Preterm birth and low birthweight have been associated with increased risk of heart failure and cardiovascular disease in young adulthood. However, results from clinical studies of myocardial function are not consistent. Echocardiographic strain analyses allow detection of early stages of cardiac dysfunction, and non-invasive estimates of myocardial work can provide additional information on cardiac function. We aimed to evaluate left ventricular (LV) myocardial function including measures of myocardial work in young adults born very preterm  or with extremely low birthweight (< 1000 g) (PB/ELBW), compared with term-born age- and sex matched controls.63 PB/ELBW and 64 controls born in Norway in the periods 1982–1985, 1991–1992, and 1999–2000 were examined with echocardiography. LV ejection fraction (EF) and LV global longitudinal strain (GLS) were measured. Myocardial work was estimated from LV pressure-strain loops after determination of GLS and construction of a LV pressure curve. Diastolic function was evaluated by determination of the presence or absence of elevated LV filling pressure, including measures of left atrial longitudinal strain.The PB/ELBW with mean birthweight 945 (standard deviation (SD) 217) grams, mean gestational age 27 (SD 2) weeks, and mean age 27 (SD 6) years had LV systolic function mainly within normal range. Only 6% had EF < 50% or impaired GLS >-16%, but 22% had borderline impaired GLS between − 16% and − 18%. Mean GLS in PB/ELBW  -20.0, -18.9)) was impaired compared to controls ), p = 0.003. Lower birthweight was associated to more impaired GLS (Pearson correlation coefficient − 0.2). Means of EF, measures of diastolic function including left atrial reservoir strain, global constructive and wasted work, global work index and global work efficiency was similar in PB/ELBW and controls.The young adults born very preterm or with extremely low birthweight had impaired LV-GLS compared to controls, although systolic function mainly within normal range. Lower birthweight was associated with more impaired LV-GLS. These findings could indicate an elevated lifetime risk of developing heart failure in preterm born individuals. Measures of diastolic function and myocardial work were similar compared to controls.The online version contains supplementary material available at 10.1186/s12872-023-03253-4. Due to improvement in neonatal intensive care over the last decades neonates born extremely preterm (< 28 weeks of gestation) now have survival rates > 80% –3, thus Large register-based studies have found increased risk of heart failure in adolescents and young adults born preterm , 12, butTraditionally, definitions of, and guidelines regarding management of heart failure have been based on measures of EF. In later years, echocardiographic speckle-tracking derived strain analysis has allowed detection of subclinical early stages of LV dysfunction, and its role in risk stratification is increasing . AdditioWe had the opportunity to investigate myocardial function in a cohort of young adults born very preterm or with extremely low birthweight, who have been followed since birth by the Project Extreme Prematurity in Bergen, Norway. The aim of this study was to investigate the impact of preterm birth and low birthweight on left ventricular myocardial function at young adult age, by adding new echocardiographic parameters such as MW and LA longitudinal strain to measures of LV EF, LV longitudinal strain and traditional echocardiographic measured markers of diastolic function.The Project Extreme Prematurity, organized by the WestPaed Research group in Bergen, Norway, has included three regional cohorts of in total 153 young adults born very preterm or with extremely low BW (PB/ELBW), and in total 139 individually age and sex matched term-born controls. Inclusion criteria were birth at GA < 29 weeks or extremely low BW < 1000 g. Subjects born in 1982–1985 (cohort 1) and in 1991–1992 (cohort 2) were retrospectively recruited, while those born in 1999–2000 (cohort 3) were prospectively recruited. The inclusion and longitudinal follow-up of these cohorts have been described in detail previously , 28. In During the period 2017–2020 the participants were invited to a third follow-up, including a first-time echocardiographic examination. A total of 127 participants were examined, including 63 PB/ELBW subjects (43% men) and 64 controls (44% men) . Of the participants, 49 belonged to cohort 1, 37 to cohort 2, and 41 to cohort 3.The Regional Committee for Medical and Health Research Ethics of the Western Norway Health Authority approved the study (REC 2017/0068). Written informed consent was obtained from all participants.All echocardiographic examinations were performed on a Vivid E9 ultrasound system  using a 5Sc (1.5–4.6 MHz) or equivalent 4Vc-D (1.4–5.2 MHz) transducer for all imaging. All images were saved as three consecutive cardiac cycles during sinus rhythm, on external hard drives allowing offline analyses using the echocardiographic software, EchoPAC version 204 . All participants underwent a comprehensive functional echocardiographic examination, which included grayscale images optimized for 2-dimensional (2D) speckle analysis. The images were analysed according to recommendations from the European and American Society of Echocardiography –31 and aLV EF was calculated using the modified Simpson biplane technique and from long-axis 2-dimentional (2D) measurements using the Teicholz formula. LV wall thickness, LV internal diameter and myocardial mass index ) were calculated using long-axis end-diastolic 2D measurements. Diastolic function was evaluated as recommended by determination of the presence or absence of elevated LV filling pressure , and wasGray scale images for 2D speckle-tracking analysis were acquired at frame rate (frames/second) to heart rate (beats/minute) ratio 0.7–0.9. Longitudinal strain curves from one ventricular cycle from standard apical four, three and two chamber view images, analysed for 18 subsegments, were used for LV longitudinal strain assessment. For LA longitudinal strain assessment, we used longitudinal strain curves from one atrial cycle from apical four chamber view images, with zero reference point set at the start of the ECG R-wave.Speckle-tracking of the LV and the LA were performed using automated function imaging (AFI). Visual inspection ensured that the region of interest (ROI) included the whole of the myocardium from the atrioventricular valve annulus to the LV apex or LA roof and from the endocardial border to the epicardial border. If the automatic tracking was not satisfactory, the ROI was adjusted manually until the best possible tracking was obtained. LV tracking compromised by artefacts/shadows or image acquisitions with less than five of six appropriately tracked segments per apical view were excluded. Peak systolic longitudinal strain was measured at aortic valve closure for LV measures and at end-systole for LA measures. MW was calculated by the EchoPAC software after determination of LV peak systolic global longitudinal strain (LV-GLS) and construction of a LV pressure curve. The LV pressure curve was derived from non-invasive brachial blood pressure (BP) measures and the timing of the cardiac cycles` isovolumetric and ejection phases, which were defined by opening and closure of the mitral valve. The area of the LV pressure–strain loop represents MW. Since work by definition equals force times length, the use of pressure and strain does not provide a direct measure of work, but can be used as a valid approximation of it as the method is found to strongly correlate to invasively measured MW , 23. GloIn this paper, LV-GLS describes the average peak systolic longitudinal strain from all three left ventricular apical views, and