screened for OSA a cohort of 163 adult patients admitted to “Leon Daniello” Pneumology Hospital of Cluj-Napoca. The study was conducted according to the guidelines of the Declaration of Helsinki. The approval of the Human Research Ethics Committee (number: 493/2019) was obtained and patients signed an informed consent.Inclusion criteria for patients were age ≥ 18 years, and presence of minimum 3 clinical symptoms of OSA. The symptoms were snoring, witnessed apneas, gasping/choking episodes, excessive daytime sleepiness not explained by other factors, nocturia, morning headaches and decreased concentration and memory.We excluded from the beginning patients with decompensated or unstable cardiopulmonary disease, chronic respiratory disease such as chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF) and sarcoidosis, cor pulmonale, known history of pulmonary embolism, significant right and left-sided valve disease, known cardiomyopathies, congenital heart disease, pericardial disease, malignancy, psychiatric disorders or recent surgery.Finally, 106 participants were eligible for taking partin the study. They were divided into two groups; 69 patients were clinically diagnosed with OSA and they created the study group. The control group was formed by 37 sex and age-matched subjects, who, following respiratory polygraphy, did not have OSA criteria. At that time, the OSA patients were not under continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BIPAP) treatment . OSA was diagnosed in the event that AHI was greater than or equal to 5, with recorded symptoms of daytime sleepiness, insomnia, involuntary sleep episodes during wakefulness, mood disorders, snoring, breathing disturbances or documented history of stroke, hypertension, ischemic heart disease. Patients with AHI between 5 and 15 are considered a mild form of OSA, patients with AHI values between 15 and 30 are counted as moderate forms and patients with AHI greater or equal to 30 are considered to have severe OSA27.All enrolled participants  underwent cardiorespiratory sleep study using Nox T3 polygraphy device for a wholenight. The sleep study involved continuous recording from nasal cannulae, oxygen saturation, heart rate, tracheal sounds (microphone), thoracic and abdominal movement and body position. The results of the polygraphy were analyzed and approved by trained personnel. Apnea was defined as a complete cessation of inspiration for at least 10 s (s). Hypopnea was defined as a limiting in airflow by at least 50% for at least 10 s. Obstructive apnea was described as the absence of respiratory airflow in the presence of paradoxical thoracic and abdominal movement28: basal right ventricle (RV) diameter in the apical four chamber view (A4C) at the end-diastole, tricuspid annular plane systolic excursion (TAPSE), S’ wave and fractional area change (FAC), as parameters of RV systolic function in a standard A4C; left ventricular ejection fraction (LVEF), mean tricuspid regurgitant gradient and pulmonary artery systolic pressure (SPAP) respectively. The LVEF was measured using manual tracing (biplane Simpson’s) method.Echocardiographic data were obtained for all participants. All echocardiography images were acquired on a Vivid E95 scanner  and analyzed offline using EchoPac BT13 software . The following conventional RV echo measurements were performed using a 2D matrix-array (M5S) according to current recommendationsBy using a real time 3D phased-array transducer (4 V-D), 3D full volume data set of the RV over 4–6 cardiac cycles was recorded. The images were acquired in the apical window and aligned so that the entire RV could be integrated into the full volume dataset. The obtained 3D datasets were transferred to the EchoPac BT13 station for offline analysis. 3D RVEF was calculated using the 4D RV quantification function of the system (4D- AutoRVQ). 3D STE was performed using the GE 4D LV quantification function of the system (4D-autoLVQ), this software being adapted for the evaluation of RV since it was designed for the left ventricle STE analysis. After the three apical long axis and short axis view alignment, topographic landmarks were manually placed at the level of the tricuspid annulus and RV apex. The outline for the end-systolic and end-diastolic boundaries of the RV was automatically defined and manual adjustment was done where necessary. Accordingly, the automatic alignment of endocardial and epicardial contours was followed by manual correction, confirming the myocardial wall, where needed, in order for all segments to be included in the strain analysis. The software automatically calculated the global longitudinal strain (GLS) values. Bull’s eye diagrams, tracking curves were stored. Fig. .Figure 22 (kg/m2). The same person performed all the measurements using the same tools. Obesity was defined as a body mass index (BMI) ≥ 30 kg/m2.In all patients, fasting blood samples were drawn in order to evaluate levels of amino-terminal-pro-brain-natriuretic-peptide (NT-pro BNP). Plasma levels were measured by sandwich enzyme-linked immunosorbent assay . Values were expressed as pg/mL. Body weight and height were measured and recorded. Body mass index (BMI) was calculated with the formula of body weight/heightTo evaluate the reproducibility of the 3D-STE measurements, we have randomly selected 20 patients in whom measurements were repeated by a second operator, who was blinded to the results of the first operator. We calculated an inter-observer correlation coefficient of 0.867.® Statistical Software version 19.7 . Quantitative data were examined for normality of distribution using the Shapiro–Wilk test and expressed as median and 25–75 percentiles. Qualitative data were expressed as frequency and percentage. Comparison between two groups for categorical variables was by chi-square test and by Mann–Whitney test for continuous variables. Correlation between variables was assessed by Spearman correlation coefficient. The sample size was calculated from the first 10 controls and 16 OSA patients. For the OSA patients we determined a 3D RV GLS of − 14.5 ± 5, and for controls a 3D RV GLS of − 20.6 ± 0.7. For a type 1 (a) error of 0.05 and a type 2 (b) error of 0.1, we calculated a sample size of 18 controls and 36 OSA patients. The sensitivity and specificity of strain vector and the others standard parameters cutoff points were settled by the basis value indicated by the Youden index from the receiver-operating characteristic (ROC) curve to predict the disease. A “p” value lower than 0.05 was considered statistically significant.Statistical analysis was performed using the MedCalc“The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by Ethics Committee of the University of Medicine and Pharmacy “Iuliu Hațieganu”, Cluj-Napoca number 493 on 21.11.2019.Informed consent was obtained from all participants involved in the study.The baseline characteristics for both groups are detailed in Table Posibile pulmonary hypertension as assessed by echocardiography, i.e. sPAP > 37 mmHg was present in 84.1% of OSA patients, respectively 15.9% of OSA patients did not have PHT. There was significant difference in NT pro BNP values between the two groups.The healthy volunteers’ mean 3D global longitudinal strain of the RV was significantly higher than in patients with OSA. Similar results were also obtained for the 3D RVEF.The standard RV function parameters  correlated significantly with 3D RV GLS Table . FurtherAll echocardiographic parameters were entered into a ROC model to calculate a cut-off value for predicting the presence of OSA Table . 