We aimed to perform a systematic review and meta-analysis of the association between obstructive sleep apnea (OSA) and cardiac as well as coronary impairment evaluated using imaging modalities. Finding of this study will provide more robust evidence regarding OSA-induced cardiovascular damage.We systematically searched through PubMed, EMBASE, and Cochrane library databases for relevant literatures on the association between OSA and cardiovascular damage evaluated using imaging modalities, and manually searched the references of selected articles for additional relevant articles. For each clinical parameter relevant to the meta-analysis, we first evaluated the methodological heterogeneity of the relevant studies and thereafter pooled the data together using fixed effect or random effect model. The difference in the relevant indices of cardiovascular damage between OSA patients and controls was evaluated using the standardized mean difference.n = 62) evaluated cardiac alterations in OSA patients. According to the inclusion and exclusion criteria, 46 studies yielding 3082 OSA patients and 1774 controls were pooled for the meta-analysis. For left cardiac structure and function, OSA patients exhibited significantly wider left atrial diameter; higher left atrium volume index; wider left ventricular end-systolic diameter, left ventricular end-diastolic diameter, and left ventricular mass; higher left ventricular mass index; wider interventricular septum diameter and posterior wall diameter; and higher left ventricular myocardial performance index . In addition, compared with controls, left ventricular ejection fraction was significantly decreased in OSA patients (p = 0.001). For right cardiac structure and function, OSA patients displayed a significant increase in right ventricular diameter and right ventricular myocardial performance index (both p < 0.001). Finally, compared with controls, OSA patients displayed significant decrease in tricuspid annular plane systolic excursion and RV fractional area change (p = 0.001).Of the 82 articles included in the final systematic analysis, 20 studies explored the association between OSA and coronary atherosclerosis. OSA patients had higher rate of coronary atherosclerosis assessed by coronary artery calcification score and plaque volume. Moreover, the severity of OSA and coronary atherosclerosis displayed a positive correlation. The rest of the studies (Overall, this systematic review and meta-analysis provides imaging evidence in support that OSA patients are at a higher risk of developing coronary atherosclerosis and display cardiac remodeling and dysfunction.The online version contains supplementary material available at 10.1186/s13643-021-01759-6. Obstructive sleep apnea (OSA) is a common disorder that affects nearly 1 billion adults worldwide . SubstanCardiac imaging modalities can provide accurate assessment for coronary atherosclerosis and cardiac abnormalities. Early identification and evaluation of cardiovascular alterations in OSA patients may impact the risk stratification. Currently, evidence from the perspective of imaging is accumulating for exploring the relationship between OSA and cardiovascular damage –10. ThesThis study was conducted in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines .We systematically searched through PubMed, EMBASE, and Cochrane library databases for relevant literatures on the association between OSA and cardiovascular damage evaluated by imaging modalities. Only articles written in English and published between January 1st, 2005, and June 30th, 2020 were considered. The following terms were used to search eligible articles: “sleep apnea, obstructive”, “sleep-disordered breathing”, “coronary atherosclerosis”, “coronary artery calcification”, “coronary artery calcium”, “coronary plaque”, “cardiac remodeling”, “ventricular function, left”, “ventricular dysfunction, left”, “left ventricular hypertrophy”, “ventricular function, right”, “ventricular dysfunction, right”, “computed tomography”, computed tomographic angiography”, “intravascular ultrasound”, “optical frequency domain imaging”, “echocardiography”, and “cardiac magnetic resonance imaging”. In addition, we manually searched the references of the selected studies to find other potential sources. An example of search strategy is provided in Two investigators (Mi Lu and Zhenjia Wang) independently reviewed the titles and abstracts to identify relevant articles. A further screening was based on full-text articles to see whether they were eligible for inclusion. Any disagreement was resolved by discussion.The inclusion criteria were as follows: (1) enrolled participants were adults; (2) all participants underwent polysomnography (PSG) or portable sleep monitoring; (3) English-language articles. In addition, articles that conducted meta-analysis must also meet the following criteria: (1) the study must include at least two separate groups, OSA group and non-OSA group; (2) non-OSA was defined as apnea hypopnea index (AHI) < 5; (3) the study must have reported values of the corresponding parameters in mean with standard deviation or median with range. The exclusion criteria were as follows: (1) duplicate reports; (2) reviews, case reports, or animal experiments; (3) patients with other sleep disorders, such as central sleep apnea, obesity hypoventilation syndrome, and periodic limb movement disorder; (4) patients who received or are receiving OSA treatment; (5) participants with major comorbidities, such as structural heart disease, cardiomyopathy, pulmonary hypertension, and chronic obstructive pulmonary disease.The search and retrieval of relevant articles was performed independently by two researchers (Mi Lu and Zhenjia Wang). For each included study, details of the first author, year of publication, country, sample size, participants’ age, gender, body mass index (BMI), mean AHI, OSA diagnostic method and criteria, history of hypertension, diabetes, hyperlipidemia, etc. were extracted. For articles included in meta-analysis, parameters reflecting cardiac morphology and function were also extracted. Any disagreements were resolved by consensus.The Newcastle–Ottawa Scale (NOS) was used to assess the quality of included studies due to their case–control study design. The studies were assessed for the following criteria: selection , comparability , and exposure . The quality score ranges from 0 to 9.I2 and chi-square tests, where I2 > 50% and a chi-square p < 0.05 indicated significant heterogeneity between studies. In such cases, the random effects model was used to generate pooled effects. By contrast, the fixed-effects model was instead used when there was an acceptable heterogeneity. We conducted subgroup analyses based on the age of 50 years and BMI of 30 kg/m2 when significant heterogeneity existed. Sensitivity analyses were conducted to test the robustness of the overall results using the leave-one-out method. Publication bias was assessed using a funnel plot. We used Egger tests to assess the asymmetry of the funnel plot. The trim-and-fill computation was used to estimate the effect of publication bias on the interpretation of the results. All analyses were performed using Stata/SE version 14.0 . Statistical significance was set at p < 0.05.A meta-analysis will be carried out if included studies are sufficiently homogeneous. Standardized mean difference (SMD) with 95% confidence intervals (CI) will be used to determine the difference in the relevant indices of cardiovascular damage between OSA patients and controls. Some studies stratified patients according to OSA severity  and thus reported the corresponding data within each stratum. Two formulae were used to combine subgroups and calculate the overall means and standard deviations see . HeterogFinally, the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system was used to assess the quality of evidence for each outcome presented in the systematic review . We recoThe literature search yielded 366 citations. After removing duplicates, screening titles and abstracts, and reading the full text, only 82 articles were included in the final systematic review Fig. . Of thesIn this review, twelve articles evaluated the association between OSA and CAC score. The characteristics of the articles are shown in Table n = 4) and non-invasive (n = 5) imaging modalities. The characteristics of the studies are summarized in Table A total of 9 studies explored the relationship between OSA and coronary plaque characteristics by using invasive , with non-significant heterogeneity. No significant publication bias (p = 0.757) was found among the studies. Differences in LAVI were reported in 6 studies involving 238 OSA patients and 163 controls. This meta-analysis found that LAVI in OSA patients was significantly higher than that in controls , with statistically significant heterogeneity. The subgroup analysis indicated that heterogeneity in OSA patients with age ≥ 50 years or BMI < 30 kg/m2 was significantly decreased. In this analysis, there was publication bias on Egger test (p = 0.036).The parameters of left atrial diameter (LAD) and left atrium volume index (LAVI) were used to assess LA remodeling. The relationship between OSA and LAD was reported in 13 studies involving 1107 OSA patients and 317 controls. This meta-analysis revealed that compared to controls, OSA patients displayed significantly wider LAD , with non-significant heterogeneity. No significant publication bias (p = 0.646) was found among the studies. LVEDD was assessed in 18 studies involving 918 OSA patients and 406 controls. This meta-analysis found that compared to controls, OSA patients displayed significantly wider LVEDD , with non-significant heterogeneity. No significant publication bias was found among the studies (p = 0.638). Differences in LVM were reported in 7 studies involving 708 OSA patients and 612 controls. Our analysis revealed that compared to controls, LVM was substantially higher in OSA patients , with statistically significant heterogeneity. Further subgroup analysis showed that heterogeneity in OSA patients with age < 50 years or BMI < 30 kg/m2 was significantly decreased. No significant publication bias was found among the studies (p = 0.807). Differences in LVMI were reported in 23 studies involving 1515 OSA patients and 641 controls. Compared to controls, OSA patients exhibited significantly higher LVMI , with statistically significant heterogeneity. No significant publication bias was found among the studies (p = 0.562). Differences in IVSD were reported in 24 studies involving 1375 OSA patients and 808 controls. We found that compared with controls, OSA patients have significantly wider IVSD , with statistically significant heterogeneity. And Egger test revealed a significant publication bias among the studies (p = 0.021). Differences in PWD were reported in 22 studies involving 1348 OSA patients and 1047 controls. The meta-analysis showed that OSA patients exhibited significantly wider PWD than that in controls , with statistically significant heterogeneity. No significant publication bias was found among the studies (p = 0.087). There was no apparent change in the heterogeneity of LVMI, IVSD, and PWD when the subgroups were performed using the age of 50 years or the BMI of 30 kg/m2 as the threshold.LV remodeling was assessed based on left ventricular (LV) end-systolic diameter (LVESD), LV end-diastolic diameter (LVEDD), LV mass (LVM), LV mass index (LVMI), interventricular septum diameter (IVSD), and posterior wall diameter (PWD). Differences in LVESD were reported in 24 studies involving 1526 OSA patients and 620 controls. This meta-analysis found that compared to controls, the OSA patients had significantly wider LVESD , with statistically significant heterogeneity. There was non-significant publication bias (p = 0.465). Differences in LV MPI were reported in 8 studies involving 512 OSA patients and 385 controls. This meta-analysis found that compared to controls, OSA patients displayed