LV-4 C-LS is used to describe the peak systolic LV longitudinal strain from the apical four chamber view Fig. .LA reservoir, conduit, and contractile strain generated from LA longitudinal strain analyses from the apical four chamber view images are used to describe LA reservoir function during LV systole, conduit function during early diastole, and booster pump function during late diastole Fig. . All lonMyocardial global constructive work (GCW), which contributes to ejection, is used to describe the mean net effect resulting from positive LV work (shortening) during systole plus negative LV work (lengthening) during isovolumetric relaxation in all 18 LV segments. Myocardial global wasted work (GWW), which does not contribute to ejection, is used to describe the mean net effect resulting from negative LV work during systole plus positive LV work during isovolumetric relaxation in all 18 LV segments. Global work index (GWI) is used to describe total performed LV work from the opening to the closure of the mitral valve, and global work efficiency (GWE) is used to describe global constructive work relative to the total of global constructive and waste work (GWE = GCW/(GCW + GWW)). MW values are described as pressure percentages (mmHg%) as they are derived from LV pressure-strain loop analysis Fig. .2 /s [EF Simpson and EF Teicholz ≥ 50% were considered normal and EF < 50% considered reduced. LV-GLS >-16% was considered abnormal, -16% to -18% borderline normal, and <-18% normal , 33. Abn2 /s .Mean reference values of measures of MW are former described in the NORRE study as GWI 1896 mmHg%, GCW 2232 mmHg%, GWW 78.5 mmHg% and GWE 96% , 35.Mean reference values of LA strain are previously described as 39% for reservoir strain, 23% for conduit strain, and − 17% for contractile stain based on findings in a meta- analysis which included both ECG p-wave (P-P gated) or QRS complex (R-R gating) as initiation of LA stain calculations .All imaging and analyses were performed by a single experienced cardiologist (B.E). A random sample of 10 study participants were obtained for inter- and intra-rater analyses. Another experienced cardiologist (T.O) performed the re-analysis for inter-rater reliability. Both were blinded to group affiliation (PB/ELBW or control) and to the original results during re-analyses.Inter-rater reliability measured by a 2-way mixed-effect model for absolute agreement was 0.8  0.04, 0.9) for EF Teich, 0.9  for LV-GLS, 0.8  for GWI, and 0.8  for LA reservoir strain. Intra-rater reliability measured by a 2-way mixed-effect model for absolute agreement was 0.8  for EF Teicholz, 0.8  for LV-GLS, 1.0  for GWI, and 0.9  for LA reservoir strain.BP was calculated as the average of three measurements with an automated oscillometric device  at rest in supine position.Descriptive variables are presented as numbers (%) and outcome data as means with 95% CI or standard deviation (SD). The Kolmogorov- Smirnov test was used to test the normality of the outcome variables, and independent samples t-test  or two samples Kolmogorov-Smirnov test was applied for comparison between groups, as appropriate. For comparison of descriptive data Chi-square test or Fisher`s exact test was applied, as appropriate.Linear regression analyses were used to identify confounders. Analyses of covariance (ANCOVA) was used for comparison between PB/ELBW and controls for height, weight, and BSA (according to Du Bois formula) adjusted for sex, for LV longitudinal strain adjusted for BSA and echocardiography transducer difference, and for EF, LA volume index, LA strain, and MW parameters adjusted for transducer difference.Re-analyses were done excluding outliers, but this did not significantly affect the results.To investigate whether the difference in echocardiographic measures between PB/ELBW and controls differed by sex, an interaction term for sex and group affiliation was added.Comparisons of descriptive variables and outcome data between subgroups of study participants were done by Chi-square test or Fisher`s exact test, Welch´s ANOVA or classic one-way ANOVA , or by multiple comparison analyses (with Sidak correction) with the same adjustments as described above, as appropriate.Pearson correlation coefficient (PCC) was used to explore associations between echocardiographic measured myocardial function and descriptive variables. GA was set to 40 weeks in controls when correlations regarding GA was made.Inter- and intra-rater reliability were measured by a 2-way mixed-effect model for absolute agreement.All tests were two-sided, and p < 0.05 was considered statistically significant. All statistical analyses were performed using SPSS version 26.0 .The participants consisted of 63 PB/ELBW subjects and 64 age- and sex matches controls. The PB/ELBW group had significantly lower height and weight, with consequently lower BSA, compared to the control group. There was no significant difference for mean age, body mass index, BP, or smoking status between the groups. The age range was 18–37 years in both the PB/ELBW and the control group. BW in the PB/ELBW group ranged from 450 to 1480 g with mean BW 945 (SD 217) grams. GA ranged from 23 to 34 weeks with mean GA 27 (SD 2) weeks  versus − 20.6%  (p = 0.003) .Among the PB/ELBW, 4 had reduced EF Simpson, 11 had borderline impaired LV-GLS, and 3 had impaired LV-GLS. Among the controls one had reduced EF Simpson, 6 had borderline impaired LV-GLS, and none had impaired LV-GLS.Parameters of LV diastolic function were mainly normal and similar in the PB/ELBW and controls. Of the PB/ELBW, 2 had abnormally low septal e´ velocity, 3 had abnormally low lateral e´ velocity, none had abnormally high average E/e´, 1 had abnormally high tricuspid-valve regurgitation peak gradient, and none had abnormally high LA volume index.Of the controls, 2 had abnormally low lateral e´ velocity, and 3 had abnormally high LA volume index, otherwise the parameters were normal. None of the participants had more than one abnormal parameter associated with diastolic dysfunction.The mean LA reservoir strain, conduit strain, and contractile strain were similar in PB/ELBW and controls Table ; Fig. 5.LA reservoir strain, conduit strain, and contractile strain were also similar in PB/ELBW and controls when re-analysed while using atrial cycle with zero reference point set at the start of the ECG p-wave.Myocardial work MW was calculated after determination of LV-GLS and BP in 49 PB/ELBW and 51 controls. Mean LV-GLS was significantly impaired and mean BP was similar in these PB/ELBW compared to these controls. Mean LV-GLS was − 19.4%  in PB/ELBW and − 20.6  (p = 0.003) in the controls. Mean BP was 112/69 mmHg (SD 11/7) in PB/ELBW and 111/69 mmHg (SD 11/8) in controls (p = 0.9 and 1.0). One control had systolic BP > 140 mmHg, otherwise BP were below 140/90 mmHg in all participants.MW is influenced by the contraction power of the myocardial fibres, the LV loading conditions, and the wall stress applied on the LV segments . LV dimeThe MW described as means of GWI, GCW, GWW, and GWE were not significantly different in PB/ELBW and controls, and the measures were close to former described reference values . HoweverGWI, GCW, GWW, and GWE were not significantly associated to BW or GA.Participant characteristics and echocardiographic findings across the three cohorts of PB/ELBW are described in a table in Additional file 2. There were no differences between the cohorts regarding measures of left ventricular systolic and diastolic function, including measures of MW. Additionally, there was no significant associations between treatment in the prenatal and neonatal period  and measures of myocardial function.In 63 young adults born very preterm or with extremely low BW, we found impaired LV-GLS compared to sex-and