3D RV Gp < 0.001), followed by TAPSE (p = 0.02). No significant differences between the other ROC curve comparisons were found.In order to evaluate which echocardiographic method has the ability to be the most discriminative regarding the positive diagnosis of OSA, comparison of ROC curves was calculated Table , Fig. 3.p = 0.001). Additionally 3D RV GLS is maintaining the significant status amidst 3D STE evaluation (p = 0.01) in differentiating the severity of the disease. Concerning the capacity in differentiating between the grades of OSA severity, NT pro BNP compared to the echocardiographic method showed no significant difference  was present in 41 patients and non-severe OSA with AHI < 30 was present in 28 patients. All patients included in the severe group also presented PHT. When evaluating which echocardiographic method is better associated with severe OSA cases, FAC and sPAP obtained the highest statistical significance among 2DE parameters , compared to control group. RV GLS was independently associated with sPAP and OSA severity, in the absence of significant changes of other echocardiographic parameters of RV systolic function, such as TAPSE or FAC. In concordance with these results, Li et al.34, described significantly reduced RV lateral strain (LS) and strain rates of RV apical segments in patients with mild OSA compared with healthy controls. Hammerstingl et al.35, found that RV 2D GLS was significantly impaired in patients with higher AHI, and was positively correlated with the severity of OSA. Furthermore, conventional echocardiography parameters, like TAPSE, S’ wave and FAC were not significantly reduced in these subjects, assuming that they are not sensitive enough in detecting RV subclinical dysfunction.Previous studies have shown that patients with OSA displayed impairment of 2D RV GLS. As Buonauro et al.36, RV speckle tracking imaging has fallen back in this matter. As Blanchard and DeMaria37, mentioned in their review article on RV 3D strain in pulmonary hypertension, RV has a thin wall, making endocardial and epicardial borders difficult to track, moreover the software packages for 3D strain analysis available now are designed for the left ventricle.The last decade brought in significant advancements in the, 3D imaging of the left ventricle (LV), but as stated by ReichekOur results suggest that 3D RV GLS is a reliable echocardiographic method with higher specificity in predicting OSA, when compared to the standard RV function parameters. Moreover, we have found that NT pro BNP, a known important biomarker of cardiac stress and implicitly of LV and RV systolic dysfunction is not equally sensitive in predicting RV dysfunction in OSA patients compared to 3D RV GLS.40, evaluation of the role of 3D specific parameters in this pathology, being in progress42. The superiority of 3D RV strain over 2D RV strain in RV function assessment against cardiac magnetic resonance imaging (MRI) was already demonstrated in a study population with a wide variety of cardiovascular pathologies43.All 2D and 3D echocardiographic variables assessed in the study were significantly reduced in OSA patients compared to the controls, with strong correlations between FAC, sPAP and 3D RV GLS, and with lesser, but still significant association for S’ wave and TAPSE. There are already several studies in literature demonstrating reduced 2D echocardiographic parameters in OSA population25, who have shown that in a subset of PHT patients, sPAP correlated weakly with RV longitudinal strain (LS). Extrapolating to our study, the lower values of 3D RV GLS in OSA patients are mainly due to the disease itself and in a less extent due to the presence of PHT. Similar results were found by Altekin et al.44. In their study, they used the STE method to assess the presence of right ventricle dysfunction before the occurrence of RV failure and PHT in OSA patients. They concluded that strain could be a reliable method to detect subclinical right ventricle dysfunction among patients with OSA, even in the absence of PHT. On the other hand, Li et al.20 demonstrated in their study that 2D and 3D LS are the variables that correlate better with severity of PHT, demonstrating clinical superiority over circumferential strain, radial strain and conventional RV function parameters.Regarding the presence of sPAP, we obtained in the ROC analysis that a cutoff of > 30 mmHg has a high specificity in predicting the disease. The question arising in this case is if the evaluation of pulmonary artery systolic pressure, could really be a reliable parameter for predicting OSA, considering that in our study, as mentioned before, there were also patients diagnosed with OSA without the presence of PHT, situation in which 3D RV GLS demonstrated a more confident parameter to assess. These findings are supported by the study of Smith et al.45. Right ventricular (RV) remodelling in obesity is less well studied than LV remodelling, but it has been reported to include subtle RV cavity dilatation and RV hypertrophy46. Sokmen et al. have demonstrated in their study that isolated obesity in young adults was associated with subclinical abnormalities in RV structure and function. It is important to mention that they did not perform a sleep study to determine the contribution of OSA to RV changes 47. Correspondingly, in another study evaluating RV function and structure by echocardiography, RV mass and volume was shown to be increased in obese subjects46. On the other hand, some studies found no relation between obesity and RV function or structure49. For example, Yildirimturk et al. showed no changes in the RV functions in obese and overweight who were otherwise healthy subjects. There was no correlation found between the BMI and the RV diameters or functions49. Subsequently, approximately 20% of adults with OSA are non-obese. Studies show that this category of OSA patients are four times more likely to develop hypertension than obese without OSA50. Non-obese patients are at risk for early atherosclerosis approximately 2.7 times more than obese subjects without OSA51. In our study, even though the BMI values in both groups indicate at least overweight, there was a significant difference between the OSA and the control group. The fact that the groups were not BMI matched, remain an important limitation of the study.It is well known that OSA is most common in people who are overweight or obese. Obesity is an important anatomical factor, but BMI is not perfect to classify the obese OSA patients because the main factor is fat deposit in the upper airway and abdominal fat52 As far as we know a validated value of 3D RV GLS in OSA population has not yet been established,therefore our results may be taken into consideration in future research. We found that lower strain values below the cutoff for RV GLS were associated with the positive diagnosis of OSA, with higher sensitivity and specificity than standard day to day 2D parameters. Especially the cutoff value of 3D RV GLS has an important value, considering that, as far as we know, there is not a standard value validated in OSA. In recent literature there have been proven cutoff values for 3D RV strain vectors in patients with PHT, proven to be highly important for mortality risk assessment25. As mentioned before, we have used for the 3D ST evaluation of RV, a software designed for the LV. Being originally created for the evaluation of LV, segmentation is rather limiting for use in RV. It is difficult to delineate the exact location of the septal free wall edge with regard to the fixed segments, which makes it challenging to separate segments from each other. Moreover, the septum is composed of the same fibers as those found in the LV and has to deal not only with loading conditions in the RV but as well with the higher LV afterload17. On that account, like the authors of other published studies of RV strain56, we decided to include the septum in the strain analysis, as a part of the RV, because its shortening plays a part in the ejection phase of the RV and any changes in its contractility reduces the RV performance57. On the contrary, there are studies which excluded the septum segments from the analysis based on the fact that ventricular septum is composed of left and right components, which makes it hard for the echocardiography to differentiate58. Consequently, inclusion of septum will include LV strain values. Extremely, impaired septal strain in patients with associated LV failure, might contribute to the reduction in global RV strain25. It is important to mention that, in our study, patients with LV systolic dysfunction were not included, all participants having LVEF above normal.Our study also defines cutoff values, which may be clinically applicable for identifying patients with obstructive sleep apnea and for better characterization of disease severity. There are no extensive studies or indexing to sonomicrometry for the classification of normal RV strain values. Alternatively, normal 2D LS is obtained from a five-study meta-analysis of healthy controls38. Furthermore, similar to our study, Buoanauro et al., demonstrated that subclinical RV dysfunction associated with severe cases of OSA can be determined via STE, in patients with normal RVEF and TAPSE33. Regarding 3D RVEF, some reports described that RVEF is similar in patients with and without OSA59, which is in contradiction with our results. In our study, 3D RVEF had lower values in the group of OSA compared to healthy volunteers. Furthermore, the cutoff obtained in the ROC analysis may predict RV dysfunction with a good specificity, but lesser than 3D RV GLS and NT pro BNP. Concerning the capability in distinguishing between the severity grades of OSA, 3D RVEF is correlated with the severe cases, but not as strong as 3D RV GLS. On the contrary there is a study in literature showing a strong