significantly higher LV MPI  with statistically significant heterogeneity. Non-significant publication bias was found among these studies (p = 0.915). Additionally, there was no apparent change in the heterogeneity of LVEF and LV MPI when subgroup analyses were performed using the age of 50 years or the BMI of 30 kg/m2 as the threshold.LV dysfunction was diagnosed based on LV ejection fraction (LVEF) and LV myocardial performance index (LV MPI). Differences in LVEF were reported in 39 studies involving 2552 OSA patients and 1737 controls. This meta-analysis found that compared with controls, LVEF was significantly lower in OSA patients  was used in three studies to assess the RA remodeling. Of these, only Sun et al.  found thp < 0.001), with statistically significant heterogeneity, while no apparent change in the heterogeneity when the subgroups were performed using the age of 50 years or the BMI of 30 kg/m2 as the threshold. No significant publication bias was detected among the studies (p = 0.184). Three studies used RV FWT to assess right ventricular remodeling. However, only one study found that there was significant difference in terms of RV FWT between severe OSA patients and controls [RV remodeling was evaluated based on the right ventricular (RV) diameter (RVD) and RV free-wall thickness (RV FWT). Differences in RVD were reported in 15 studies involving 845 OSA patients and 470 controls. The meta-analysis found that compared to controls, OSA patients exhibited significantly higher RVD , with statistically significant heterogeneity. Subgroup analysis showed that heterogeneity in OSA patients with BMI < 30 kg/m2 was significantly decreased. No significant publication bias was found among the studies (p = 0.052). Differences in TAPSE were reported in 10 studies involving 435 OSA patients and 419 controls. Herein, TAPSE was found to be significantly lower in OSA patients than controls , with statistically significant heterogeneity. There was no apparent change in the heterogeneity when the subgroups were performed using the age of 50 years or the BMI of 30 kg/m2 as the threshold. No significant publication bias was found among the studies (p = 0.12). Differences in RV FAC were reported in 5 studies involving 294 OSA patients and 158 controls. In this meta-analysis, we found that compared to controls, OSA patients displayed a significantly lower RV FAC , with non-significant heterogeneity. No significant publication bias was found among the studies (p = 0.222).Assessment of RV dysfunction was based on RV MPI, tricuspid annular plane systolic excursion (TAPSE), and RV fractional area change (RV FAC). Differences in RV MPI were reported in 8 studies involving 303 OSA patients and 346 controls. This meta-analysis found that OSA patients displayed significantly higher RV MPI than the controls  OSA increases the risk of developing coronary atherosclerosis. (2) There were significant alterations in patients with OSA regarding the parameters of cardiac remodeling and dysfunction, which illustrated that atrial enlargement, ventricular hypertrophy, and cardiac dysfunction were more common among OSA patients. (3) OSA is associated with subclinical myocardial injury.Numerous studies included in this review reported OSA was associated with CAC score. However, in some instances, the association was no longer significant after adjustment for traditional risk factors such as BMI. While in the real-world study, several of these risk factors were shared by patients with OSA and coronary atherosclerosis, which illustrates the complexity of the interaction between OSA and CAC score. In addition, the same CAC score may represent two different types of lesions. One type is spotty calcification, which is a mixed plaque with small punctate calcification, and another one is pure small calcified plaque lesion . HoweverAll included studies demonstrated that OSA increases the risk of developing coronary plaque burden. Qualitative analysis showed that non-calcified and mixed plaque was more likely to present in OSA patients. Quantitative analysis showed that plaque volume was higher in patients with OSA than those without. However, there were inconsistent findings on the features of vulnerable plaque. Kent et al.  found noThe linking of OSA to increased coronary plaque burden has been established. OSA and related intermittent hypoxia induces endothelial dysfunction mainly by activating numerous inflammatory responses, which will further accelerate coronary atherosclerosis. Indeed, OSA patients display increased secretion of circulating proinflammatory cytokines, chemokines, and adhesion molecules –97. Our 2 as the threshold, suggesting that age and BMI may be potential sources of heterogeneity.This meta-analysis summarized the relationship between OSA and cardiac structure and function, as assessed by echocardiography. We found OSA patients exhibit significant alterations in several parameters of cardiac structure  and function . In addition, one CMR study also showed that individuals with severe OSA were more likely to have lower LVEF, and higher AHI levels are strongly associated with higher LVM. Even though there were publication biases regarding LAVI and IVSD findings, trim-and-fill test revealed the bias did not impact on the estimates of LAVI . Additionally, in some instance, the heterogeneity in OSA patients was significantly decreased when the subgroups were performed using the age of 50 years or the BMI of 30 kg/mSeveral mechanisms other than intermittent hypoxia might also be implicated for cardiac remodeling and dysfunction in patients with OSA. For instance, the negative intrathoracic pressure increases transmural pressure of the atria, ventricles, and aorta. Meanwhile, arousals during apneic and hypopnea episodes activate sympathetic pathway and increase the blood pressure. Over time, these events increase the LV and RV afterload and induce ventricular hypertrophy, cardiac diastolic and systolic dysfunction, and heart failure .OSA-related myocardial injury is increasingly well understood. In a rat model, Chen et al. found that IH-induced increased the expression of myocardial transforming growth factor-beta and oxidative stress concomitant with lower levels of tissue-inhibitor of metalloproteinase-1 and higher levels of collagen-1 mRNA and fibronectin mRNA. Taken together, these findings suggest that IH promotes cardiac fibrosis . Our recFirstly, web of science, google scholar, and Scopus databases were not searched, so we cannot claim to have been exhaustive in retrieving all studies. Secondly, no subgroup analysis of OSA stratification was performed because of the limited number of studies with AHI < 15 or AHI > 30 events/h. Finally, all included studies were cross-sectional studies and thus a causal relationship cannot be determined.OSA patients have an increased risk of developing coronary atherosclerosis and subclinical myocardial injury. In addition, OSA patients are more likely to have cardiac remodeling and dysfunction, such as atrial enlargement, ventricular hypertrophy, and cardiac dysfunction, than controls.Additional file 1: Table S1 A example of search strategies. Table S2 Equations. Table S3 Certainty of evidence. Figure S1 Forest plot. Figure S2 Funnel plot. Figure S3 Sensitivity plot.


Clinical validation was performed in patients (n = 8) undergoing Impella support.Acute heart failure and cardiogenic shock remain highly morbid conditions despite prompt medical therapy in critical care settings. Mechanical circulatory support (MCS) is a promising therapy for these patients, yet remains managed with open-loop control. Continuous measure of cardiac function would support and optimize MCS deployment and weaning. The nature of indwelling MCS provides a platform for attaining this information. This study investigates how hysteresis modeling derived from MCS device signals can be used to assess contractility changes to provide continuous indication of changing cardiac state. Load-dependent MCS devices vary their operation with cardiac state to yield a device–heart hysteretic interaction. Predicting and examining this hysteric relation provides insight into cardiac state and can be separated by cardiac cycle phases. Here, we demonstrate this by predicting hysteresis and using the systolic portion of the hysteresis loop to estimate changes in native contractility. This study quantified this measurement as the enclosed area of the systolic portion of the hysteresis loop and correlated it with other widely accepted contractility metrics in animal studies . Quantified systolic area was well correlated in animal studies with end-systolic pressure–volume relationship (r = 0.84), preload recruitable stroke work index (r = 0.77), and maximum slope of left ventricular pressure (dP/dtmax) (r = 0.95) across a range of inotropic conditions. Comparable results were seen in patients with dP/dtmax (r = 0.88). Diagnostic capability from ROC analysis yielded AUC measurements of 0.92 and 0.90 in animal and patients, respectively.Hysteresis is well estimated from device signals alone (Mechanical circulatory support hysteretic behavior can be well modeled using device signals and used to estimate contractility changes. Contractility estimate is correlated with other accepted metrics, captures temporal trends that elucidate changing cardiac state, and is able to accurately indicate changes in inotropy. Inherently available during MCS deployment, this measure will guide titration and inform need for further intervention. Ischemic disease is the leading cause of acute heart failure and cardiogenic shock, life-threatening conditions where impaired contractility and inadequate cardiac output lead to hemodynamic instability and systemic hypoperfusion , 2. PromMechanical circulatory support (MCS) devices offer a therapeutic modality where mechanical pumps restore hemodynamic stability for patients in heart failure , 6. PercMechanical circulatory support devices themselves present a platform to determine cardiac state in unique ways without additional intervention. Device signals can vary with patient state, especially in the setting of residual cardiac function . While dTo demonstrate the utility of hysteresis, we propose that the portion related to contraction may reflect underlying cardiac contractility. Here, we present an approach to model and estimate MCS device-heart hysteresis and demonstrate its utility through quantification that can estimate changing cardiac contractile state. While device signals have been previously used to estimate contractility, they were not done so in the context of hysteretic interaction with the heart using percutaneous devices , 19. We Device-derived hysteresis estimation provides insight into cardiac state without additional intervention or need to measure intracardiac pressures during MCS support. Quantification of the systolic portion of hysteresis specifically allows a novel, continuous, and reliable measure of cardiac contractility during the use of MCS. Such a contractility marker will be crucial for determining and optimizing the appropriate degree of support, indicating the need for further intervention, and developing future closed-loop control of MCS devices.These methods aim to demonstrate the utility of device-heart hysteresis modeling from a percutaneous mechanical circulatory support device. Contractility is specifically estimated using hysteresis modeling and compared with other common measures of contractility in acute animal models and patients undergoing PCI.The Impella  percutaneous MCS device was used as the paradigmatic device in this study due to its availability, mode of operation, and clinical indication. This catheter-mounted mixed-flow pump bridges the aortic valve to unload the left ventricle in the setting of impaired function Fig. A. Blood As a mixed-flow pump, the amount of blood flow through the pump depends on both the pump rotational speed and the pressure head, the difference between aortic pressure and left ventricular pressure (LVP). This relationship is characterized by a performance curve that relates flow rate through the pump with the pressure head at a given rotor speed. A modified performance curve can be generated using the directly measured motor current signal, a measure of pump power and a surrogate of load experienced by the pump, to show its inverse curvilinear relationship with pressure head under steady and non-pulsatile flow conditions Fig. C 15, 2020. In thThe modified pump performance curve hysteresis loop reflects the cardiac cycle and can be sequentially separated into cardiac phases of relaxation, filling, and contraction in a counter-clockwise direction, with the points corresponding to end-diastole and end-systole being readily identifiable Fig. C. Our prThe viscoelastic behavior of blood flow and the pump can be directly used to estimate pressure head without using intracardiac pressure measurement. Hysteretic behavior is not unique to motor current measurements and also exists in traditional pump performance curves. Modifying existing approximations for pump hysteresis that are based off of the Euler fluid equations, which relate fluid pressure gradient with flow velocity and flow acceleration, can yield an estimation for pressure head without need for additional measurement of intracardiac pressure . Motor ci), the motor current’s rate of change The pressure head across the device  and preload recruitable stroke work index (PRSWi) with reduced sensitivity to loading conditions , 26. TheV0) that remains relatively constant. Contractility is then estimated using the slope from pressure–volume measurements [V0 [V0 and can produce conflicting results for the same contractile state [Classically, contractility is described as increasing ventricular elastance that is characterized by the peak elastance at end-systole, or ESPVR. Visualized in a pressure–volume diagram, ESPVR is displayed as a line connecting the point of end-systole with a hypothetical volume intercept (urements . Howeverents [V0 . In addile state .P/dtmax) is used when additional intervention is available [Difficulty in consistently measuring ESPVR values and its sensitivity to afterload has led to increased interest in PRSWi as a more stable and robust measure of contractility , 30. PRSvailable .There are many contractility metrics that each have limitations in their utility and availability in the clinic. To best represent the context of the results, we compared all three measures with our new measure of contractility derived from MCS device parameters alone.A series of four acute animal models  were used to assess hysteresis modeling and contractility quantification across a range of inotropic conditions induced by pharmaceutical and mechanical interventions. All animals were maintained in accordance with National Institutes of Health (NIH) and Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC) guidelines ; body temperature, oxygen saturation, and electrocardiogram were continuously monitored for the duration of the studies. Anesthesia was induced via intramuscular injection of telazol (6 mg/kg) and maintained using inhaled isoflurane after intubation. An Impella CP was placed into the left ventricle via the right femoral artery. A pressure–volume catheter , placed via the left carotid artery, measured continuous LVP and volume. Appropriate placement and aortic valve competency were monitored via fluoroscopy.0 values to calculate ESPVR in subsequent interventions. Boluses were given for pharmaceutically induced positive inotropic (epinephrine at 1 µg/kg), and negative inotropic (esmolol at 1.8 mg/kg) conditions. Local ischemia was induced by injecting compressible 45–105 µm diameter microspheres  into the left main coronary artery through a Judkins left catheter placed via the left femoral artery. Serial boluses of 0.25 mL of microspheres mixed with 10 mL of isotonic saline and 10 mL of contrast were serially injected until LVEDP rose to > 20 mmHg or there was evidence of ventricular decoupling [Pharmaceutical interventions delivered via the femoral venous sheath induced changes in contractility, and mechanical interventions allowed assessment and induction of an acute heart failure model. Each condition was assessed at two Impella speeds (P-3 and P-6), which are commonly used speed settings that avoid suction from high flow rates and retrograde flow during diastole. A preload reduction to alter loading condition was induced by mechanical occlusion of the inferior vena cava by a balloon-tipped catheter introduced via the right femoral vein. Ventricular pressure–volume data from these points were extrapolated to determine Vcoupling .A research-grade data acquisition system  continuously recorded a single-lead electrocardiogram and the Millar pressure–volume catheter. Impella signals were recorded on a time-synced controller and retrieved after each trial. LVP signals are used as the reference to evaluate hysteresis estimation and are not part of the systolic area calculation. All calculations of contractility parameters were performed retrospectively.max from the LVP tracing as a reference. There were no recorded adverse events for any of the eight patients. All calculations of contractility parameters were performed retrospectively.Anonymized data were obtained for eight adult patients undergoing elective Impella-supported high-risk PCI due to the availability of hemodynamic measures. Data were obtained with informed consent and with approvals from an Ethics Review Committee and relevant Institutional Review Boards. In total there were two female and six male patients ranging from 49 to 69 years of age. All patients were either NYHA Class II or III heart failure and hemodynamically stable prior to the procedure. Impella device signals were recorded on the controller through the duration of the intervention with support provided at a range of speeds . Continuous digital LVP tracings, used as a reference signal, were also available from an indwelling pigtail catheter for the duration of the trial. Following procedures, device signals and continuous left ventricular tracings were downloaded and registered for analysis. Hysteresis estimation was evaluated using the indwelling left ventricular tracing as a reference signal to evaluate performance. Changes in contractility were also calculated using dP/dtt-test and visualized using correlation and Bland–Altman plots with repeated measures. Correlation coefficients from regression analysis were used to compare each combination of contractility measures for the pooled animal results. These changes are shown normalized to a baseline state to account for differences in scale between measures and calibration. Prescriptive performance to indicate changes in contractility as determined against moving average changepoint detection in dP/dtmax were performed for each contractility measure using receiver-operator characteristics (ROC) curves and quantified using the area under the curve (AUC). Differences between individual animals and patients are assessed using one-way ANOVA and the Fisher z-transformation of the correlation coefficient for each combination to support data pooling. All methods used standard confidence intervals (95%) and significance values (p < 0.05). Data and statistical analyses were performed in MATLAB .Hysteresis estimation in animals and patients were evaluated using a two-sided paired Hysteresis systolic area can be modeled and calculated using device-only parameters as a marker for tracking changes in underlying cardiac contractility. We evaluated its performance in a series of four acute animal models and eight patients.P/dtmax for comparison with systolic area at 113 distinct points. These points spanned a range of conditions, including microbead-induced acute heart failure with ESPVR from 0.44 to 1.80 mmHg/mL, PRSWi from 10.6 to 76.5 mmHg, and dP/dtmax from 653 to 2731 mmHg/s. Anonymized data from eight patients validated the hysteresis estimation and the systolic area at 10,940 points. Patients displayed varying states with dP/dtmax ranging from 315.5 to 3300.1 mmHg/s.The four acute animal models allowed the use of invasive diagnostic tools for measurement of ESPVR, PRWSi, and dp > 0.82). Correlation with direct measurement was strong  with a mean bias of − 0.02 and limits of agreement from − 2.0 to 2.0  with improved limits of agreement (− 0.57 to 0.7)  and in close agreement with reference direct measurement   and dP/dtmax  with a slightly weaker correlation to PRSWi   and comparable with the results seen in the animal models  and patient datasets (AUC 0.90). Furthermore, there was no significant deviation in performance between increasing (AUC 0.99) and decreasing (AUC 0.95) contractility. As a comparison, these results were comparable or superior to results from ESPVR (AUC 0.89) and PRSWi (AUC 0.80) compared to dP/dtmax. This indicates that changes in systolic area can in itself be readily used as a useful predictor for increasing or decreasing contractility. While a calibrated relationship between systolic area and each metric may be found with device-specific characterization, these results show that changes in contractility and trends can be adequately captured from existing MCS devices without alteration.Notably, all contractility measures remained similarly correlated but not calibrated, even between the existing contractility markers. However, this does not prevent this approach from being an indicator of changing contractility. This diagnostic capability is evaluated using ROC analysis Fig. . DirectiDevice hysteresis can be used to provide insights into changing physiologic state. Here, we demonstrate its utility via the hysteresis-derived systolic area as a new measure of contractility that can be calculated in real-time without additional intervention in the setting of MCS use. This measure can continuously monitor trends in contractility during MCS support and may be readily implemented for the care of patients in cardiogenic shock in order to provide immediate feedback, especially during ramp tests and weaning protocols. Indeed, we investigated the approach in patients undergoing PCI, and future steps include implementation during longer duration MCS use within intensive care units and in support of cardiogenic shock. This approach allows continuous monitoring and provides immediate feedback during ramp tests and weaning protocols. In addition, future investigation of device-specific characterization methods could lead to calibrated absolute measures of hysteresis and contractility rather than normalized trends. Another limitation of this work is the reliance on the Impella-specific design and device signals. While the concept may be generalized to other forms of percutaneous MCS, the approach as described here is reliant on signals that are readily available and specific to the Impella design.Widely implementing this measure for MCS devices in ICUs will also lead to increased data that can contribute to determining optimal control of these devices towards improved outcomes. Future studies with contractility trends stratified by patient outcomes can determine trajectories and support strategies that lead to recovery. These data are critical to informing future automated control of these devices and prognostic capabilities.Together with our other work to estimate end-diastolic pressure and cardiac output –16, thisReal-time quantification of cardiac state during the entire duration of mechanical circulatory support will make clinical practice safer and more efficient. Here, we employ a hysteresis estimation technique to indicate alterations in native contractility that can prompt changes in therapy or further diagnostic investigation with other devices and imaging. Future studies with contractility trends stratified by patient outcomes can determine trajectories and support strategies that lead to recovery. These data are critical to informing future automated control of these devices and prognostic capabilities.