age matched controls, but mainly normal systolic function including estimates of MW. Diastolic function including measures of LA longitudinal strain was preserved. Lower BW was associated with more impaired LV-GLS and increasing chronological age was associated with decreasing diastolic function.Our finding of similar EF in young adults born preterm or with low BW compared to controls, but reduced LV function measured by longitudinal strain, are similar to studies by Huckstep et al.  and LewaSimilar to our study, Goss et al.  reportedTo add further information on myocardial function we estimated MW non-invasively. In subjects with cardiac remodelling and elements of myocardial fibrosis, which has been reported in preterm born young adults , 44, we The additive value of these new parameters describing myocardial function over the traditional ones is still object of study, and further studies are needed to establish clinical utility and prognostic impact. Estimation of MW could add information to distinguish whether reduced contraction patterns are caused by newly emerged hypertension or attenuated contractility, since the increased afterload will reduce EF and LV-GLS, but increase GWI and GCW . This maOur study population consisted of three cohorts born in different decades (early 1980s to 2000), in a period with significant changes in the neonatal medical treatment. There was no difference in parameters of left ventricle myocardial function across the cohorts. However, the study samples within the cohorts of the preterm born were too small to reveal minor group differences regarding myocardial function.There has been an increasing use of prenatal corticosteroids and assisted ventilation during the period, and the use of surfactant was introduced in the early 1990s. Additionally, the techniques have improved, from assisted ventilation mainly by intermittent or continuous positive pressure ventilation via an endotracheal tube in the early period to increasing use of nasal continuous airway pressure and high frequency oscillatory ventilation during the 1990s . The PB/This study is part of a long-term cohort study following individuals born PB/ELBW and individually age and sex matched term-born controls. The study design, and similarity of the PB/ELBW and control group at the time of the assessment reduces the risk of confounding. To diminish procedure related variance the echocardiographic imaging and off-line analyses were performed by one highly trained sonographer using the same ultrasound system and echocardiographic software. The calculated intra- and inter-rater variability were good to excellent .There were limitations to the study. Only 42% of the eligible PB/ELBW subjects were examined. Those who did not participate had similar GA, occurrence of moderate or severe bronchopulmonary dysplasia , and dayOnly four chamber view images were used for analyses of LA strain while reference values and guidelines are based on measures of two- and four chamber view images. The mean values for LA strain might therefore deviate from reference values, but would not affect the analysis of group difference between PB/ELBW and controls. However, the mean LA peak longitudinal strain in our control group (39.7%) was similar to former reported reference values in healthy subjects (39%). Although R-R gated LA strain analysis is recommended in the guidelines and more frequently used, P-P gating has been found to correlate better to new-onset heart failure and to 3-dimentional echocardiographic-derived measures , 52. LA LV-GLS, but not estimates of MW, were found impaired in PB/ELBW compared to controls. The study was not designed to prove the superiority of MW to LV-GLS, and although analyses of MW have been considered an advancement of LV strain analyses due to reduction of the strain analysis` load dependent limitations , 21, theYoung adults born very preterm (< 29 weeks of gestation) or with extremely low BW (< 1000 g) had impaired LV-GLS compared to term-born controls, although mainly normal systolic function. Myocardial function measured by MW and diastolic function were preserved. Lower BW was associated with more impaired LV-GLS and increased chronological age was associated with decreasing diastolic function. These findings could indicate an elevated risk in preterm born young adults of developing heart failure. Given the increasing survival rate of preterm born neonates it is of public health interest to generate prevention strategies to reduce modifiable risk factors and to implement long-term cardiovascular follow-up in this group. Further studies are needed to investigate the impact of preterm birth and low BW on myocardial function in young adulthood to optimize risk stratification.Below is the link to the electronic supplementary material.Additional File 1: Flow chart of the study populationAdditional File 2: Characteristics and echocardiographic measures of participants born very preterm/with extremely low birthweight by cohort


Proper ventriculo-arterial coupling results in optimal cardiac output, adequate peripheral organ perfusion, and efficient circulation.The relation between stroke volume and the developed arterial pressure defined by the relative elastances of the left ventricle and arterial circuit reflect ventriculo-arterial coupling. Decoupling of either or both commonly occur in sepsis and are associated with inefficient LV ejection that can lead to LV failure. Ventriculo-arterial decoupling in sepsis can lead to decreased effectiveness of cardiovascular treatments.The left ventricular (LV) ejection phase interaction between the cardiac function and the arterial system is called ventriculo-arterial coupling (VAC) and reflects global cardiovascular performance and efficiency . The goaSeptic shock is a life-threatening condition resulting from an uncontrolled host inflammatory response to infection  leading In this regard, septic shock can disrupt the normal interaction between both the heart ejecting its stroke volume and the arterial central vessels receiving it causing ventricular–arterial decoupling. Such decoupling in septic shock is a key factor in the pathologic processes of hemodynamic instability  and the This review will focus on the macro-physiological aspects of LV VAC in septic shock and why treatments aimed at restoring cardiovascular homeostasis are affected.Ventriculo-arterial coupling (VAC) refers to the dynamic interaction between the ventricular pump ejection and the subsequent change in arterial pressure , 5–7. ItLeft ventricular systolic pump function can be simplistically quantified as the end-systolic pressure–volume relations (ESPVR) whose slope, called end-systolic elastance (Ees) Fig. , definesSimilarly, the arterial outflow pressure can also be described as the relation between changing LV stroke volume and end-systolic pressure Fig. . The sloThe ratio Ees/Ea defines VAC Fig. . Normal In disease states where the cardiovascular system is involved either primarily or secondarily to treatments, VAC is frequently altered . Furthermyocardial depression with preserved cardiac output (CO)heterogeneous response to vasopressors in hypotensionpulmonary artery hypertension in acute respiratory distress syndrome (ARDS)Patients with septic shock show a large heterogeneity in response to standardized treatment making the effective application of such standardized treatments across patients problematic . Much ofMyocardial depression is often seen in septic patients, though CO may not be decreased if fluid resuscitation is also given, owing to the associated decrease in arterial pressure caused by sepsis-induced vasoplegia. We have previously described the physiology of VAC in critically ill septic patients  and the In analyzing a cohort of septic shock patients