association between OSA and RVEF60.Furthermore, in our research we also evaluated the role of 3D RV strain in predicting OSA severity compared to standard 2D parameters. The better association with the severe forms of OSA was demonstrated by FAC. Similarly, 3D RV GLS showed good correlation with the severe OSA cases. In the study of Altekin et al., it was shown that TAPSE and values of tissue Doppler were lower in patients with moderate-sever OSA than in the controls and mild OSA; also, they found out that patients with moderate to severe OSA have lower RV strain and RV systolic strain values than controls61, showed a close association between RVEF and RV wall stress, which is the principal trigger to NT pro BNP secretion in OSA, PHT and others RV conditions. This relationship may explain the utility of the biomarker as a tool in detecting RV systolic dysfunction and consequently, OSA. At a cutoff value of > 136 pg/ml, with a sensitivity of 91.8%, we have demonstrated that NT pro BNP may be used in the positive diagnosis of OSA, but with a lower accuracy than 3D RV GLS. On the other hand, there are published studies which show that NT pro BNP is not elevated in patients with OSA 62. These results are sustained by another paper63 explaining that BNP levels are not elevated in the study group compared to controls. Kita and coworkers64 showed that BNP levels are elevated in patients with severe OSA. These results are in contradiction with those of our study. NT pro BNP is not associated with severe cases of OSA, thus it may not be considered a reliable method to differentiate between the severity of disease.A study by Quaife et al.65. It is already known that OSA has a detrimental effect on both RV and LV function. Several studies support that, effective OSA therapy improves RV and LV function in OSA patients67. The positive effect of CPAP therapy was shown by Chu et al. They proved that after six months treatment with CPAP, RV structure and function had significantly improved, including increased RV ejection fraction and improved RV strains, which practically indicated a pathophysiologic association between RV performance and OSA66. In another study, Vitarelli et al. showed that 3D RV ejection fraction was lower and RV dyssynchrony was greater in patients with moderate-severe OSA compared with control subjects. Moreover, RV 3D STE abnormalities improved after chronic application of CPAP67. Recently Colish and colleagues found RV and right atrial (RA) diameters positively influenced by 12 months of CPAP treatment in a group of 47 OSA patients68. In opposition with these studies are the results of Hammerstingl et al. After 6 months of CPAP therapy, they found a significant increase in systolic LV ejection fraction, bur global RV function parameters, TAPSE and interventricular septum diameter, did not change significantly over the treatment period35. All in all, in order to prevent permanent impairment of the left and right ventricular structure and function as a result of OSA, early use of CPAP therapy is recommended in all patients with relevant OSA.Comprehensive assessment of each individual's characteristics, as well as monitoring and follow-up, are essential to effective management of OSA. Continuous positive air pressure (CPAP) therapy is a first-line treatment for patients diagnosed with OSA69, there has not been a direct validation for use in the RV. 3D STE would gain utility for future use from validation using sonomicrometry or even better cardiac IRM. Sixth, this is a single center study, with a limited number of patients. Future prospective, long term follow up studies will be necessary to determine the meaningful cutoff values of 3D RV GLS for the detection of RV dysfunction in OSA patients and their prognostic role. However, 3D STE has been disclosed as clinically applicable in LV function assessment, therefore, 3D RV STE might be a valuable method to evaluate RV function in OSA.Some limitations of our study consist in the initial exclusion of patients with reduced LVEF, history of ischemic disease and cardiopulmonary decompensated disease. Thus, our results may only be applied to populations that are similar to those in our study. Second, the OSA and control group were not BMI matched, even though the BMI values in both groups indicate at least overweight. Third, an important part of strain analysis had to be rejected because of suboptimal image quality. This included subjects with poor apical view, too large RV for the 3D sector or image dropout. Fourth, 3D STE analysis originally designed for the LV was used for RV assessment in our study. The results obtained apply only to the software used in our study and could not be generalized, considering that 3D STE parameters are restricted by the intervendor variability. Fifth, despite the fact that 3D STE has been validated for strain vectors of LVIn summary, our study it is the first to show that 3D RV strain imaging may have independent diagnostic and assessment value in patients with OSA. Moreover, 3D RV GLS is a reliable method of assessing the RV global function in OSA, because it correlates well with other established measurements of RV systolic function, like TAPSE, S′ wave and FAC. Furthermore, 3D RV GLS was shown to be a more reliable and accurate parameter in identifying severe cases of OSA, while NT pro BNP showed no association. The role of 3D STE in OSA patients, should be addressed by further prospective studies, as current data yield few studies. If such studies do demonstrate predictive value, 3D strain could eventually become a standard part of the RV echocardiographic exam, much like TAPSE and S’ wave are today.


Introduction: Cardioplegia is a pharmacological approach essential for the protection of the heart from ischemia–reperfusion (I–R) injury. Over the years, numerous cardioplegic solutions have been developed, with each cardioplegic approach having its advantages and disadvantages. Cardioplegic solutions can be divided into crystalloid and blood cardioplegic solutions, and an experienced surgeon chooses the type of solution based on the individual needs of patients in order to provide optimal heart protection. Importantly, the pediatric immature myocardium is structurally, physiologically, and metabolically different from the adult heart, and consequently its needs to achieve cardioplegic arrest strongly differ. Therefore, the present review aimed to provide a summary of the cardioplegic solutions available to pediatric patients with a special focus on emphasizing differences in heart injury after various cardioplegic solutions, the dosing strategies, and regimens. Material and methods: The PubMed database was searched using the terms cardioplegia, I–R, and pediatric population, and studies that investigated the influence of cardioplegic strategies on markers of cardiac muscle damage were further analyzed in this review. Conclusions: A large body of evidence suggested more prominent benefits achieved with blood compared to those with crystalloid cardioplegia in pediatric myocardium preservation. However, standardized and uniform protocols have not been established so far, and an experienced surgeon chooses the type of cardioplegia solution based on the individual needs of patients, while the severity of myocardial damage strongly depends on the type and duration of the surgical procedure, overall patient condition, and presence of comorbidities, etc. Cardiovascular disease (CVD) is a leading cause of death and disability globally, accounting for approximately 17.5 million deaths worldwide every year. The prevalence of CVDs is increasing with age in both genders, while on the other hand, the incidence of congenital heart diseases is reported as 7–9/1000 live births . Some CV2+ overload, and the accumulation of inflammatory cells . Th. Th11]. capacity . Despitecapacity .Even though myocardial protection is essential for successful cardiac surgery, the most effective choice for cardioplegia remains unknown, and the search for an ideal cardioplegic solution is ongoing. Therefore, the present review aims to summarize the effects of cardioplegic solutions on myocardial protection in order to provide a better understanding how cardioplegic strategies should be tailored to different ages and pathologies.In the late 19th century, scientists discovered that a high concentration of potassium could stop the heart in diastole, which could be used as an approach in open-heart surgery. However, refractory ventricular fibrillation following the procedure raised a concern and limited the concept of high-serum potassium cardiac arrest. In the early 1950s, doctor Melrose continued research in this field by formulating a potassium citrate solution since