MWI, MCW and MWE were significantly reduced in KD children despite normal LVEF and normal GLS. These abnormalities seems independent from CADL. Thus, in KD with normal LVEF and normal GLS, estimation of MWI may be a more sensitive indicator of myocardial dysfunction.Kawasaki disease (KD) can be associated with high morbidity and mortality due to coronary artery aneurysms formation and myocardial dysfunction. Aim of this study was to evaluate the diagnostic performance of non-invasive myocardial work in predicting subtle myocardial abnormalities in Kawasaki disease (KD) children with coronary dilatation (CADL). A total of 100 patients (age 8.7 ± 5 years) were included: 45 children with KD and CADL (KD/CADL) (Z-score > 2.5), 45 age-matched controls (CTRL) and, finally, an additional group of 10 children with KD in absence of coronary dilatation (KD group). Left ventricular (LV) systolic function and global longitudinal strain (GLS) were assessed. Global myocardial work index (MWI) was calculated as the area of the LV pressure-strain loops. From MWI, global Constructive Work (MCW), Wasted Work (MWW) and Work Efficiency (MWE) were estimated. Despite normal LV systolic function by routine echocardiography, KD/CADL patients had lower MWI , MCW  and MWE  compared to CTRL. Furthermore, MWI was significantly reduced in children belonging to the KD group in comparison with controls  and was comparable between KD/CADL and KD groups (KD/CADL vs KD p = 0.896). Moreover, KD/CADL patients with normal GLS (n = 38) preserved significant differences in MWI and MCW in comparison with CTRL It is an acute inflammatory disorder of unknown etiology, which predominantly affects the coronary circulation leading to aneurysm formation4.Kawasaki disease (KD) represents the leading cause of acquired heart disease in children in developed countries6 and normal coronary arteries7.In addition, late myocardial abnormalities and biopsy proven myocardial fibrosis have been found up to 11 years after the acute disease, even in presence of normal left ventricular (LV) systolic function8.Although KD carries with it some myocardium inflammation, routine echocardiographic measurements of LV systolic function are often normal, limiting their usefulness9. Moreover, recent studies have demonstrated abnormal strain in patients with KD, despite normal left ventricular ejection fraction11.Speckle tracking echocardiography (STE) has previously identified patients with coronary disease with good sensitivity13, and may be inaccurate in specific settings14.Unfortunately, even if lower than standard echocardiographic parameters of LV function, STE indices are load dependent15. Nevertheless, myocardial work estimation has been evaluated invasively in the past decades, being consequently not feasible in routine assessments.An alternative proposed approach is the estimation of myocardial work, which is defined as cardiac output multiplied by aortic pressure, and it can be calculated as the area within the pressure–volume loop during one cardiac cycle17.Recently, a non-invasive method has been introduced to quantify global and segmental myocardial work, that match longitudinal strain with standardized LV pressure-curves, adjusted to brachial cuff pressure and valvular events18 demonstrated the ability of regional non-invasive myocardial work index (MWI) to identify acute coronary occlusion in patients with NSTE-ACS.Non-invasive MW showed a strong correlation with invasive work measurements in recent validation studies. Moreover, Boe et al.We hypothesized that, in children with KD and coronary dilatation, despite normal LV systolic function measured by two-dimensional ejection fraction (EF), indices of myocardial work will be impaired.Therefore, the aim of the present study was to investigate, for the first time, the ability of non-invasive myocardial work indices to evaluate subtle changes in myocardial function among KD patients with coronary dilatation and normal LVEF.31males with coronary artery dilatation (Z-score > 2.5) were selected and included in the KD/CADL group. Among those, 38 had coronary aneurysms and 13 presented giant coronary aneurysms. The average maximal coronary diameter in the KD/CADL group was 6.5 ± 3.8 mm, while the average Z-score was 8.9 ± 6.9. Twenty-five children presented dilatation of LMCA (left main coronary artery); 10 of LAD; 25 of RCA. Also, 3 children presented dilatation of LMCA, LAD and RCA; 14 of LMCA and RCA; 2 of LAD and RCA. No patients presented thrombus or stenosis of the coronary artery. KD/CADL patients were compared with 45  age- and weight-matched controls (CTRL) and to an additional group of 10 children  with Kawasaki disease in absence of coronary dilatation (KD group) . HR was found to be significantly higher in KD/CADL group compared to CTRL . Patients were not on any medication, apart from aspirin or warfarin regimens. The average time between KD onset and the assessment of myocardial work by echocardiography in KD children was 2 ± 2 years (time range: 16–2855 days).LV dimensions were comparable in KD/CADL group and CTRL as regard to the absolute values  or normalized for the Z score . LV dimensions of children with KD in absence of coronary aneurysms are presented in Table No significant differences were observed in LVEF values between KD/CADL children and CTRL  Fig. A.Figure CMR was performed in 13 CTRL and in 13 patients from KD group for a clinical indication: ten for the presence of giant coronary aneurysms, the remaining three patients for the presence of symptoms (angina or tiredness) on exercise. Coronary arteries were confirmed to be enlarged by the CMR findings. No patients presented thrombus or stenosis of the coronary artery.Among the patients who underwent CMR, nine received adenosine stress for a clinical indication: six patients presented with giant coronary aneurysms and three were experiencing symptoms on exercise. LV ejection fraction measured by CMR assessment did not differ in KD/CADL children compared to CTRLs  Fig. B.Moreover, 2 out of 13 patients from the KD/CADL group, who received gadolinium injection, presented with LV LGE . Only one child out of nine from the KD/CADL group, revealed perfusion defects after adenosine stress.Global longitudinal strain values were within the normal range both in the KD/CADL and in the KD group, and we found no significant differences compared to CTRL   was significantly reduced in children belonging both to the KD/CADL or the KD group compared to controls  were analysed separately (n = 38), they maintained a significant difference in MWI and MCW in comparison with controls  . CMR data are available only in two children with GLS reduction: one child presented CMR positive for LGE and adenosine inducible ischemia, while the other child presented normal CMR findings. Also, MW indices were reduced in children with GLS < − 19% compared to children with normal strain , MCW , MWE  or GLS . Also, we observed modest correlations between the LAD size and the same parameters , but not significant correlations between these and the RCA size.Weak correlations were identified between MWI , MCW , MWE  or GLS  and the aneurysm dimensions assessed by z-score. Also, MWI , MCW , MWE  but not GLS , were very weakly correlated with the number of coronaries involved in the disease.Furthermore, classical LV ejection fraction assessed either by echocardiogram or CMR did not significantly correlate with the LMCA , LAD  or RCA sizes  or with the number of coronaries involved in the disease .Intra-observer variability was very good for longitudinal strain  and good for MWI . Inter-observer variability was also very good for longitudinal strain  and good for MWI .This is the first study assessing the diagnostic performance of non-invasive myocardial work in a cohort of children and young patients with KD with and without coronary dilatation. Our data, firstly, demonstrated that non-invasive myocardial work, and its derived indices, is reduced in patients with KD even in absence of coronary aneurysm. MWI could detect subtle myocardial abnormalities better than GLS and LVEF.7. Kang et al. demonstrated impaired left atrial reservoir function in children with KD in the acute phase19.Myocardial involvement in KD has been extensively elucidated with several studies showing the characteristic abnormal histology, which appears to be similar in all the patients with KD10 using strain and strain rate showed that children with KD (n = 32), despite normal LV systolic function values assessed by routine echocardiographic measurements, had reduced longitudinal myocardial deformation properties.McCandless et al.11 have recently demonstrated that children in the convalescent/chronic phase of KD (n = 67) are characterized by a subtle reduction in strain rate compared to the acute phase, that it is more pronounced in patients with coronary aneurysm than in those without.Moreover, Sanchez et al.11, we have confirmed a reduction of global longitudinal strain even if not statistical significant, in a sample of 45 children with established diagnosis of KD complicated by coronary dilatation when compared to CTRLs and also in group of ten children with KD in absence of coronary aneurysms.In agreement with these studiesOur study was the first to assess non-invasive MWI and its derived indices in children with KD complicated by CADL. We detected an abnormally reduced MWI, MCW and MWE in the group of patients with KD and CADL, compared to the CTRL.On the other hand, LV ventricular ejection fraction, measured either by echo or by CMR, showed no significant differences between KD group and CTRL in our cohort of patients.Only two (15.4%) out of 13 patients with KD, who underwent CMR with gadolinium injection, presented LV LGE . Similarly only one (11.1%) child out of nine who underwent CMR adenosine, revealed perfusion defects.In our study cohort, we observed a significant impairment of MWI also in a group of 10 KD children without CADL. Furthermore, we found modest correlations among the aneurysm size on LMCA, LAD and MW indices and not significant correlations between these and the RCA size. Also, we identified weak correlations between MWI , or its derived indices , and the aneurysms dimensions assessed by z-score. Finally, MWI , MCW , MWE , presented a weak correlation with the number of coronaries involved in the disease.20, performed on endo-myocardial biopsy specimens obtained during follow-up from 54 patients who had typical clinical manifestations of KD, showed significantly increased incidences of myocardial hypertrophy, disarray of myocardial fibres, and micro-vascular lesions in the group of patients with KD and coronary artery lesions, compared to those without.Indeed, a previous study of Ai-Min Liu et al.In our study, in a subgroup of children with KD complicated by CADL but with