in whom Ea and Ees were measured at several time intervals , we noteMost clinicians consider that reduced myocardial function should cause reduced systemic flow. However, by analyzing VAC during sepsis, one can see how blood flow can be maintained despite a reduced Ees and a preserved LV ejection fraction (LVEF). Recall that LVEF depends on both contractility and arterial elastance. Vasodilators increase LVEF while vasopressors decrease it. This implies that the use of vasopressors or other agents that selectively increase arterial tone in a septic shock patient with myocardial depression, while potentially improving blood pressure, may decrease LVEF enough to reduce CO. Indeed, the use of nitric oxide synthetase inhibitors in sepsis uniformly demonstrated that the increase in arterial pressure was associated with a decrease in CO . FurtherThe case of myocardial depression and preserved CO in a septic shock patient following volume resuscitation nicely illustrates how by measuring VAC we can understand whether our treatments can have hemodynamic consequences beyond the apparently responsive (for example preserved CO) or non-responsive (persistent low MAP) macro-hemodynamic values coming from bedside monitoring displays. A decoupled physiology means a high myocardial energetic cost to maintain the “normal values” of CO , and expA typical example of such pathophysiological inference on clinical management is described by one of the patients in whom we administered norepinephrine to restore MAP < 65 mmHg despite fluid resuscitation in the presence of preserved CO. In this case, we observed  that vasThe current recommended approach to rapidly counteract the impact of sepsis on blood flow in the first few hours after diagnosis and promptly restore adequate blood flow and perfusion pressure consists of an initial volume expansion (VE) with crystalloids to achieve the mean arterial pressure (MAP) of at least 65 mmHg . If thisThis standardized approach to cardiovascular stabilization achieves the target in restoring MAP in the majority of patients but not in all. Previously reported success rate for VE was around 60%, and we also reported that such approach is not successful in all cases , and undFrom a physiological point of view fluid resuscitation increases circulating blood volume and thus mean systemic pressure (Pms) –18, whicWe showed in a previous clinical study that NE could increase Ea and MAP in most hypotensive septic patients but did not achieve a MAP > 65 mmHg in a majority and induced ventriculo-arterial uncoupling to levels seen prior to resuscitation . This deWhen dobutamine was added to VE and norepinephrine in a few patients, it restored normal VAC and CO, suggesting that inotropic support may improve contractility in septic patients who may be affected by septic cardiomyopathy.These observations support the concept of monitoring VAC at the bedside in septic shock patients to personalize treatment and assess the response. We recently suggested a structured approach that incorporates VAC measurement and hemodynamic monitoring to better inform treatment decisions (FIG BEAT modified) . Based oPulmonary hypertension (PulHPT) and right ventricular (RV) dysfunction can have significant implications in sepsis complicated by acute respiratory distress syndrome (ARDS). ARDS occurs in approximately 6–7% of the patients with sepsis , 20, wheIn combined sepsis and ARDS, the development of pulmonary hypertension leads to disrupted right-sided VAC , 23, makPulmonary hypertension leads to an increase in the afterload on the right ventricle (RV). In the context of sepsis with ARDS and pulmonary hypertension, RV ventriculo-arterial decoupling occurs due to both an increase in pulmonary Ea and a decrease in RV Ees. Thus, the right ventricle’s ability to generate pressure and sustain CO is limited. As RV workload increases further, its contractile function may become impaired, further decreasing RV stroke volume and CO, while increasing right atrial pressure. Such venous congestion further impairs organ blood flow.Overall, the disruption of RV VAC due to both pulmonary hypertension and right ventricular dysfunction in sepsis with ARDS can have significant consequences on cardiovascular function. Monitoring and managing the hemodynamic status of these patients is essential to optimize ventricular performance and maintain adequate blood flow throughout the body. Interventions may include vasopressors to sustain RV coronary blood flow, inotropic agents, and therapies aimed at reducing pulmonary vascular resistance to improve ventricular–arterial interaction and overall cardiac function , 25.Since VAC is defined by the ratio of arterial elastance (Ea) to left ventricle (LV) end-systolic elastance (Ees), the tools used must be capable of measuring both Ea and Ees .Invasive ventricular catheterization allows for pressure/volume loop analysis, which was initially demonstrated by Suga and Sugawa –29 can bTo assess ventriculo-arterial coupling (VAC) in critically ill patients, diagnostic tools that can be easily brought to the bedside and used repeatedly are required. Non-invasive methods can be used. Ea can be estimated as the ratio of end-systolic pressure to stroke volume. End-systolic pressure is approximately 90% of systolic pressure. Ea is calculated as [0.9 × systolic arterial pressure]/SV) . HoweverEes can be estimated using the modified single-beat method proposed by Chen et al. It is the most accurate and well-validated to estimate Ees –32. ThisTo facilitate the bedside calculation of Ees, we developed a mobile app called “iElastance” Fig. , freely The application is easy to use and provides rapid bedside assessment of VAC following a focus echocardiographic examination. While the application cannot replace clinical evaluation and judgement, it can be helpful, especially in critically ill patients where the initial therapeutic intervention did not achieve the expected effect, In the recent literature, the iElastance app has been reported to be easily measurable and have a clinical impact , 35.Measuring the coupling between the right heart ventricle and the arterial system in septic patients is also essential for understanding RV performance and its interaction with the pulmonary circulation, especially in light of the pathophysiological scenarios described above .Similar to the left heart, invasive ventricular and pulmonary artery catheterization allows for pressure/volume loop analysis. However, non-invasive approaches have also been introduced for assessing the right side of the heart –39, the The considerable variability observed in responses to time and treatment of septic shock patients poses challenges when trying to apply standardized interventional protocols. The inherently varied VAC status of these patients affecting Ees, Ea or both requires that the bedside clinician develop a deeper understanding of the mechanisms underlying the hemodynamic instability and to measure VAC in complex patients. Non-invasive echocardiographic assessment of VAC has shown to be a valuable tool in evaluating the intrinsic factors contributing to hemodynamic impairment in human septic shock and monitoring the effectiveness of therapeutic interventions Table .Table 1EGiven that septic shock patients often have impaired cardiovascular reserve, a more personalized approach to therapy, tailored based on volume responsiveness and VA coupling, may be essential to achieve effective and efficient resuscitation from severe sepsis. Integrating bedside assessment of Ea and Ees with dynamic indexes of fluid responsiveness provides a multi-modality approach that enhances our understanding of the pathophysiology and should guide personalized management of the severe hemodynamic instability seen in septic shock.