he hypothesized that cardiac complications previously described are derived from chloride ions but not from potassium. He noticed that high concentrations of potassium citrate, applied via infusion into coronary arteries, caused reversible cardiac arrest. The concentration of the applied potassium citrate solution was 77 mmol/L. The mechanism that can explain cardiac arrest involves depolarization of the myocardial membrane, i.e., the influx of calcium ions leads to contraction, while the release and sequestration of calcium causes heart arrest in the diastole phase . The mosThe end of 1960s and beginning of 1970s was associated with the return of a high-to-moderate potassium concentration solution as an attractive strategy in triggering cardioprotection. In fact, in 1975 St. Thomas’ Hospital (STH) solution was introduced by Hearse and Braimbridge in open-heart surgery in London. STH represents one of the widely used extracellular cardioplegic solution worldwide . Investi® and has been extensively applied as a cardioplegic strategy for myocardial protection [In 1970s, Bretschneider and his group formulated Histidine-Tryptophan-Ketoglutarate (HTK) solution as an intracellular crystalloid solution for administration in cardiac surgery. Moreover, this solution was introduced into clinical practice in 1977 and modified in the 1980s ,25. Althotection . In the + ions can enter across the small Na+ “window” current, thus causing an elevation in intracellular sodium ion levels, which promotes a reversal of the voltage-dependent Na+/Ca2+ exchanger. As a result, there is an exchange of three sodium ions for one calcium ion, thus enabling intracellular calcium overload. Due to ionic homeostasis alterations, cardiomyocyte contractility and excitability are disturbed, resulting in diastolic arrest. Nowadays, most cardioplegic solutions contain potassium at a concentration of more than 15 mM and represent the standard-of-care for cardioplegic arrest in open-heart surgery [It has been well known that intracellular potassium levels play a pivotal role in the maintenance of cardiovascular system homeostasis. Physiological potassium levels below 16 mM produce a resting membrane potential of approximately −85 mV, thus enabling the hyperpolarization of smooth muscles in blood vessels. Nevertheless, increasing potassium ion concentrations (16 mM–25 mM) elevate the resting membrane potential to a less negative value compared to baseline values, i.e., to approximately −80 mV to −50 Mv ,27. At t+-channel blockers, ATP-sensitive K+ (K-ATP) channel openers, calcium antagonists, and esmolol, etc. Na+-channel blockers, such as lidocaine, procaine, and tetrodotoxin (TTX), act by blocking the voltage-gated sodium fast channels, thus preventing the 0 phase, i.e., fast depolarization in the cardiac cycle. The activation of K-ATP channels by nicorandil, diazoxide, and adenosine during reduced blood and oxygen supply to the heart leads to a drop in the duration of action potential, thus minimizing the deleterious effects of ischemia on the myocardium. A drop in the duration of action potential might decrease the influx of Ca2+ via L-type channels and release it from sarcoplasmic reticulum, which strongly influences cardiac contractility [Although depolarized cardiac arrest as an approach has been widely used in cardiac surgery, the occurrence of myocardial stunning, arrhythmias, and inflammation, etc. have led researchers to look for a different strategy for providing myocardial protection. In that sense, hyperpolarization has been imposed as a subject of interest to scientists as a potentially promising alternative to depolarized cardioplegia . Hyperpoactility . ProtocoThe cardioplegic solution is applied to the coronary arteries and causes electromechanical cardiac arrest, which gives cardiac surgeons the opportunity to perform surgery in a bloodless field. The administration of cardioplegia can be anterograde, retrograde, or both. Anterograde cardioplegia involves an application that follows anatomical routes and regular coronary circulation through insertion in the proximal aorta. On the other hand, retrograde perfusion is performed by direct intubation of the coronary sinus, and it is indicated in patients with severe aortic regurgitation and severe coronary artery stenosis. Retrograde perfusion is suggested for patients with a hypertrophic myocardium and severe coronary heart disease because anterograde applications will not provide adequate myocardial perfusion ,32,33,34Cardioplegia can be performed with hot, cold, and intermediate lukewarm solutions. The most common application in clinical practice involves the application of cardioplegic solutions together with hypothermia, because lowering the temperature also reduces the energy needs of cells. The application of cold cardioplegia takes place for about twenty minutes in order to maintain the heart temperature in the range of 10–15 °C. It has been shown that in this way, the heart can be exposed to ischemia for about 4 h . HypotheContinuous cardioplegia possess certain advantages over multidose cardioplegia in the case of clogged blood vessels. Namely, continuous application better supplies the myocardium with a solution and largely removes harmful metabolites . HoweverOver the years, various cardioplegic solutions and methods have been developed, with each cardioplegic approach having its advantages and disadvantages. All of them should be used appropriately, taking into account the characteristics of myocardial injury and the duration of ischemia. The ideal cardioplegic solution should provide safe and permanent rest of the heart during the intervention, while reducing the change in electrolytes through the myocardial cell membrane. Cardioplegic solutions can be divided according to their composition into crystalloid and blood cardioplegic solutions. An experienced surgeon chooses a cardioplegic solution based on the individual needs of patients in order to provide optimal heart protection while reducing complications.+, Ca2+, and Mg2+, and intracellular, which contains low concentrations of Na+ and Ca2+  and the common addition of bicarbonate [Crystalloid solutions that have been most commonly used in pediatric surgery include STH and HTK (Custodiol) solutions. The detailed characteristics of each of these solutions are described below, but common to all crystalloid cardioplegic solutions is a Karbonate ,35,44.STH solutions. A solution that has been used in practice for the longest time is STH, which represents an extracellular crystalloid cardioplegia. Procaine is added to the solution in order to reduce the need for oxygen and improve heart recovery. In a previous study, the effect of adding procaine in increasing concentrations to the modified STH solution was assessed, and it has been shown that a concentration of 0.05 mmol/L leads to an improvement in myocardial recovery by 15–20%, which indicates its positive effect in cardiac surgery. If the concentration of procaine is increased slightly, no protective effect would be observed, while with a further increase, harmful effects could be observed .HTK (Custodiol). Also known as HTK (histidine–tryptophan–ketoglutarate) solution, it is an intracellular crystalloid solution that has been also used in cardiac surgery. Commercial Custodiol solution contains a low concentration of sodium for performing cardiac arrest in diastole by inhibiting the rapid phase of the action potential . This soCrystalloid cardioplegia was present until the early 1980s, after which the author Buckberg showed that the addition of blood as an agent for transmitting cardioplegia solutions could have numerous benefits. Buckberg et al. introduced the concept of applying blood solutions that have advantages over crystalloids ,49. NameDel Nido cardioplegia has been used worldwide for patients of all ages, from neonates to adults, and the content is presented in Despite numerous studies conducted in the pediatric population, it is still not possible to clearly identify the best and most effective protocol in all children. In the following text, there is a review of studies that investigated the effects of blood and crystalloid cardioplegia, as well as the influence of factors, such as age and cyanosis, in children on the extent of myocardial ischemic injury . StudiesThe undoubted advantages of crystalloid solutions involve the long-lasting effect of a single dose, easier application, and lower cost. Additionally, the standardization of crystalloid cardioplegia among different health care institutions is simpler compared to blood cardioplegia. In fact, the complexity of the standardization of blood cardioplegia is a consequence of a variety of available delivery