normal GLS (n = 38), MWI was found to be still reduced compared to CTRL, being able to distinguish the former from the healthy ones.Hence, measuring global non-invasive MWI seems more appropriate to study cardiac function in KD children with normal LVEF and GLS.23. Also, it has been recently demonstrated to show similar physiological information as pressure/strain loops24.Myocardial work, calculated from LV pressure/volume or pressure/length loops during cardiac catheterization procedures, has been validated as a reliable marker of ventricular contractility for 40 years16 introduced a method to calculate the non-invasive MW, using speckle tracking analysis and estimating LV pressure from brachial artery cuff pressure.In this setting, a study from Russell et al.26. In this setting, Manganaro et al., demonstrated a good reproducibility for the assessment of MW, further supporting its potential use in clinical practice.Moreover, the NORRE sub-study provided reference ranges in adults for non-invasive MW in a multicentre study design27. Most recently, Chan et al.28 reported data of MW indices in patients with hypertension, ischaemic and not-ischaemic dilated cardiomyopathy.To date, MW has been evaluated as a reliable predictor of response to CRT in patients with heart failure29.Furthermore, a previous study from our group demonstrated that the measurement of MW indices is a sensitive and early marker of myocardial ischemia during transient acute coronary occlusion12. In our study, KD patients showed reduced MWI with significantly reduced BP. In states of normal contractility, in presence of reduced BP one would expect strain to be higher and so MWI. The fact that, in our study, MWI is reduced in KD patients, despite a reduced BP, strongly suggests that the physiologic difference is due to a reduced myocardial deformation. For this reason, we believe, that the lower BP we found in KD patients is not a confounder, but it rather strengths the physiological value of our findings.As described above, myocardial work indices are based on strain and blood pressure. Strain is afterload dependent. For this reason, any increase in afterload may cause a strain reduction in presence of normal contractilityRegarding HR, it was found to be significantly higher in KD group compared to CTRLs .30 demonstrated that peak systolic longitudinal strain showed a biphasic response to HR, initially increasing in response to early physiological heart rate increase (e.g. in the setting of exercise), and then remaining constant or falling at HR > 150 bpm.However, according to the Treppe phenomenon, the increase in HR in normal inotropic states, leads to an increase in cardiac contractility until a certain threshold, and then the inotropic effect decreases. Accordingly, Davidavicius et al.In our study in KD patients with significantly lower BP and an average HR of 100 ± 25 bpm, it could be expected that longitudinal strain and, then, myocardial work would be higher, in presence of normal contractility. The fact that MWI is reduced despite an increase in HR, strongly suggests that the physiologic difference between KD and CTRL might be due to a reduced myocardial contraction.All the published studies have already demonstrated compelling data, including decreased LV longitudinal systolic strain and reduced mitral and septal annular early diastolic tissue velocities in patients with KD.Even though the actual aetiology of altered LV mechanics in these patients remains unclear, it is tempting to speculate that structural alterations of the myocardium might play a contributory role. For this reason, the AHA algorithm, designed to improve early diagnosis for incomplete cases of KD, uses echocardiographic evidence of decreased systolic function as supporting criteria. Our study demonstrated for the first time that MW indices are reduced in KD patients with CADL even in presence of normal LVEF and LV GLS. Reduced non-invasive MW of the LV, thus, may be a more robust indicator of myocardial involvement in KD according to our data in the convalescent/chronic phase of KD complicated by CADL in children.18. This can be partially explained by the fact that we did not perform any specific acquisition for valvular timings and this may be particularly relevant in paediatric patients in presence of relatively high heart rate.This is the first clinical application of MW in paediatric age. We provided, for the first time, paediatric normal values for MW indices in 45 healthy children. In our experience the feasibility of this technique is excellent, because 2-dimensional imaging quality in paediatrics is generally higher than adults. Indeed, in this study no subject was excluded because of poor image quality. On the other side, intra and inter-observer variability for MWI was relatively higher than previously rates published in adultsThis study carries several limitations.First of all, it does not provide prospective long-term follow-up data, in order to establish whether patients with worse non-invasive MW might have worse clinical outcome. Thus, further larger prospective multicentre studies would be needed to answer this question.Furthermore, we could not correlate MW indices with CMR findings of LV LGE or perfusion defects after adenosine stress, since only three patients in the KD group presented those alterations.20.Moreover, the average time between KD onset and the assessment of myocardial work by echocardiography in KD children was 2 ± 2 years (time range: 16–2855 days). However, ultrastructural studies on endomyocardial biopsy specimens demonstrated that the coronary microvascular lesions in patients with KD, characterized by microvascular dilatation or endothelial cell injury, persisted after convalescent stage even up to 23 yearsFinally, genetic testing results were not included in the present study.The estimation of myocardial work by pressure-strain loops is a novel tool for the evaluation of patients with KD. MWI, MCW and MWE were significantly reduced in KD patients with dilated coronaries. In KD patients with normal GLS, estimation of MWI, MCW and MWE may be a sensitive indicator of myocardial dysfunction in KD.All methods were performed in accordance with the relevant guidelines and regulations.The study population comprised 100 children  of at least one vessel. Patients during the acute phase of KD were excluded from this study. The acute phase was defined as follow: from day 1 of illness through day 14 of illness; day 1 of illness was the first day of fever as documented in the admission note. Patients with atypical/incomplete KD and those with delayed treatment (> 10 fever days) were excluded. Only KD patient with a normal ejection fraction were included in the study (LVEF ≥ 55%). The control population consisted of age- and gender-matched children who underwent echocardiography for murmur evaluation and they were found to have no cardiac abnormalities. Finally, we included an additional group of 10 children with Kawasaki disease in absence of coronary dilatation (KD group) . Echocardiograms with inadequate images of coronary arteries or the LV myocardium were excluded from the analysis.All the patients underwent transthoracic echocardiography, according to the Royal Brompton Hospital standard protocol2. Chamber size and function were assessed as previously described31 and according to the latest guidelines32. Values for LV diameters and thickness were adjusted for body size and age expressed as z-scores according to the Boston Children’s Hospital z-score system33.For the left anterior descending, left main and right main coronary arteries, serial echocardiogram measurements of vessel diameters were converted into BSA-adjusted Z-scores using published normal regression equations. Coronary artery dilatation (CADL) was defined as coronary artery diameter z-score > 2.5. Aneurysm was defined as a coronary diameter between 4 and 8 mm. For children under the age of 5, a diameter of > 3 mm was considered an aneurysm. Giant aneurysms were defined by a coronary diameter above 8 mm, in all age groups30. Additional information on speckle tracking analysis and LV Ejection Fraction (EF) methods is available in our Global longitudinal strain was assessed as previously described18, represented by the latest vendor-specific version of the Automated Function Imaging software (EchoPAC Version 202), and allowing the evaluation of myocardial work as a function of time during the whole cardiac cycle. The authors obtained simultaneously blood pressure by a cuff manometer at the time of 4ch/3ch/2ch image two-dimensional echocardiographic views acquisition18.Myocardial work index (MWI), and its derived indices, were estimated using a customized software The MW module  in AFI asks the user to provide blood pressure and valvular event times as input to the myocardial work estimation. A bull’s eye Fig.  with theMyocardial Constructive work (MCW): work performed by a segment during shortening in systole adding negative work during lengthening in IVR;Myocardial Wasted work (MWW): negative work performed by a segment during lengthening in systole adding work performed during shortening in IVR;Myocardial work efficiency (MWE): constructive work divided by the sum of constructive and wasted work (0–100%).Derived indices from MWI are defined as follows:In our experience the added time to perform MW study by expert sonographers is 3 ± 2 min.Further information on “Myocardial work” methods is provided in our Cardiovascular Magnetic Resonance (CMR) images were evaluated for the presence of aneurysms of the main epicardial coronary arteries. The right coronary artery, left main coronary artery, left anterior descending coronary artery, and left circumflex coronary artery were assessed. These were also evaluated for the presence of thrombi. Thrombi were diagnosed as a low-signal mass against the wall of the aneurysmal coronary artery, with a filling defect in the aneurysm in both the coronary sequences and the sequences with delayed enhancement.18 and classified as normal or abnormal, which includes hypokinetic, dyskinetic, or akinetic wall motions. A 17-segment model was used for analysis. Segmental myocardial first-pass perfusion after adenosine stress was evaluated qualitatively and assessed as normal or as revealing a perfusion defect. Delayed contrast-enhanced images were evaluated visually for areas of late gadolinium enhancement (LGE) indicating scar due to myocardial infarction. Delayed hyperenhancement were categorized as subendocardial  or transmural .Myocardial wall motion was qualitatively analysed34 using a standard statistical software program  and is extensively described in Statistical analysis was performedThe study protocol has been approved by local Research Committee.Written informed consent was obtained from the parents.Supplementary Information.