The average levels for PICP, P3NP, and Gal-3 were 457.2 ± 240 µg/L, 242 ± 199.9 µg/L, and 10.7 ± 3.7 ng/mL, respectively. In regression analysis, PICP was strongly associated with all four echocardiographic parameters . P3NP and Gal-3 were only associated with the EF . Conclusion: Our study evidenced that PICP, a collagen-derived biomarker, is associated with important echocardiography parameters, suggesting that it can serve as an indicator of the presence of subclinical systolic and diastolic dysfunction in patients with advanced CKD.Background: Myocardial fibrosis represents a mainstay pathway in the pathophysiology of uremic cardiomyopathy. This process leads to structural and functional changes in the heart, which can be detected by echocardiography. The purpose of our study was to determine the association between four echocardiographic parameters (ejection fraction (EF), global longitudinal strain (GLS), mean E/e’ ratio, and left atrial volume indexed) and biomarkers associated with cardiac fibrosis, such as procollagen type I carboxy-terminal propeptide (PICP), procollagen type III N-terminal peptide (P3NP), and galectin-3  in patients with end-stage renal disease (ESRD). Methods: 140 patients with ESRD were enrolled and investigated by echocardiography and the serum levels of the aforementioned biomarkers were determined at baseline. Results: The mean EF was 53.63 ± 8%, the mean GLS was −10.2 ± 5.3%, the mean E/e’ ratio was 9.8 ± 4.3, and the mean left atrial volume indexed (LAVI) was 45.8 ± 14.2 mL/m Patients with chronic kidney disease (CKD) present an elevated cardiovascular risk, being considered the leading cause of death in this high-risk population . When thThe pathophysiological image of cardiovascular disease (CVD) in patients with ESRD includes traditional associated factors such as sympathetic overactivity, diabetes, dyslipidemia, and smoking, and the unconventional ones represented by inflammation, vascular calcifications, increased arterial stiffness, and autonomic instability ,3. TheseCardiac fibrosis, described by the increased collagen type I deposition and cardiac fibroblast activation and differentiation into myofibroblasts, is a common pathophysiologic escort of most heart diseases such as myocardial infarction, different types of cardiomyopathies, and hypertensive heart disease . These cMyocardial biopsy is the gold-standard method for quantifying myocardial fibrosis, defined as an excess of collagen fibers within the myocardium. In advanced CKD, an excessive accumulation of collagen type I takes place as a result of an accelerated synthesis and decreased degradation . Since mEchocardiography is a useful tool in the detection of the structural and functional cardiac disease changes and may indicate the development of myocardial fibrosis in persons with advanced CKD. Conventional echocardiography is a helpful instrument in everyday practice, but new methods such as two-dimensional speckle tracking echocardiography were developed with the goal of detecting early subclinical abnormalities. The left ventricular GLS is a parameter derived from this technique, with great prognostic value for patients with CKD, confirmed in various studies so far ,9,10,11.Clinically available cardiac biomarkers, such as PICP, procollagen type I N- terminal propeptide (PINP), P3NP, C- terminal telopeptide of collagen type I (CITP), matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinase (TIMPs), Transforming Growth Factor-β (TGF-β), specific E3 ubiquitin protein ligase 1, connective tissue growth factor (CTGF), corin, mesenchymal cell products, and inflammatory factors, recommended for noninvasive assessment of myocardial fibrosis, were investigated extensively  and wereIt is well-known that cardiac fibrosis involves multiple cells and molecular pathways with molecular markers used for the identification of mast cells, endothelial cells, macrophages/monocytes, cardiomyocytes, and cardiac fibroblasts that have an important role in the fibrotic response. Among these biomarkers, fibrogenic growth factors such as platelet-derived growth factor (PDGF) and TGF-β, inflammatory cytokines (TNF-α and IL-6), neurohumoral pathways , and exosomes may deliver a novel promising strategy for cardiac fibrosis diagnosis [In the same trend, the current pattern of kidney disease detection benefits from the modern advancement in molecular analysis and identifies biomarkers for evaluating and characterizing kidney diseases; therefore, the most promising biomarkers with a strong foundation in the pathophysiology of kidney disease were found to be neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), TIMP-2, α1-Microglobulin, liver-type fatty acid-binding protein (L-FABP), uromodulin (UMOD), interleukin-18 (IL-18), TNF-α and IL-1β, P3NP, and epidermal growth factor (EGF) . As expeIn this context, the purpose of our study was to determine the association between four echocardiographic parameters  and biomarkers associated with cardiac fibrosis, such as PICP, P3NP, and Gal-3, in patients with end-stage renal disease. To the best of our knowledge this is the first study that evaluates and compares associations of PICP, P3NP, and Gal-3 biomarkers with echocardiographic measurements in patients with ESRD. Preliminary data from this study were previously reported at the European Society of Cardiology Congress in 2022 .Our study took place between October 2019 and October 2022 in the Nephrology Department of the Clinical Hospital Dr. C. I. Parhon from Iași, Romania.2, were asymptomatic, hemodynamically stable, and in sinus rhythm. The exclusion criteria included a poor acoustic window, atrial fibrillation, the presence of a cardiac pacemaker, an indication for emergency hemodialysis, NYHA class IV, severe pulmonary hypertension, active malignancy, or other pathologies with a life expectancy of less than one year. The study design is depicted in We included 140 patients with ESRD, not yet on dialysis, who had an estimated glomerular filtration rate (GFR) of ≤15 mL/min/1.73 mThis was a cross-sectional cohort study in adult patients, for which the approval of the hospital’s ethics committee was obtained prior to the study. For investigating the association with mortality, an extension cohort study was added, with a follow-up period of three years. The primary endpoint at three years was all-cause mortality. Secondary endpoints included cardiovascular death, starting of dialysis, or kidney transplantation. Follow-up was carried out either by telephone-based approach, or by accessing the electronic health records of the Clinical Hospital Dr. C. I. Parhon in Iași.All study participants provided written informed consent, and ethical committee board at the participating site approved the study protocol. This research was conducted in full agreement with the Declaration of Helsinki.The patients who met the inclusion criteria were examined clinically and with echocardiography. All participants underwent venous blood sampling immediately prior to echo study. Bloods samples were spun and frozen at −80 °C and analyzed subsequently using standardized commercially available kits.There were no interferences to be corrected related to the medication or hydration of the patients during the study. The presence or absence of a preemptively performed arterio-venous fistula was not considered exclusion criteria.All echocardiographic evaluations were performed using the Philips CX50 ultrasound system , with the help of QLAB 7.1 software . In order to minimize the variability, the ultrasound analysis was performed by the same observer according to the recommendations of the American Society of Echocardiography and the European Association of Cardiovascular Imaging . Later, All patients benefited from a comprehensive echocardiographic evaluation of both the cardiac anatomy  and of the functionality, the systolic and diastolic function of the left and right ventricles, atrial function, valvular function, and pulmonary artery pressure.In this study, we chose to focus on the parameters of the systolic function of the left ventricle. First of all, the ejection fraction of the left ventricle was calculated by the biplane Simpson method, using 2D echocardiography in end diastole and end systole, using two standard views, apical four chambers, and apical two