techniques. Crystaloid solutions do not alter the visibility of the operative field as blood cardioplegia does, which is of a great significance since enabling a visible operative field is one of the most important facts for performing surgical maneuvers .In 1997, the first clinical trial was conducted with the focus on addressing the question of the effectiveness of blood cardioplegia compared to crystalloid solutions in a pediatric population. This research involved 138 pediatric patients and revealed that both types of cardioplegia solutions, applied with an antegrade hypothermic dosing strategy, improved the postoperative ventricular function. Interestingly, blood cardioplegia did not exert protective effects in cyanotic patients .In the early twenty-first century, information regarding cardioprotection in heart surgery was scarce since strategies proven in adults were implemented in pediatric surgery without enough investigation and adjustments to the needs of pediatric hearts. A study conducted during the beginning of 21st century focused on the influence of crystalloid cardioplegia but in different age groups. It included fifty-eight patients randomly divided into a group of infants and children over 12 months of age who were subjected to elective open heart surgery. It was discovered for the first time that factors, such as age and degree of cyanosis, influence metabolic alterations in ischemic–reperfusion conditions. This group of authors showed that crystalloid cardioplegia is associated with myocardial injury with different heart responses in reperfusion depending on the age and occurrence of cyanosis . CyanosiFurther research in this area, which focused on the differences in cold blood and cold crystalloid cardioplegia, was conducted by Caputo and his coworkers . Forty nTwo years later, Modi et al., in 2004, compared three different approaches, cold crystalloid, cold blood, and cold blood cardioplegia, during ischemia followed by a warm blood solution in reperfusion in children . One hunOne cohort study involved neonates and infants subjected to biventricular repair surgery. One group of children were receiving Plegisol, while others were managed with a mix of crystalloid cardioplegia and dilute blood . The cardiac index was determined and the postoperative period was monitored. Plegisol exerted better cardioprotective effects in neonates, while this advantage appeared to be less pronounced with age . A furthIn 2013, a group of researchers decided to investigate and compare for the first time repeated oxygenated warm blood cardioplegic solution and Custodiol in a population of 218 neonates . Until 22+ accumulation and consequently cell injury [Although DN cardioplegia was firstly introduced at 1990s, the first extensive study aimed at comparing its efficacy and safety with those of a standard cold blood cardioplegic solution was conducted in 2017. DN solutions are interesting due to their convenient application in a single dose that does not require interrupting the procedure for repeating the dose and prolonging aortic cross-clamp times as in case of STH solutions. This prospective randomized clinical trial strongly suggests the superior effects of del Nido cardioplegia compared to those of conventional cold blood cardioplegia (STH) manifested as long-acting effects, better impact on both cardiac function and structure, and a reduction in mortality . In accol injury ,71. Anotl injury . It may Evidence suggests that one dose of del Nido is sufficient for an aortic cross-clamp duration of over 90 min, while a longer period would require an additional dose. Previous research suggests shorter aortic cross-clamp times, as well as reduced or similar levels of markers of myocardial injury, after del Nido compared to those in blood cardioplegia pediatric patients ,73,74. AWhen the efficacy of STH and del Nido cardioplegia was assessed in a randomized controlled trial in a pediatric population, no difference in myocardial injury, i.e., the level of cTn-I, was revealed, while STH appeared to be more potent in reducing the myocardial inflammatory response to ischemia and improving metabolic status .Importantly, hemodilution as a complication following cardiopulmonary bypass leads to increased hospital stays and mortality rates. Therefore, it is important to choose the type of cardioplegic solution associated with a lower risk of hemodilution, such as blood compared to crystalloid cardioplegia ,78.In the majority of studies, blood cardioplegia exerted more beneficial effects in pediatric heart preservation compared to crystalloid; nevertheless, it is important to note that the degree of myocardial injury is also strongly affected by the type and duration of the surgical maneuver, overall patient condition, and existence of comorbidities, etc. Hypothermic cardioplegia has been proposed as a strategy that provides the greatest protection for cardiomyocytes during ischemia. Moreover, intraoperative hematocrit changes during open heart surgery represent an important issue to be considered, and blood cardioplegia appears to have an advantage over crystalloid solutions since it is associated with higher hematocrit levels and a reduced risk for postoperative organ failure due to hemodilution. The uniform recommendations among health institutions worldwide do not exist, and so far, the most important determinants for the choice of the myocardial protection method are the clinical results and the surgeons’ experiences. Additionally, the method should be effective, simple, and economically acceptable. An experienced surgeon chooses a cardioplegic solution based on the individual needs of patients in order to provide optimal heart protection while reducing complications.


Right ventricular (RV) and pulmonary vascular dysfunction appear to be common in sepsis. RV performance is frequently assessed in isolation, yet its close relationship to afterload means combined analysis with right ventricular outflow tract (RVOT) Doppler and RV–pulmonary arterial (RV–PA) coupling may be more informative than standard assessment techniques. Data on feasibility and utility of these parameters in sepsis are lacking and were explored in this study.This is a retrospective study over a 3-year period of one-hundred and thirty-one patients admitted to ICU with sepsis who underwent transthoracic echocardiography (TTE) with RVOT pulsed wave Doppler. RVOT Doppler flow and RV–PA coupling was evaluated alongside standard measurements of RV systolic function and pulmonary pressures. RVOT Doppler analysis included assessment of pulmonary artery acceleration time (PAAT), velocity time integral and presence of notching. RV–PA coupling was assessed using tricuspid annular planar systolic excursion/pulmonary artery systolic pressure (TAPSE/PASP) ratio.PAAT was measurable in 106 (81%) patients, and TAPSE/PASP was measurable in 77 (73%). Seventy-three (69%) patients had a PAAT of ≤ 100 ms suggesting raised pulmonary vascular resistance (PVR) is common. RVOT flow notching occurred in 15 (14%) of patients. TRV was unable to be assessed in 24 (23%) patients where measurement of PAAT was possible. RV dysfunction (RVD) was present in 28 (26%), 26 (25%) and 36 (34%) patients if subjective assessment, TAPSE < 17 mm and RV dilatation definitions were used, respectively. There was a trend towards shorter PAAT with increasing severity of RVD. RV–PA uncoupling defined as a TAPSE/PASP < 0.31 mm/mmHg was present in 15 (19%) patients. As RV dilatation increased the RV–PA coupling ratio decreased independent of LV systolic function, whereas TAPSE appeared to be more susceptible to changes in LV systolic function.Raised PVR and RV–PA uncoupling is seen in a significant proportion of patients with sepsis. Non-invasive assessment with TTE is feasible. The role of these parameters in assisting improved definitions of RVD, as well as their therapeutic and prognostic utility against standard parameters, deserves further investigation.The online version contains supplementary material available at 10.1186/s13054-022-04160-4. Increased pulmonary vascular resistance and RA-PA uncoupling is present in a significant subset of patients with sepsis, and measurement with TTE is feasible.Measurement of PAAT and RV-PA uncoupling could aid in improving definitions of right ventricular dysfunction.The therapeutic and prognostic role of these parameters in sepsis remains unknown, and further prospective studies are warranted.The online version contains supplementary material available at 10.1186/s13054-022-04160-4. RVD is common in sepsis and seems to be associated with increased mortality , 2. PatiThe objective of this exploratory study was to generate hypothesis for future prospective study in