However, a subtype of patients are known to have a higher incidence of ventricular arrhythmias and sudden cardiac death, the so called “arrhythmic MVP.” In recent years, several studies have been published to identify the most important clinical features to distinguish the benign form from the potentially lethal one in order to personalize patient’s treatment and follow-up. In this review, we specifically focused on  The prolapsing mitral valve was first described in the late 1960s , but it Cardiac imaging plays a key role in the diagnosis of MVP and in the detection of the major arrhythmic high-risk features. Overall, the reported incidence of premature ventricular beats (PVBs) in MVP may vary from 49% to 85% in the adult population. Typically, the most common site of origin of these PVBs is the postero-basal portion of the Left Ventricle (LV) at the level of PM, or they are of fascicular origin ,11. ThisTTE and transesophageal echocardiography (TEE) are the reference techniques to evaluate leaflet anatomy . The “clFirst mentioned by Bharati et al. , MAD refThe assessment of MAD is of importance, as it has emerged as an independent risk factor for VA in several studies, probably due to its link to the mechanical stretch of the myocardium . While lNotably, an unusual systolic motion of the posterior mitral ring and the adjacent myocardium may also be found in patients with aMVP (“Curling”) ,10. ThisThe presence of fibrosis at the PM and inferior LV wall level is another key feature of aMVP and has been proposed as an independent risk factor for VA and SCD . CMR is Basso et al.  demonstrBeyond macroscopic fibrosis, recent papers have highlighted the possible role of interstitial fibrosis measured during CMR T1 mapping and extracellular volume (ECV) measurements ,30. MacrPradella et al.  and Bui In addition to this, myocardial ECV quantification by T1 mapping has emerged as an accurate tool to detect interstitial fibrosis, and it is used as a quantitative marker in ischemic and non-ischemic cardiomyopathies ,37. MostIn summary, the presence of elevated native T1 values, the reduced post-contrast T1 values, and the higher ECV values reported so far suggest that the fibrotic alterations in patients with MVP may go far beyond the presence of macroscopic LGE. Actually, all these observations support the hypothesis that the presence of diffuse fibrosis may also be a trigger for VA, and that it may represent an initial step preceding the development of macroscopic fibrosis detected by LGE sequences. For these reasons, our recommendation would be to routinely use T1 mapping in combination with LGE in the evaluation of these patients, even if the clinical significance of elevated T1 and its association with an increased risk of SCD or arrhythmia in MPV patients needs further investigation and validation.Recently, the hypothesis of subclinical myocardial inflammation or ischemia as an additional pro-arrhythmic mechanism in patient with MVP has also been evoked as a potential VA trigger . For thi18F-fluoro-deoxy-glucose (FDG) positron emission tomography [Actually, in 85% of their small series of patients, tracer uptake at the same level of fibrosis found in LGE was demonstrated with mography . DespiteHowever, intriguingly, it must be considered that FDG is a standard tracer for inflammation imaging; thus, it is nonspecific and the question of ischemia is not addressed with this method. Moreover, a different cellular glucose uptake at the level of PMs may also be responsible for these results. Thus, for the moment, only a potential link with inflammation may be postulated. Thus, further studies are needed before considering a routine assessment of inflammation in patients with suspected aMVP.aMVP is a complex syndrome that exposes patients to a higher risk of VA and SCD . CardiovFinally, some patients may be candidates for mitral valve surgery because of the severity of mitral regurgitation. It is important to remember that no statistically significant data describe the evolution of ventricular arrhythmia burden after surgery and whether surgical mitral valve repair may reduce the overall arrhythmic risk. In a very small and insufficiently powered series of patients , mitral In conclusion, at the present time, the current guidelines do not provide guidance about risk stratification, treatment, and follow-up in aMVP patients. From the perspective of individualized management of patients with suspected aMVP, the high-risk features detected by cardiac imaging represent important tools to identify the minority of patients for whom a more aggressive management might be considered, including pharmacological treatment, catheter ablation procedures , implantCase 1 : Primary prevention ICD implantation after multi-modality imaging work-upCase 1 : PrimaryA 22 year-old female patient was known for mitral valve prolapse since infancy. Her baseline ECG showed negative T waves in the infero-lateral leads A and mitCase 2 : Secondary prevention ICD implantation after cardiac arrest and multi-modality imaging work-upCase 2 : Seconda1 mapping was high in all basal left ventricular segments. The patient then underwent an EPS, which showed the induction of ventricular tachycardia and ventricular fibrillation. A subcutaneous ICD was finally implanted as a secondary prevention measure, and treatment with 80 mg/day of nadolol was started. No arrhythmic events were present at the one-year follow-up.A 40 year-old man was known for mitral valve prolapse since adolescence and was periodically followed by a cardiologist. Baseline ECG was not remarkable A, mitral


Background and Objectives: There is emerging evidence of the usefulness of left atrial strain (LAS) in the assessment of diastolic dysfunction (DD). In this study we assess the sensitivity and specificity of LAS, to determine cut-off values and their association to DD with increased left atrial pressure (LAP) in patients with well-treated arterial hypertension. Materials and Methods: We performed a cross-sectional study on 180 subjects with well-treated arterial hypertension. All patients underwent transthoracic echocardiography. Patients were divided into two groups: a group without increased LAP and/or DD and a group with increased LAP DD. Results: In multivariate logistic regression, LAS proved to be the strongest statistically significant predictor of DD with increased LAP , with AUC 0.885 and a set cut-off value of 24.27% with high sensitivity of 78.9% and specificity of 84.6%. The set cut-off for LAS > 24.27% was significantly highly prevalent in the group of DD with increased LAP 78.9% when compared to the group without increased LAP 15.4%, p < 0.0001. Conclusion: The findings of this study suggest that LAS could be a useful and highly sensitive and specific marker in the evaluation of DD. There is the potential for using LAS in everyday practice as a standard parameter in diastolic function assessment. Early detection of asymptomatic diastolic dysfunction (DD) is crucial in preventing incident heart failure and improving the survival of patients with arterial hypertension . The firThis cross-sectional study, approved by the institutional review protocol/ethical committee, included 180 patients of both sexes, in whom arterial hypertension had been previously diagnosed and treated. All participants underwent a 24-h ambulatory blood pressure monitoring (ABPM) and transthoracic echocardiographic examination. Inclusion criteria were normal values of arterial blood pressure during ABPM, sinus rhythm in electrocardiogram (ECG), left ventricular (LV) ejection fraction (EF) ≥ 55%, no significant valvular heart disease (defined as moderate or severe regurgitation or stenosis) and no associated cardiac diseases, previous cardiac valve or revascularization surgery or secondary/gestational arterial hypertension. Based on the echocardiography exam, according to the 2016 American Society of Echocardiography (ASE) guidelines , all patBlood pressure (BP) measurements were performed, according to the 2018 recommendation of the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and the European Society of Cardiology (ESC) , during We performed echocardiography on all patients using Vivid E9  machine equipped with an M5S-D, 1.5–4.6 MHz transducer, with simultaneous ECG monitoring. For each acquisition, 3 cardiac cycles of uncompressed data were stored in cine-loop format and analyzed without blinding offline by 1 investigator, who was blinded to the clinical characteristics of the patients. All measurements were performed by previously described methods .2), A2 endocardial area at end-diastole (cm2), L-ventricular length at end-diastole (cm), t = average wall thickness (cm), 1, 05-specific gravity of the muscle (g/mL). To obtain the indexed value (LVMi) the LVM was divided by BSA.Measurement of LA volume from the Simpson method used 4-chamber and apical 2-chamber views at ventricular end-systole, maximum LA size (LAV), and then normalized for body surface area (BSA) as LAV index (LAVi). The apical 2- and 4-chamber views were used to measure left ventricular end-diastolic and end-systolic volumes using the biplane method of disks and EF was calculated. Parasternal long-axis view (2D) was used to measure wall thickness–inter-ventricular septum (IVS) and posterolateral wall (PLW) and the same view was used to measure the standard antero-posterior diameter of the left atrium. Left ventricular mass (LVM) was calculated via area–length method automatically by software according to measures obtained from parasternal cross-sectional view in which mid-ventricular systolic and diastolic epicardial and endocardial surface, with the exclusion of papillary muscles, were traced, as well as the systolic and diastolic mitral-to-apical distance in apical 4-chamber view. LVM = 1, 05 (5/6A2 (L + t)) – (5/6A2L), where A1 is epicardial area at end-diastole  Doppler was obtained at the tips of mitral leaflets, and peak early (E) and late (A) diastolic filling velocities, E/A ratio, and E-wave deceleration time (DTE) were obtained. Tissue Doppler imaging of the mitral annulus was performed at the septal and lateral positions, from which values for the peak early (e′) velocities were obtained and averaged. E/e’ ratio was calculated from E velocity and averaged e’ velocities obtained from septal and lateral positions of the mitral annulus. The maximum tricuspid regurgitation velocity was measured in the apical 4-chamber view at the position of tricuspid annulus using continuous-wave (CW) Doppler.Strain analysis: For all patients, using EchoPAC Clinical Workstation Software  in post-processing, global left ventricular strain (LVGS) and peak reservoir left atrial strain (LAS) were determined. All images were taken at the frame rate of 60–80/s. Three consecutive cardiac cycles were recorded. Cardiac cycles from three different apical approaches were recorded: 4-chamber view (4CH), 3-chamber view (3CH) and 2- chamber view (2CH). Mitral and aortic valve closure, as observed in the apical 3-chamber view, is used as a recommended end-diastole and end-systole. Endocardial edges were manually marked by the “point-and-click” approach. The epicardial edge was then automatically generated by the system to form a so-called region of interest (ROI). When the ROI was defined, the software automatically divided the same into segments, and the quality score of each segment was automatically calculated, and those segments were classified as acceptable or unacceptable. There was a possibility of manual correction of the edge of each initially unacceptable segment. Those segments that did not have adequate image quality were excluded from the analysis. Left ventricular strain: The LVGS was determined for all 6 left ventricular walls, and the software algorithm automatically segmented the left ventricular walls into 18 sections to form a single bull’s eye model. The mean peak longitudinal strain (LAS-) was calculated as the mid-value of LAS for all segments. The resulting LVGS value was used for further analysis. Left Atrial Strain: A total of 12 segments were analyzed. The software automatically generated longitudinal strain curves for each segment, as well as a curve representing the mean value for all analyzed segments. The first and maximum positive deviation of the strain value was measured at the end of the atrial filling, when the atrium was most stretched —reservoir strain (LAS). We set the starting point of strain analysis as P-wave.t-test for independent samples and a Mann–Whitney test were used to compare the mean values of the variables of the examined groups. A p value < 0.05 was considered statistically significant. Multivariate regression analysis was used to determine the association between different echocardiographic parameters and DD with elevated LAP independently of age, sex