chambers. Cut-off values of 52% and 54% were used to define a normal ejection fraction in men and women, respectively . Using tIn addition, the global longitudinal strain of the left ventricle was calculated after obtaining three standard views , with the help of the QLAB 7.1 software . Cine loops with good image quality and high frame rate were used. After manually tracing three points of interest in end diastole, the software automatically traced the endocardial contour, which was corrected as needed. The region of interest (ROI) was automatically estimated and manually adjusted to be adapted to the left ventricular wall thickness. Subsequently, the global longitudinal strain was calculated, with the generation of the bullseye plot. For this study, we used the mean value reported by the two observers. A normal GLS value was considered to be >−18.9%, adapted to the used vendor .Enzyme linked immunosorbent assay (ELISA) was used to measure the serum level of PICP, P3NP, and Gal-3. Peripheral blood samples were collected into serum separator tubes during the clinical examination and samples were allowed to clot for 2 h at room temperature. The serum tubes marked with a specific ID were separated by centrifugation (10 min. at 4500 rpm) and stored in aliquots of 2 mL Eppendorf tubes at −80 °C for subsequent ELISA.Aliquots of serum samples were thawed naturally at room temperature for each assay. The level of PICP (cat. no. MBS026891), P3NP (cat. no. MBS045955), and Gal-3 (cat. no. MBS722196), purchased from MyBioSource Inc., San Diego, CA, USA, were used according to the manufacturer’s recommendations. Briefly, 50 or 100 µL of standards, blanks, and samples were added into the marked ID wells, followed by 100 or 50 µL of HRP-conjugate reagent and incubated at 37 °C for 1 h. The plate was then washed 4–5 times using a multi-channel pipette and 50 µL of substrate A and 50 µL of substrate B were added to all wells, incubated at 37 °C for 15–25 min., followed by 50 µL of stop solution addition to each well, and the optical density was determined at 450 nm using the Biochrom EZ Read 400 Microplate Reader . The data were generated in electronic format with the help of the Galapagos Expert Software . All measurements were performed in triplicate.Afterward, the results were calculated using the standard curve constructed by plotting the average absorbance of standards against the known concentrations of standards  using MyAssays online software. The levels of all biomarkers were expressed as nano-grams per millilitre of serum (ng/mL) and were used to calculate subsequent statistics.p < 0.05) was used to assess the independent associations between variables. The independent T test was used for comparing the means of two independent groups.The statistical analysis was performed using the SPSS Statistics 25 software . Non-normally distributed variables were expressed as median with interquartile range (IQR), and normally distributed variables as mean ± standard deviation (SD). To determine the correlations between the variables, the Pearson correlation coefficient was used. Stepwise multivariate regression analysis including all univariate associates  and followed-up for 3 years. A total of 88% of the patients started hemodialysis and 12% underwent kidney transplantation. A total of 58 patients (41.4%) died during the follow-up period.The data in 2), 16.4% were smokers (daily smoking), and 33.5% were diabetics (HbA1c ≥ 6.5%). All patients were hypertensive (SBP ≥ 140 mmHg and/or DBP ≥ 90 mmHg) and the majority had grade 3 hypertension (SBP ≥ 180 mmHg and/or DBP ≥ 110 mmHg) (92.2%). A total of 11.4% of patients had a history of acute myocardial infarction, and 5.7% had been revascularized, either by angioplasty or by coronary artery bypass grafting. The average value of hemoglobin was 9.72 ± 2 g/dL and that of uric acid was 7.51 ± 2 mg/dL.The average age of the included group was 59 ± 15 years. A total of 25.7% of the included patients were obese .In the analyzed cohort, the mean width of the inter ventricular septum and the posterior wall was 13.1 ± 1.8 mm and 13 ± 2.2 mm, respectively, indicating a high prevalence of LVH. The mean left ventricular end-diastolic diameter was 51 ± 5.8, with a mean left-ventricular end-diastolic volume of 137.1 ± 46.3 mL. When looking at the systolic parameters of the left heart, the mean EF determined by the Simpson biplane method was 53.63 ± 8%, with 52.1% of the patients in NYHA class I and 47.9% of patients in NYHA class II. In the analyzed population, GLS varied between −1% and −23%, with an average value of −10.2 ± 5.3%. The mean E/e’ was 9.8 ± 4.3, with 90.4% of the patients having at least grade I diastolic dysfunction. The mean left atrial volume indexed was 45.8 ± 14.2 mL/mWhen regarding the right part of the heart, we observed a mean right atrial volume of 52.7 ± 26.4 mL and a mean right ventricular fractional area change (RV FAC) of 42.3 ± 5.9%. The mean tricuspid annular plane systolic excursion (TAPSE) was 23.1 ± 3.8 mm, with a mean S’ velocity of 9.3 ± 2.6 cm/s. The mean inferior vena cava diameter was 17 ± 3.5 mm, indicating a normal volemic status .The average levels for PICP, P3NP and Gal-3 were 457.2 ± 240 µg/L, 242 ± 199.9 µg/L, and 10.7 ± 3.7 ng/mL, respectively.We then focused on studying which of the three biomarkers were more likely to predict a decreased left ventricular systolic or diastolic function . For this, we performed regression analysis .p = 0.0002, R2 = 0.69; p = 0.0001, R2 = 0.81; p = 0.00002, R2 = 0.89; p = 0.003, R2 = 0.73, respectively). The Line Fit Plot of PICP and GLS is depicted in In regression analysis, PICP was associated with the ejection fraction, GLS, mean E/e’ and LAVI , but the analysis for the other parameters did not reach statistical significance.P3NP and Gal-3 levels were associated with the ejection fraction . There were no significant differences for the EF and mean E/e’ between the two groups. PICP and Gal-3 levels were higher in patients with diabetes . The values for P3NP did not reach statistical significance . After three years of follow-up, there were 31 deaths recorded in patients with diabetes (53.3%) and 27 deaths in the non-diabetic population (21.9%).In this cohort, 33.5% of the patients were diabetics. GLS was significantly higher in patients without diabetes mellitus (−11.4 ± 6%) compared with patients with diabetes (−9.3 ± 5%), p = 0.003). The mean GLS was higher in the non-smoking group, but the results did not reach statistical significance . There were no significant differences in the mean E/e’ and LAVI between the two groups. There were significant differences in the PICP and Gal-3 levels between the smoking and non-smoking group . The values for P3NP did not reach statistical significance . After three years of follow-up, there were 13 deaths in the smoking group (56.5%) and 45 deaths in the non-smoking group (38.4%).A total of 16.4% of the included patients were active smokers. The EF was significantly higher in the non-smoking group  are associated with echocardiographic parameters in patients with advanced CKD, bringing new evidence in the context of an understudied high-risk population.p = 0.014) [In CKD, as an adaptive mechanism for the volume and pressure overload, the left ventricle responds with both hypertrophy and dilatation. In the context of LV hypertrophy, the interstitial space increases alongside an augmentation of the myocardial demands in oxygen, leading to myocardial fibrosis and accumulation of collagen, explaining the subclinical systolic dysfunction. In our study, as surrogates of the systolic function of the LV, we chose two parameters, LV ejection fraction, and global longitudinal strain. Despite a near normal mean ejection fraction of 53%, our patients presented low values of GLS, suggesting subclinical systolic dysfunction. Moreover, the mean GLS value in this cohort was −10.2 ± 5.3% , in line with the data published by Hensen et al. regarding this parameter in patients with CKD [Regarding the diastolic function of the left ventricle, we chose to focus on the mean E/e’ ratio and LAVI, with over 90% of the included patients presenting with diastolic dysfunction. It is important to point out that the mean E/e’ ratio in our cohort was 9.8 ± 4.3, suggesting normal filling pressures. This parameter represents an