this area. We assessed RVOT Doppler waveform analysis and RV–PA coupling ratios and explored these parameters in relation to RV function, RV dilatation and pulmonary pressures.This is a single-centre, retrospective analysis of RVOT systolic flow profiles recorded by pulsed wave Doppler (PWD) in all patients (> 18 years) admitted with a primary diagnosis of sepsis who had a transthoracic echocardiogram (TTE) performed in ICU. Of 455 patients who were admitted to our unit with sepsis during July 2018–April 2021, 131 patients had a full transthoracic echo (TTE) study by cardiac sonographers that included PWD of the RVOT. Of those, 106 were sufficient for analysis. Those with congenital heart disease or known intracardiac shunts were excluded.Echo and clinical data were obtained from local intensive care echocardiography and clinical system databases, respectively. Measurement of PAAT, presence of 'notching’, RVOT ejection time (ET) and RVOT velocity time integral (VTI) were performed using an offline software analysis package by intensive care specialists with advanced echo qualification  Fig. .Fig. 1RVAn average measurement of PAAT was taken from 3  consecutive RVOT Doppler profiles. PAAT corrected for heart rate (PAATc) was calculated using the formula PAAT × 75/HR . BlindedRVOT Doppler profiles were categorised as No notch (NN) and Notched (N) Fig. . The notTAPSE/PASP was used as non-invasive measure of RV- PA coupling. A ratio of < 0.31 mm/mm Hg was used as the cut-off to define RV–PA uncoupling based on previously published data .2) + RAP (estimated to be 10 mmHg) . Further data are provided in Additional file There was a lower admission pH in those with RVD defined by TAPSE < 17 mm  as compared to other definitions of RVD. The correlation between TAPSE/PASP and PAAT was moderate but significant .RV–PA coupling was measurable in 77 (73%) of patients. RV–PA uncoupling, defined by a TAPSE/PASP ratio of < 0.31 mm/mmHg, was present in 15 patients (19%). PAAT was significantly lower in those with RV–PA uncoupling: 74 (14) vs. 92(20) ms, p < 0.001) and TAPSE/PASP ratio (0.34(0.23) vs. 0.52(0.22), p < 0.001), respectively. In patients with RV–PA uncoupling, the odds ratios for RV dilatation and RVD by subjective assessment were  and , respectively. Those with RV–PA uncoupling had lower RVOT VTI values as shown in Fig. Comparison of RV–PA coupling ratios to traditional assessments of RVD revealed significantly lower RV–PA coupling ratios in those with RVD by subjective assessment and RV dilatation: TAPSE/PASP ratio (0.29 (0.16) vs. 0.53(0.21), Figure 2 . PASP was significantly higher in those with RVOT Doppler notching .Pulmonary hypertension (PH), defined as PASP ≥ 35 mmHg, was present in 56 (68%). A TRV of > 2.8 m/s was present in 37 (45%) and a TRV of > 3.4 m/s was present in 10 (12%). A moderate but significant inverse correlation was found between PAAT or PAATc and 4xTRVp = 0.4 and p = 0.12, respectively). There was no significant difference in PASP in those with RVD by TAPSE < 17 mms (p = 0.7).Severity subgroups of PH were as follows: mild (35–49 mmHg) in 37 (35%), moderate (50–70 mmHg) in 15 (14%) and severe (> 70 mmHg) in 3 (2.8%). Analysis of variance between RVD subjective severity and RV dilatation subgroups revealed no significant difference in PASP values (p = 0.003) and normal to severe PH (p = 0.05).As expected, there was a significantly shorter PAAT with increasing severity of PH by subgroup analysis of variance (p 0.03). Post hoc pairwise comparison revealed a significant difference between those with normal to mild (p = 0.2). TAPSE was significantly lower in those with reduced LV systolic function . There was no significant difference in RV–PA uncoupling in those with reduced LV systolic function .Left ventricular systolic function was decreased in 29 (27%) patients defined by an ejection fraction (EF) of < 50%. 11 (10%) had combined reduced LVEF and RVD by subjective assessment. PAAT was not significantly different in those with normal or reduced EF . Hospital mortality was significantly higher in those with PAAT ≤ 100 ms . In those with TAPSE/PASP < 0.31 mm/mmHg, there was a trend towards increased ICU and hospital mortality that was not statistically significant .There was a trend towards increased ICU mortality in those with PAAT ≤ 100 ms that was not statistically significant .ICU and hospital mortality odds ratios were not significant for TAPSE < 17 mm, subjective RVD or RV dilatation: /end-systolic to arterial elastances (Ea) using right heart catheterisation (RHC) are considered gold standard but are impractical at the bedside. Animal studies have shown that with increasing severity of septic shock the initial preservation of RV–PA coupling is lost and progression to uncoupling occurs . TAPSE pIn our study, we found that those with RV- PA uncoupling  between TTE measured PAAT and 4xTRV2 in the non-critically ill. In contrast, a moderate inverse correlation was found in our study. These conflicting results may be accounted for by the vastly different patient populations studied. Critically ill patients have varying degrees of RVD, tricuspid regurgitation severity and often inadequate spectral Doppler traces, all of which may affect values of TRV for calculation of PASP.TRV to estimate pulmonary pressures was unavailable in 24 (23%) patients where RVOT Doppler flow measurement of PAAT was available. This is an important finding as we know that a significant proportion of patients with pulmonary vascular dysfunction will be missed if pulmonary pressures derived from TRV are relied upon in isolation , 32. It In the presence of increased PVR, reflected waves propagate more rapidly, with less attenuation, arriving at the RVOT during systole and causing systolic notching Fig. . SystoliThere are several limitations in this present study that are inherent to its retrospective, single-centre design. As such, conclusions drawn can be hypothesis generating only. Small numbers and lack of multivariate analysis means conclusion about survival and echo parameters is limited.2 and Pa02/Fi02 ratio, were not known at the time of echo and may have influenced values obtained. The evaluation of RVD by subjective assessment in a single-centre introduces bias. However, subjective assessment of size and function are commonly practiced at the bedside and therefore it is a pragmatic parameter to evaluate. In addition, the finding of significantly lower RVOT VTI as subjective RVD severity increased offers some reassurance that qualitative assessment correlated with semi-quantitative measurement techniques. The relatively small number of patients with moderate to severe RVD limits generalisability of the findings. Importantly, our data do not allow RVD induced or worsened by respiratory failure to be distinguished from direct effects of sepsis or pre-existing RVD.The small number of patients limited the utility of multivariate analysis and exploration of cut-off values for RV–PA coupling and PAAT by receiver operating curve analysis. Only those who had a TTE were included introducing possible selection bias. The type and dose of haemodynamic support and loading conditions at the time of TTE were not known. Given many of the echo parameters assessed are load dependent, interpretation and generalisability of the findings are limited. The ventilator settings and gas exchange, in particular driving pressure, plateau pressure, PEEP, PaC0It was not known if the RVOT PWD was taken during expiration or inspiration and respiratory variation can significantly alter values obtained. Though it is suggested that taking an average of 3- 4 consecutive cycles, as was done in this study, is a reasonable method to mitigate the effects of respiratory variation . ChronicA short PAAT suggestive of raised PVR is found in a high proportion of patients with sepsis. A significant proportion of patients with sepsis have RV–PA uncoupling. Shorter PAAT and lower RV–PA coupling ratios seem to be associated with increasing severity of RVD; however, much remains unknown about their therapeutic and prognostic role above standard parameters. Categorising patients with sepsis-related RVD into those with and without raised PVR and RV–PA uncoupling could provide incremental information to help differentiate ‘RVD phenotypes’ and enable more precise definitions in future prospective study design.Additional file 1. Table of baseline characteristics of ICU survivors and nonsurvivors.Additional file 2. Table and descriptive plots of echo parameters and P/F ratios.Additional file 3. Table of echo and biochemical data in those who received mechanical ventilation.Additional file 4. Table and descriptive plots of RV function and blood gas parameters on ICU admission.