and BMI. The predictive quality of the variables on outcome was evaluated using receiver operating characteristic (ROC) curves. The area under the curve (AUC) was obtained to assess its diagnostic performance, AUC comparison was performed by DeLong’s method. Hosmer and Lemeshow test was used to examine the quality of the obtained combination of echocardiographic parameters in multivariate binary logistic regression. The test showed that the combination was good (p = 0.538).Continuous variables with normal distribution were presented as mean ± standard deviation and others as median, quartiles, frequencies and percentages. The Student’s The basic parameters of the groups are presented in p < 0.0001), and there was a significantly higher prevalence of smoking history 47% vs. 25%, p = 0.002, respectively. Statistically, significant differences were observed between the majority of examined echocardiographic parameters compared between groups  and DTE .Univariant and multivariate binary logistic regression was used to examine the influence of examined parameters on the occurrence of DD with elevated LAP. Results are presented in The sensitivity and specificity of different echocardiographic parameters in diagnosing DD with elevated LAP were tested by ROC analysis. Statistically significant predictors of DD with elevated LAP according to the area under the curve were LAS (AUC 0.885 with cut-off 24.27%), E/e’ , LVGS  and DTE , p < 0.0001. When results of the ROC analysis were compared for chosen parameters in pairs, E/e’ was proven to be a better predictor of DD with elevated LAP than LVGS (p = 0.03) and DTE (p = 0.006). Peak LAS was a significantly better predictor of DD with elevated LAP when compared with LVGS (p = 0.027) and DTE (p = 0.004), but no significant difference was observed when compared with E/e’ (p = 0.4).The set cut-off for LAS > 24.27% was significantly highly prevalent in the group of DD with increased LAP 78.9% when compared to the group without increased LAP 15.4%, p < 0.000  are key factors that initiate a systemic pro-inflammatory state that causes coronary microvascular endothelial inflammation, which contributes to LV stiffness and HFpEF development and progression . This paThere has been emerging and growing evidence the usefulness of LAS in the literature. Nevertheless, the data on the hypertension population is scarce. The usefulness of LAS has been proven to have a great prognostic value: in the incidence of atrial fibrillation after aortic valve replacement in patients with non-dilated left atria , reducedMondillo et al. found that LAS indices were reduced in hypertensive patients with normal LA size, suggesting that strain abnormalities precede structural LA changes in hypertension . SahebjaThe LAVi parameter of the left atrial structure is one of the cornerstones of the currently used parameters in diagnosing DD . In our A systematic review of 40 meta-analyses  revealed a normal reference range for reservoir strain of 39% 95% CI, 38–41%) . Only a –41% . OnStudies related to LVGS in arterial hypertension report that LVGS is less negative in individuals with arterial hypertension ,40, whicWe acknowledge that the limitations of the study are: Firstly, there was a small number of patients, and it was a one-center study; therefore, the data may be geographically and ethnically influenced. Secondly, the measurements are performed only noninvasively and not invasively. Invasive measurement is the gold standard for intracardiac pressure measurements but are difficult to achieve in everyday clinical practice due to numerous reasons; future studies could confirm the results of noninvasively measured parameters. Thirdly, the calculation of LAS is not very simple and not performed routinely in everyday practice, and it is still costly due to non-standard software, but in future years, with the advancement of technology, these difficulties can be overcome. Fourthly, the lack of data on follow-up or biomarkers such as natriuretic peptides. These data realized in future studies could provide significant value about LAS as a predictor of heart failure or adverse cardiovascular outcomes in a population of patients with arterial hypertension.In conclusion, the results of our study indicate that a set cut-off value below 24.27% for left atrial strain is a valuable, highly sensitive and specific marker of diastolic dysfunction that could be used in everyday practice to facilitate diastolic function assessments and easily reveal patients with diastolic dysfunction with increased left atrial pressure that is a risk factor and precedes heart failure in the population of patients with arterial hypertension. Our study and other larger studies can add additional value to include LAS in DD assessment in future clinical practice guidelines.


The updated listing criteria for heart transplantation are presented on behalf of the three heart transplant centres in the Netherlands. Given the shortage of donor hearts, selection of those patients who may expect to have the greatest benefit from a scarce societal resource in terms of life expectancy and quality of life is inevitable. The indication for heart transplantation includes end-stage heart disease not remediable by more conservative measures, accompanied by severe physical limitation while on optimal medical therapy, including ICD/CRT‑D. Assessment of this condition requires cardiopulmonary stress testing, prognostic stratification and invasive haemodynamic measurements. Timely referral to a tertiary centre is essential for an optimal outcome. Chronic mechanical circulatory support is being used more and more as an alternative to heart transplantation and to bridge the progressively longer waiting time for heart transplantation and, thus, has become an important treatment option for patients with advanced heart failure.The online version of this article (10.1007/s12471-021-01627-x) contains supplementary material, which is available to authorized users. Netherlands Heart Journal [In 2008 a committee under the supervision of both the Netherlands Society of Cardiology and the Netherlands Association for Cardiothoracic Surgery (NVVC and NVT) published the first guidelines for heart transplantation in the  Journal .Here we present updated listing criteria for heart transplantation, on behalf of the three centres involved in heart transplantation in the Netherlands: the Erasmus MC Rotterdam, the University Medical Centre Groningen and the University Medical Centre Utrecht. These new Dutch listing criteria mainly follow the updated guidelines of the International Society for Heart and Lung Transplantation (ISHLT), and are adapted to the local situation where necessary .The situation with regard to the number of heart transplantations in the Netherlands has not improved since 2008. On the contrary, the discrepancy between patients on the waiting list for heart transplantation and the number of donor hearts available has increased further, resulting in increasing waiting times.Fig. Survival after heart transplantation is good, as can be seen in Fig. S2  and as reported by the ISHLT , especiaGiven the scarcity of suitable donor hearts, there is presently no room for substantial broadening of the indications for heart transplantation. This would only result in an even bigger discrepancy between the number of patients on the waiting list and the number of heart transplantations performed, with an accompanying further increase in waiting time. Therefore, careful selection of potential candidates for heart transplantation is still mandatory.Because of the long waiting time, even for patients with acute progressive heart failure who are in urgent need of a transplant, the use of mechanical circulatory support (MCS) with a left ventricular assist device (LVAD) as a bridge to heart transplantation is growing substantially. Presently, according to the ISHLT registry, already 50% of heart transplants are performed using an LVAD as a bridge to transplantation .MCS is becoming more and more important in the treatment of advanced heart failure and the mid-term outcome with regard to survival and functional recovery is approaching that of heart transplantation –8, althoIn the light of the foregoing, selection of those patients who may expect to have the greatest benefit from a scarce societal resource in terms of both life expectancy and quality of life is inevitable Tab. .Table 1IMaximum tolerated doses of renin-angiotensin-aldosterone system inhibitors, beta-blockers and mineralocorticoid receptor antagonists.CRT-P/D has been considered and/or implanted in accordance with guidelines.Revascularisation, rehabilitation and other interventions to improve cardiac status and quality of life of patients have been considered and/or performed.VO2max ≤ 12 ml/min per kilogram on beta-blockers, ≤ 14 ml/min per kilogram in patients not on beta-blockers, or VO2max < 50% of predicted VO2 in younger patients and women.Patients who should be considered for heart transplantation are mainly those with severe symptoms of heart failure, and in rare cases those with intractable angina or malignant rhythm disturbances, for whom there is no alternative form of treatment available and whose prognosis is poor. In daily practice this means patients with severe, symptomatic, end-stage heart failure (New York Heart Association (NYHA) class IIIB to IV) despite (evidence-based) optimal medical and device therapy as apparent from the following:Strong motivation and a request by the patient to receive a heart transplant are mandatory.The selection of patients is based on three items, which have to be combined and put into context with the rest of the data. These diagnostic criteria are: cardiopulmonary stress testing, prognostic stratification and diagnostic right-heart catheterisation .VO2 ≤ 12 ml/min per kilogram should be used to guide listing. In patients intolerant to beta-blockers, a cutoff ≤ 14 ml/min per kilogram should be used. Especially in younger patients and women, ≤ 50% of predicted VO2 can be used as an additional criterion. In obese patients, expressing peak VO2 as ml/min should be considered, to prevent falsely low values when using ml/min per kilogram. Patients should not be listed solely on the criterion of a peak VO2 measurement [A maximal cardiopulmonary exercise test is defined as achievement of an anaerobic threshold on optimal pharmacological therapy with a respiratory quotient ≥ 1.05. In patients on beta-blockers, a cutoff for peak Assessment of prognosis is important in advanced heart failure to plan treatment and timely referral to a transplant centre, but can be difficult in the individual patient. Risk markers and prognostic scores are discussed extensively elsewhere . Heart fA Seattle Heart Failure Model estimated 1‑year survival of < 80% or a Heart Failure Survival Score in the high/medium risk range should be considered as reasonable cutoff points for listing. These scores are, however, not comprehensive and may overestimate survival in younger cardiomyopathy patients. Moreover, they do not incorporate haemodynamic data and cardiopulmonary exercise results.Patients should not be listed solely on the basis of prognostic scores for heart failure survival –15.Right-heart catheterisation should be performed in all adult candidates in preparation for listing for heart transplantation and repeated annually (or more often in the case of severe pulmonary hypertension) until transplantation. Often these diagnostic catheterisations are performed in the transplant centre, after optimal medical therapy. The test is performed to assess the severity of heart failure, to support optimisation of treatment and to determine the pulmonary vascular resistance (PVR). A higher PVR correlates with worse outcome after heart transplantation , 17.