important tool for diagnosing diastolic heart failure and is correlated with mortality in CKD patients .p = 0.0002, R2= 0.69), GLS , E/e’ ratio , and LAVI . Taking all the data presented above into consideration, we can suggest that a combined multimodality imaging and biological approach can help estimate, in a non-invasive manner, the amount of cardiac fibrosis in CKD patients.PICP, a product in the metabolism of collagen type 1, was proven useful for the diagnosis and prognosis of heart failure and is associated with GLS values in patients with diabetes ,29. Morep = 0.01, R2 = 0.31). P3NP levels were not associated with the value of GLS, E/e’ ratio or LAVI.P3NP, a product in the metabolism of collagen type III, has prognostic value in heart failure, post-myocardial infarction can predict the incidence of AF and the recurrence after catheter ablation and the risk of ICD intervention . Despitep = 0.02, R2 = 0.35).Gal-3, a marker of inflammation is involved in aldosterone-mediated fibrosis, being an adjunctive novel biomarker that can be used in heart failure patients . Along wThe present study also evidences that smokers and patients with diabetes exhibit lower values of EF and GLS and higher values of PICP and Gal-3. This is in line with the literature data pointing towards a profibrotic status in these patients ,45,46.The limitations of this research include its design, which is not a prospective and randomized one, with no control group, followed by the unfeasibility to determine causality since it is an observational study.In conclusion, this study evaluated the association between PICP, P3NP, and Gal-3 biomarkers and echocardiographic parameters in patients with end-stage kidney disease. Our research showed a strong association between PICP and all four echo parameters, as potential non-invasive indicators of myocardial fibrosis that impacts both systolic and diastolic dysfunction. In this cohort, P3NP and Gal-3 were only associated with the ejection fraction.


Sepsis is an archetype of distributive shock and combines different levels of alterations in preload, afterload, and often cardiac contractility. The use of hemodynamic drugs has evolved over the past few years, along with the invasive and non-invasive tools used to measure these components in real time. However, none of them is impeccable, which is why the mortality of septic shock remains too high. The concept of ventriculo-arterial coupling (VAC) allows for the integration of these three fundamental macroscopic hemodynamic components. In this mini review, we discuss the knowledge, tools, and limitations of VAC measurement, along with the evidence supporting ventriculo-arterial uncoupling in septic shock. Finally, the impact of recommended hemodynamic drugs and molecules on VAC is detailed. The hemodynamic management of septic shock is an evolving challenge guided by recommendations updated regularly. According to the 2021 Surviving Sepsis Campaign (SSC) guidelines, with a target for a mean arterial pressure (MAP) of 65 mmHg or greater, norepinephrine, dobutamine, vasopressin, and possibly angiotensin II are the recommended medications after volume optimization  is the net result of complex and constant interactions between the cardiac pump and its downstream vascular network . The objAlthough the heart and systemic vascular network have different intrinsic properties, both aim to provide adequate organ perfusion (through the generation of an outflow volume with a given level of outflow pressure). There is little sense in studying one without taking into consideration the condition of the other. Thus, the VAC concept was first proposed in 1984 as a method to evaluate the mechanical efficiency of the cardiovascular system and the interaction between cardiac performance and vascular function .Ventricular performance can be characterized by its end-systolic elastance (Ees), which reflects the ability of the ventricle to eject a stroke volume (SV) through the variation of the end-systolic pressure. In brief, it reflects the adaptability of the ventricle to the variation of afterload. From a physiological point of view, it is determined by the slope of the line passing through the point of the end of systole and by the theoretical point of zero volume (V0) on a pressure/volume loop and may be summarized by n et al. .Properties of the vascular system are defined by vascular elastance (Ea), reflecting the resistance and compliance of the main arteries. Ea may be determined from the slope that joins end-diastolic volume and pressure and may be summarized as Ea = Pes/SV .The Ea/Ees ratio is called the VAC index, reflecting the systolic performance of the left ventricle in front of the arterial compliance. Several publications estimated that the optimal VAC values are comprised of between 0.6 and 1.2  or 0.5 aEes. This method utilizes the echocardiographic measures of LVEF, Doppler-derived SV , the estimated normalized ventricular elastance at the onset of ejection [End(est)], and the pre-ejection time  to left ventricle ejection time  ratio (tNd)  , coupledio (tNd) :Ees= in critically ill patients varies from 25% to 85% –19 Figu and is aFew drugs are currently available for the circulatory support of septic shock, and one does not fit all. To stretch a point, inotropes enhance Ees, whereas vasopressors specifically increase Ea, but several drugs share both abilities. Some patients do sometimes require more inotropism than vasopressors, because around 40% exhibit sepsis-induced myocardial depression . Many of2-mediated vasodilation of coronary arteries, overall normalizing coronary blood flow and contributing to an improved cardiac function (1 and β1 stimulation (Norepinephrine (NE) is a natural catecholamine that exerts a dose-dependent vasoconstrictive effect by its agonism on α-adrenergic receptors present throughout the vasculature . NE has function . Finallymulation . Thus, cmulation  showed tmulation . In this weaning . The hig weaning .1 receptors and is still widely used in circulatory shock  in opposition to a given afterload (dicrotic notch pressure). In this context, low values of systolic–dicrotic notch pressure difference were related to VA uncoupling and could predict at baseline the ability of β-blockers to improve cardiac efficiency with a heart rate reduction, discriminating adaptive from maladaptive tachycardia . A still unresolved genuine challenge is the fine-tuning selection of candidate patients.Unlike the above drugs, β-blockers (BBs) inhibit β1 receptors but may also be of interest during septic shock under specific conditions of circulatory failure. Two recently developed BBs stand out from the others because of their pharmacokinetics and pharmacodynamics, i.e., esmolol and landiolol . These thycardia . Althoughycardia . In summin vivo and in isolated hearts ex vivo). The essential absolute gain of CO in response to APL-13 isoform is clearly linked to SV improvement without significant chronotropic effect but with an attributable contribution of the underlying degree of total peripheral resistance. VAC, as well as ventricular mechanical efficiency, are improved by more than 40% with APL-13 infusion in experimental ischemic failing hearts with an induced increase of the Ea/Ees ratio (Arginine vasopressin (AVP) and apelins (APL) belong to a family of neuropeptides with pleiotropic, often counter-regulatory, cardiovascular or related effects . AVP hases ratio . APL-13 es ratio –60. Essees ratio –64.Angiotensin II has been recently added as a recommended third-line rescue vasopressor for refractory septic shock in the SSC guidelines . This isIn conclusion, VAC is a valuable tool for understanding the interaction between the myocardial contractile function and the load opposed by the arterial circulation. Although many data are encouraging, the benefit of such an approach to in-hospital outcomes should be confirmed in the future. Additional proof of applicability and optimal targets are needed to consider VAC at the bedside in complex hemodynamic conditions, such as septic shock, where tachycardia and pharmacologic increase in vascular resistance contributes to ventriculo-arterial uncoupling in associated but overlooked myocardial injury. This would support the decision-making strategies of intensivists in today’s world of individualized medicine.