Severe pulmonary arterial hypertension (PAH) is a contraindication for heart transplantation (HT). It has been correlated with increased early and late mortality, mainly associated with right ventricular failure. Ventricular assistance devices (VADs) can promote reduction of intracardiac pressures and consequent reduction of PAH over the medium and long terms, thus enabling future candidature for HT. The diminution of early pulmonary pressure within this scenario remains unclear.To evaluate the reduction of PAH and correlate data from right catheterization with the earliness of this reduction.Cross-sectional study in a general hospital in São Paulo, Brazil.This was a retrospective analysis on the medical records of patients undergoing VAD implantation in a single hospital. Patients for whom VAD had been indicated as a bridge to candidature for HT due to their condition of constant PAH were selected.Four patients with VADs had constantly severe PAH. Their mean pulmonary artery systolic pressure (PASP) before VAD implantation was 66 mmHg. Over the 30-day period after the procedure, all the patients evolved with a drop in PASP to below 60 mmHg. Their new average was 36 mmHg, which was a drop of close to 50% from baseline values. The one-year survival of this sample was 100%.VAD implantation can reduce PAH levels. Early reduction occurred in all patients. Thus, use of VAD is an important bridge tool for enabling candidature for HT among patients with constantly severe PAH. VADs can be used as a bridge to transplantation or as the destination therapy.2Despite advances in the therapeutic arsenal for treating heart failure, comprising lifestyle changes, pharmacological therapy and cardiac stimulation devices, a considerable portion of the population progresses to refractoriness. In such situations, more advanced treatments such as heart transplantation or use of a ventricular assistance device (VAD) need to be considered. Heart transplantation remains the therapy of choice and provides greater life expectancy for patients with advanced heart failure.3 In this context, it has been observed, after VAD implantation, that patients with contraindications for heart transplantation due to pulmonary arterial hypertension presented decompression of the left cardiac cavities and reverse remodeling of the pulmonary vessels, with reversal of PAH. This gave rise to the possibility of candidature for heart transplantation. Data in the current literature show that this change occurs over the first three to six months after VAD implantation,1 with some reports of earlier reduction.Constant pulmonary arterial hypertension (PAH) is one of the main contraindications for heart transplantation.The objectives of the present study were to evaluate the reduction of PAH and correlate data from right catheterization with the earliness of this reduction.12This was a retrospective evaluation on patients with advanced heart failure who underwent VAD implantation between 2013 and 2019, through data collection from the electronic medical records. Patients for whom VAD had been indicated as a bridge to candidature for heart transplantation due to their condition of constant PAH were selected. Constantly severe PAH was defined as pulmonary artery systolic pressure (PASP) > 60 mmHg or pulmonary vascular resistance (PVR) > 3.0 Woods units, after a vasodilation test during right catheterization.The outcomes analyzed were the reduction of pulmonary artery pressures within 30 days of VAD implantation, analyzed by means of transthoracic echocardiogram, and one-year survival. This present study was approved by our institution's ethics committee on July 13, 2020 .Out of the total of 23 patients who received VAD during the period from 2013 to 2019, four had had an indication for VAD implantation due to constantly severe PAH, as a bridge to candidature for heart transplantation. The devices implanted were Heart Mate II and Heart Mate III, with half of the sample in each group. The patients’ clinical characteristics are demonstrated in Over the 30-day period after the procedure, all the patients evolved with a fall in PASP to below 60 mmHg, with an average value of 36 mmHg ± 10 mmHg . One of This is the first Brazilian report on early effective reduction of constant PAH through long-term VAD use. This case series showed an average reduction of PASP over 30 days, from 65 mmHg ± 4 mmHg to 36 mmHg ± 10 mmHg (P = 0.256). The results show that decompression of the left ventricle by the VAD acted to reduce the pressure of left ventricle filling and that, retrogradely though the principle of communicating vessels, it acted to reduce pulmonary pressure, which is a determining factor for eligibility for heart transplantation.4 High levels of pre-transplantation pulmonary pressure, resistance and gradient have been correlated with increased post- heart transplantation mortality rates. These are therefore considered to be contraindications for this procedure, given the high risk of failure of the right ventricle of the graft.Pulmonary hemodynamic evaluation remains an essential examination for inclusion of patients in the heart transplantation waiting list, through enabling evaluation of the degree of pulmonary hypertension and its reversibility with vasodilators. The main data obtained from this evaluation are the PASP, mean pulmonary artery pressure (mPAP), pulmonary artery occlusion pressure (PAOP) or pulmonary capillary pressure (PCP), transpulmonary gradient (TPG) and PVR.6 It is now known to also be efficacious with continuous flow devices.9 Zimpfer et al. demonstrated, in a cohort of 35 patients with a six-week follow-up, that there was a drop in mPAP levels by about 18 mmHg,4 which is compatible with the results demonstrated in our study. In another cohort of 50 patients, Ranjit et al found that there was a reduction in mean PASP of 20 mmHg, in an evaluation conducted three months after implantation of the device.10 These results allow us to infer that the reduction in PASP occurs mainly in the first 30 days and is maintained over the passage of the months.Use of VAD as a tool capable of reducing PAH was first demonstrated in pulsatile flow devices.We noticed that results similar to those described here had been found earlier, i.e. with favorable results within less than the 30-day period of our analysis, even without use of drugs to aid in this process, such as phosphodiesterase-5 inhibitors.The main limitation that impeded provision of additional data from this observational study was the absence of pulmonary hemodynamic evaluation by means of a pulmonary artery catheter after VAD implantation. Evaluation of PASP was performed by means of echocardiography. However, the data obtained from this cohort of patients in Brazil allowed us to confirm the findings from studies conducted elsewhere in the world, thus emphasizing the importance of VAD devices as a bridge to candidature for heart transplantation, among patients for whom this is initially contraindicated due to constant PAH.Considering that all patients who underwent VAD implantation achieved early reduction of pulmonary pressures, thus enabling candidature for heart transplantation, this study opens up the possibility of new approaches with protocols for use of VAD as a bridge for candidature among patients with constant PAH, such that these patients can subsequently be offered heart transplantation.