−5), while maintaining a systolic arterial pressure > 85 mm Hg. Drugs used for this acute challenge are prostacyclin i.v. and nitroglycerin i.v. Other drugs, such as nitric oxide, diuretics, inotropes and vasoactive agents can be used in hospitalised patients to improve haemodynamics.A vasodilator challenge should be performed when the pulmonary artery systolic pressure is ≥ 50 mm Hg and either the transpulmonary gradient  is ≥ 15 mm Hg or the PVR is > 3 Wood units , or the PVR index is > 6 Wood units · m2 (in children), or the TPG exceeds 16–20 mm Hg.When the PVR is > 5 Wood units , hepatitis B and C should be carefully analysed on an individual basis.There are scarce data on organ transplantation and MCS in selected HIV patients. In these selected patients short-term survival was similar to that of the general heart transplantation population, but data on long-term outcome are lacking –24. AlsoThe decision to accept potential candidates for heart transplantation with complex comorbidities should always consider the increasing shortage of donor hearts in general. Furthermore, it has to be realised that the management of antiretroviral therapy in combination with immunosuppressive therapy is very challenging due to substantial pharmacological interactions , 25 and Patients with a resolved hepatitis B infection may be considered candidates for heart transplantation, but require full serological and viral load testing at screening and every 3 months while listed as well as at the time of transplantation. In all patients with a chronic hepatitis B infection, liver biopsy should be performed to exclude severe disease. Cirrhosis, portal hypertension or hepatocellular carcinoma are contraindications to heart transplantation. Clearly, acute hepatitis B is also a contraindication .Patients with resolved or prior inactive hepatitis C infection may be considered candidates for heart transplantation, but require full serological and viral load testing at screening and every 3 months while listed as well as at the time of transplantation. In patients with chronic hepatitis C infection, hepatitis C virus genotyping and a liver biopsy are required. Cirrhosis, portal hypertension or hepatocellular carcinoma are contraindications to heart transplantation .Extensive analysis of hepatitis B and hepatitis C candidates by an experienced hepatologist is always indicated.An active neoplasm from origins other than superficial skin  is an absolute contraindication to heart transplantation due to the limited survival rates . HoweverCompliance, the capacity to adhere to a complex lifelong regime of drug therapy, lifestyle changes and regular follow-up, is a crucial element in attaining long-term success after transplantation . This inAlso substance abuse  and tobacco use have to be taken into consideration as it is thought that especially substance abuse is an important predictor of non-compliance . TobaccoTo evaluate the patient’s ability to comply with instructions, including drug therapy, a psychosocial assessment should be performed before listing for transplantation.Severe peripheral or cerebrovascular disease may contribute to both poor prognosis for survival as well as poor quality of life on a non-cardiac basis and therefore should be considered as a major comorbidity that can preclude eligibility for heart transplantation .The severity of symptoms and the potential options for revascularisation may affect this decision, although it is not clear whether post-transplant risk can indeed be modified by revascularisation.All comorbidities which adversely impact prognosis after transplantation should be weighed individually.Age has to be seen as a continuous risk factor for outcome after heart transplantation [antation . The incantation , 31.Chronic kidney disease is a very important risk factor for mortality after transplantation. Irreversible renal dysfunction with a glomerular filtration rate (GFR) < 30 ml/min per 1.73 m2, as estimated by the creatinine clearance or estimated GFR, should be considered an absolute contraindication for heart transplantation alone [Diabetes mellitus with signs of end-organ damage  or persistent poor glycaemic control is a relative contraindication for transplantation [antation , 32.Obesity, defined as a body mass index (BMI) > 35 kg/m2, results in patients experiencing longer waiting times and being less likely to receive a suitable donor heart. Post-transplant morbidity and mortality are higher in such patients. Therefore, it is reasonable to strongly recommend weight loss to achieve a BMI < 35 kg/m2, and preferably < 32 kg/m2, before listing for cardiac transplantation [antation –35.Cardiac amyloidosis is a rare disease characterised by the infiltration of misfolded proteins in several organs, such as heart, kidneys and peripheral nerves. Several types are known, of which AL (light chain) amyloidosis and TTR (transthyretin) amyloidosis may affect the heart. Evaluation and treatment should be restricted to experienced centres. AL amyloidosis is essentially a malignant haematological disease which should be treated by chemotherapy and preferably stem cell transplantation. TTR amyloidosis can be familial due to a mutation, or a result of older age (wild-type or senile). As the TTR protein is primarily produced in the liver, in mutant TTR amyloidosis liver transplantation or combined liver and heart transplantation has been performed in highly selected patients. The results of liver transplantation alone are disappointing because of ongoing wild-type TTR deposition in the heart after liver transplantation. The survival rate after combined liver and heart transplantation is better, but the numbers are low and reliable long-term follow-up is lacking [ lacking , 37. Rec lacking . In wildSeveral new drugs for the treatment of TTR amyloidosis, such as tafamidis and patisiran, recently became available, which will certainly impact future treatment .As stated above, the indications and contraindications for heart transplantation as well as the guidelines for the acceptance of donor hearts are broadly defined. The final decision regarding acceptance is made by the heart transplant team, which has a thorough knowledge of the treatment of patients with advanced heart failure, on the one hand, and extensive experience with heart transplantation and MCS, on the other. Heart transplantation is a very limited and complex treatment modality for only a few patients. It requires a dedicated team of specialists, consisting at least of the following: cardiologists trained in advanced heart failure, heart transplantation and MCS, as well as infectious diseases and immunology; cardiothoracic surgeons with extensive experience in surgical treatments for advanced heart failure; anaesthesiologists with cardiac experience; and specialist nurses and psychologists/social workers.To re-emphasise the point, in contrast to other complex medical therapies, heart transplantation is a form of therapy with very limited ‘resources’ and therefore requires extensive judgement to make the most optimal use of this modality. For this reason it is also important that outpatients on the waiting list for heart transplantation should be regularly re-evaluated (at least every 6 months), preferably with cardiopulmonary exercise testing and heart failure prognosis scores. If the patients have improved significantly, they should be considered for delisting .In case a patient or his/her referring physician does not agree with the decision made by the transplant team of one centre, it should be possible to obtain a second opinion from one of the other centres.All heart failure patients should undergo regular follow-up to detect progression of symptoms and disease and to estimate their long-term prognosis. Timely referral to a tertiary centre for advanced heart failure to consider advanced therapies, such as heart transplantation and MCS, is essential . MarkersWhen a patient is referred to a transplant centre, extensive written and imaging data should be supplied, including a summary of the complete medical history and current data, including: cardiac and non-cardiac history; chest radiograph; results of laboratory examination; operative report in case of prior cardiac surgery; heart catheterisation data; cardiac imaging, including echocardiogram and magnetic resonance imaging; results of exercise test, if available; psychological/social information, if available.Nederlandse Transplantatie Stichting (NTS), which has outsourced the specific allocation to Eurotransplant (ET). Organs are allocated according to blood group, body size, medical urgency and waiting time. Final acceptance of a donor heart is the responsibility of the transplantation team, which considers all the donor data in combination with the current situation of the potential recipient. For heart donation, the upper age limit is ± 65 years. The only absolute cardiac contraindication for heart donation is the presence of significant heart disease, such as angina pectoris, myocardial infarction, prior coronary bypass surgery, moderate to severe valvular disease, cardiomyopathy or important arrhythmias. General contraindications for all donations are, for example, untreated sepsis, malignancies and infections without adequate treatment.According to the Dutch law on organ donation, all organs are allocated centrally, using patient-oriented allocation according to prespecified requirements determined by the centres. Responsibility lies with the In the work-up of a potential heart donor, the medical history, an electrocardiogram and a transthoracic echocardiogram are essential, in addition to haemodynamic data and markers for cardiac damage, including troponin. In case left ventricular function cannot be reliably evaluated by transthoracic echocardiography, because of an insufficient acoustic window in a ventilated patient, transoesophageal echocardiography is mandatory. In haemodynamically unstable patients, a Swan-Ganz catheter should be used to optimise the filling pressures of the patient. Given the generally higher donor age in the Netherlands, coronary angiography is advised to rule out significant coronary artery disease in older donors (i.e. > 50 years) or other patients with risk factors for coronary artery disease.With respect to the shortage of donor hearts in the Netherlands, two important initiatives have to be mentioned that hopefully will lead to an increase in the number of useable hearts. The first is the new law on organ donation, which involves active donor registration and recently came into force. The second is the recent introduction in the Netherlands of the use of donor hearts after circulatory determined death (DCD). Until recently, only hearts from donors following brainstem death (DBD) were used for transplantation. However, about half of all organ donations in the Netherlands are DCD procedures of which the kidneys, liver and lungs are used for transplantation. Recent developments in organ perfusion and retrieval techniques also allow the safe use of hearts from these donors, as was demonstrated by several centres in the UK and resulted in a substantial increase in the number of donor hearts .As mentioned in the Introduction, due to the shortage of donor hearts and the progressively increasing waiting time, more and more patients are being treated by an LVAD as a bridge to transplantation. Indications and contraindications for LVAD therapy can be found in the ‘Consensus Document LVAD therapie van de Werkgroep Mechanical Circulatory Support NVT-NVVC’ .Already 50–70% of the patients receiving heart transplants have had an LVAD implanted first and the expectation is that this percentage will grow even further. If the number of available donor hearts does not increase substantially, given the current promising short- and medium-term outcome after LVAD implantation, the surgical treatment of advanced heart failure will change considerably in the coming years [Only patients with primarily right-sided heart failure, complex congenital heart disease or hypertrophic cardiomyopathy may undergo primary heart transplantation. All other patients will undergo long-term MCS first and only in the case of complications not amenable to LVAD replacement will heart transplantation be considered. A growing number of patients in whom an LVAD is implanted as a bridge to transplantation do already prefer not to be placed directly on the waiting list for heart transplantation , 9. On tHeart transplantation is still considered to be the gold standard therapy for refractory heart failure in carefully selected patients with a high likelihood of improvement after the transplantation.Timely referral to a transplant centre should be considered in those patients demonstrating markers of advanced heart failure, such as a requirement for i.v. inotropes, persisting NYHA class III or IV, progressive renal failure, severe left or right ventricular dysfunction, recurrent ICD shocks, more than one hospitalisation in the previous year, persisting fluid overload or increasing diuretic requirement, progressive cardiorenal syndrome and the inability to tolerate evidence-based therapy. Given the scarcity of donor hearts, careful selection of the most suitable candidates is mandatory. The growing discrepancy between potential recipients and the availability of donor hearts results in a growing number of patients who need an LVAD first, as a bridge to transplantation. New initiatives, including active donor registration and DCD heart donation, will hopefully have a positive effect on the availability of donor hearts in the Netherlands.Fig. S1. Median donor age by location according to the International Society for Heart and Lung Transplantation Fig. S2. Survival (%) after heart transplantation according to the International Society for Heart and Lung Transplantation