The coexistence of diabetes mellitus (DM) and heart failure (HF) is frequent and is associated with a higher risk of hospitalization for HF and all-cause and cardiovascular mortality. It has been estimated that millions of people are affected by HF and DM, and the prevalence of both conditions has increased over time. Concomitant HF and diabetes confer a worse prognosis than each alone; therefore, managing DM care is critical for preventing HF. This article reviews the prevalence of HF and diabetes and the correlated prognosis as well as provides a basic understanding of diabetic cardiomyopathy, including its pathophysiology, focusing on the relationship between DM and HF with a preserved ejection fraction and summarizes the potential aldosterone and the mineralocorticoid receptor antagonists approaches for managing heart failure and DM. Sodium–glucose cotransporter 2 inhibitors (SGLT2Is) are an emerging class of glucose-lowering drugs, and the role of SGLT2Is in DM patients with HF was reviewed to establish updated and comprehensive concepts for improving optimal medical care in clinical practice. Currently, heart failure (HF) affects at least 26 million people worldwide and is increasing in prevalence . SimilarThis article reviews the prevalence of HF and DM and their correlation with prognosis. This review also provides emergency and intensive care service providers with a basic understanding of diabetic cardiomyopathy, including its pathophysiology, with a focus on the relationship of DM and HF with preserved ejection fraction (HFpEF). The role of sodium–glucose cotransporter 2 inhibitors in diabetic patients with HF is also reviewed to establish updated and comprehensive concepts for the improvement of optimal medical care in clinical practice.The prevalence of DM among patients with HF with reduced ejection fraction (HFrEF) ranged from 10 to 30% . HF, espA prospective cohort study described the relatively low prevalence (3.7%) and incidence (0.02% per year) of HF and predominant diastolic HF in patients with type 1 DM, specifically those with concurrent hypertension or coronary artery disease. The relatively young study population and common use of intensive insulin therapy and concomitant statin and aspirin treatment might have contributed to the difference between the study’s prevalence and incidence and those reported for patients with type 2 DM . In addiWith regard to prognosis, patients with concomitant DM and HF have higher mortality rates than those without DM or HF ,13. A prAlthough HF with systolic dysfunction is commonly mentioned in clinical trials, HFpEF has raised increasing attention recently. Observation studies have demonstrated that diastolic dysfunction is prevalent in types 1 and 2 DM ,17. LeftWith regard to prognosis, DM exerts a negative prognostic effect on patients with HFpEF. Specifically, patients with HFpEF and DM face a higher risk for HHF and cardiovascular death than those suffering from HFpEF without DM ,22,26. MThe symptoms of diastolic dysfunction in patients with DM are often nonspecific and thus hamper early detection. Holland et al. described echocardiography as a useful tool to uncover potential diastolic dysfunction in DM. Increased E/eʹ during stress provides early information and prognosis value in the early stage of diastolic dysfunction . Over tiDM-associated HF is a complex entity involving multiple factors. DM is a documented and strong risk factor for coronary artery disease with consequent ischemic heart disease. Ischemic events are common in the diabetic population, and they mainly contribute to HF development. Meanwhile, diabetic cardiomyopathy is a unique HF subtype in the absence of cardiac ischemia or other well-established risk factors, such as hypertension. The structural and functional dysfunctions of diabetic cardiomyopathy primarily result from the insulin resistance of diabetic myocardium and consequent hyperinsulinemia. Moreover, hyperinsulinemia can induce inappropriate activation of the systemic and cardiac tissue renin–angiotensin–aldosterone system; although a state of salt and volume excess contributes to the development of diabetic cardiomyopathy. Although no clear definition describes diabetic cardiomyopathy, it currently has two different subtypes: hypertrophic dominant with preserved ejection fraction and dilative dominant with reduced ejection fraction .Myocardial hypertrophy is a common finding in diabetic hearts and a result of oxidative stress, inflammation, and upregulation of the renin–angiotensin and endothelia systems, leading to cardiac stiffness. The extent of myocardial hypertrophy correlated with glycemic control . SystoliGlucose metabolism plays a crucial role in the development of myocardial dysfunction. Advanced glycation end products (AGEs) are glycated after exposure to hyperglycaemia, and are produced from non-enzymatic glycosylation of lipids, lipoproteins and amino acids. AGEs cause increased myocardial stiffness through the formation of crosslinks in collagens and laminins, subsequently increasing fibrosis and thereby reducing cardiac compliance and LV diastolic dysfunction ,34. In aThe other glucose metabolism product, β-N-acetylglucosamine (O-GlcNAc), results in diabetic myocardium dysfunction through the modification of the Ca2þ/calmodulin-dependent protein kinase II, phospholamban, and myofilaments; these factors negatively affect cardiac systolic and diastolic function. In addition, O-GlcNAc can bind to mitochondrial proteins, impair mitochondrial function, and subsequently increase the production of ROS, which promotes inflammation and fibrosis ,37.Apart from glucose metabolism, several mechanisms have been identified to contribute to myocardial fibrosis, cardiomyocyte injury, and remodeling in DM, such as the activation of the renin–angiotensin–aldosterone system and sympathetic activity, altered myocardial insulin signaling, mitochondrial dysfunction, gene dysregulation of microRNAs and transcription factors, epigenetic modifications, oxidative stress, and endoplasmic reticulum stress . LipotoxThere has been a dramatic increase in knowledge about the role of aldosterone and mineralocorticoid receptor (MR) antagonists (MRAs) in the pathophysiology of cardiovascular diseases in recent years . The MR Four SGLT2is  are approved by the European Medicines Agency and the US Food and Drug Administration on the basis of large-scale randomized controlled trials (RCTs) and documented cardiovascular benefits. The cardiovascular benefits of SGLT2is are beyond glycemic control. Several mechanisms contribute to the cardioprotective effect of SGLT2is, and they include the reduction in preload and afterload secondary to natriuresis and a decrease in blood pressure, ketone body-based myocardial metabolism, and improvement of myocardial remodeling . SelecteSubstantial RCTs have also established the cardioprotective role of SGLT2is. In particular, the EMPA-REG OUTCOME (empagliflozin), CANVAS (canagliflozin), DECLARE-TIMI 58 (dapagliflozin), and VERTIS-CV (ertugliflozin) trials showed a significant reduction in HFH among patients with diabetes treated with SGLT2is ,49,50,51Data from clinical practice are consistent with large-scale RCTs. The CVD-Real , OBSERVEAdditionally, the Canagliflozin and Renal Events in Diabetes and Established Nephropathy Clinical Evaluation (CREDENCE) trial  and the dapagliflozin in patients with chronic kidney disease (DAPA-CKD) trial  also showed an impressive reduction in the risk of HHF.Several studies have investigated the impact of SGLT2is in diabetic patients with HF stratified by reduced or preserved ejection fraction. The DAPA-HF trial  demonstrp = 0.027) with SGLT2i use. In addition, this pooled meta-analysis suggested that the use of SGLT2is among diabetic patients reduces the risk of cardiovascular death or HHF regardless of the use of angiotensin receptor–neprilysin inhibitors (ARNIs). Patients treated with SGLT2is and ARNIs should be given urgent attention because of the risk of hypotension and renal function impairment.A prespecified meta-analysis of the DAPA-HF and EMPEROR-Reduced trials  aimed toA subanalysis study of the DECLARE-TIMI 58 trial identified cardiovascular benefits among subjects with reduced ejection fraction, those with HF without known reduced ejection fraction, and those without a history of HF. The study showed a greater risk reduction in cardiovascular death and all-cause mortality among patients of HFrEF treated with dapagliflozin in comparison with those in the other two groups. Patients of HF with or without reduced ejection fraction consistently have outcome benefits in terms of HHF . The DEFTwo post hoc analysis studies aimed to assess the efficacy of SGLT2is in diabetic patients with HFpEF. The subgroup analysis of the CANVAS program  failed tGiven the substantial evidence from large-scale RCTs and real-world results, SGLT2is is deemed a valuable therapy for the treatment of and reduction in HHF risk among patients with diabetes with underlying HF history. SGLT2is also decreases the risk of HHF or cardiovascular death among patients with HFrEF and those with or without diabetes. In 2020, the American Diabetes Association suggested that SGLT2is are preferred over glucagon-like peptide 1 receptor agonists as a second-line option added to metformin for patients with diabetes with HF history . The 202Given the bidirectional relationship between diabetes and HF and their prognostic implications, emergency service providers should be aware of diabetes-associated HF or the possibility of diabetic cardiomyopathy. At present, the pathophysiology and definition of diabetic cardiomyopathy remain unclear. As recent clinical trial data support the use of SGLT2is in a broad spectrum of HF entities and a comprehensive understanding of the role of SGLT2is in diabetic patients with HF based on cardiovascular outcome trials should help emergency and intensive care service providers identify the best choices for the optimal care of these patients in the future.