In cardiogenic shock various short-term mechanical assistances may be employed, including an Extra Corporeal Membrane Oxygenator and other non-dischargeable devices. Once hemodynamic stabilization is achieved and the patient evolves towards a persisting biventricular dysfunction or an underlying long-standing end-stage disease is present, aside from Orthotopic Heart Transplantation, a limited number of long-term therapeutic options may be offered. So far, only the Syncardia Total Artificial Heart and the Berlin Heart EXCOR (which is not approved for adult use in the United States unlike in Europe) are available for extensive implantation. In addition to this, the strategy providing two continuous-flow Left Ventricular Assist Devices is still off-label despite its widespread use. Nevertheless, every solution ensures at best a 70% survival rate  with patients suffering from heavy complications and a poor quality of life. The aim of the present paper is to summarize the features, implantation techniques, and results of current devices used for adult Biventricular Mechanical Circulatory Support, as well as a glance to future options. End-stage Heart Failure (HF) represents a growing disease, responsible for about one-third of total deaths . AlthougHowever, there remains an organ shortage, which contributes to the exponential spread of Mechanical Circulatory Support (MCS) . This imThe majority of HF patients may be adequately treated with a Left Ventricular Assist Device (LVAD), but the small percentage affected by advanced biventricular dysfunction are candidates for long-term biventricular support. As expected, not only are biventricular HF patients a more ill population, but the use of Biventricular Mechanical Circulatory Support (BMCS) doubles the mortality rate and is associated with a higher incidence of complications .Several classifications may be used to describe biventricular MCS .The first distinction concerns short-term and long-term devices; the former group includes both percutaneous and surgically placed non-dischargeable devices , while the latter is composed of the Total Artificial Heart (TAH) (orthotopic devices which requires excision of the heart) and heterotopic machines that support both ventricles in parallel to the native ones (Biventricular Assist Devices—BiVADs). This classification derives from the new OHT allocation 6-tiered system .BIVADs may ensure a minimum flow sufficient to patient's survival in case of device failure and allow for recovery.Other classifications are based on pumps mechanisms , type of flow produced (pulsatile or continuous) and on emplacement  .Short–term percutaneous assistance is represented by the Impella  system and the TandemHeart .The Impella family of products  includesStrict check and monitoring of the device position across the aortic valve with fluoroscopy and echocardiography is mandatory. The Impella 2.5, Impella CP, Impella 5.0, and Impella 5.5 can provide antegrade flow up to 2.5, 4.0, 5.0, and 5.5 L/min respectively. By continuously drawing blood from the left ventricle (LV), the Impella unloads the LV, thereby decreasing its work and myocardial oxygen demand. In addition, by delivering large volumes of blood to the aorta, Impella operation results in an increase in mean arterial pressure and cardiac output, thus improving systemic perfusion and coronary flow which augments the chances of cardiac recovery. Finally, Impella leads to a decrease in pulmonary wedge pressure and a secondary reduction in right ventricular afterload .Basing on the evidence that prolonged LV unloading with LVAD promotes reverse remodeling, cardiac repair, and pulmonary vascular resistance reduction, the impact of prolonged support (until 40 days) with an LV-Impella (the PROPELLA concept) has been investigated in the context of fulminant myocarditis with encouraging results .The right-sided device (Impella RP) can provide up to 4 L/min of flow. This 22F pump mounted on an 11F catheter is inserted percutaneously over a guidewire guided by fluoroscopy and/or echocardiography from the femoral vein via the right heart to the pulmonary artery, unloading the RV.Impella pumps cannot be coupled to an oxygenator and are appropriate for 5–21 days.TandemHeart   represenTo achieve right heart assistance, an inflow cannula is placed in the right atrium and an outflow cannula in the pulmonary artery. Both are venous cannulas, generally accessed through the left and right femoral veins, respectively, or can be surgically placed after chest opening . AlternaAn alternative option of biventricular assistance is represented by the association of a left Impella via the axillary artery with a Protek Duo cannula inserted in the jugular vein connected to a TandemHeart pump. Such total percutaneous configuration allows patient's mobilization with lower risk of infections while providing total heart support .Depending on the basal disease, left and right ventricle may present different delay or degree of recovery: the use of two separate pumps to assist the left and the right side allows progressive and distinguished trials of weaning by monitoring the response of the two ventricles to every decrease of their respective support .A number of stand-alone (without an incorporated oxygenator) centrifugal pumps which can be coupled with various cannulas are available. These are surgically inserted, using either a central or peripheral technique. CentriMag  and Rotaflow  are two common examples of magnetically suspended pumps which can support of up to weeks/months in duration . CompareThe veno-arterial ECMO represents the most common BMCS device thanks to its simple and quick deployment: this centrifugal pump including an oxygenator/heat exchanger has traditionally been surgically implanted, but recently percutaneous cannulation has been increasingly used with a trend towards lower mortality and fewer complications . AvailabECMO can achieve up to 4–10 L/min flow. Maximal duration of support is very variable in relation to patient's age and basal condition: typically, haemorragic or infective complications begin to arise 10–15 days after the implantation . However, heparin induced thrombocytopenia and heparin resistance are conditions frequently requiring the use of different anticoagulants. In this context, direct thrombin inhibitors like bivalirudin and argatroban have been established as alternatives. A recent meta-analysis  showed tConcerning Impella, according to the manufacturer, the goal activated clotting time (ACT) is 160–180 s: in some patients, purge heparin may be sufficient to achieve anticoagulation goals; when insufficient, the addition of titratable, supplemental non-purge heparin is required to provide optimal anticoagulation. Two different dextrose concentrations (5% and 20%) in the purge solutions have been tested with similar therapeutic activated partial thromboplastin time rates, thrombotic, and bleeding events. Nevertheless, anticoagulation in patients with Impella devices can often be complicated due to unpredictable purge flow rates, pre-existing coagulopathy, or heparin allergies. In this setting, a sodium bicarbonate-based purge solution  currently represents the reliable and approved alternative option . In addiPharmacological management varies according to assistance strategy: in a recovery strategy the administration of Levosimendan is commonly used to facilitate weaning with increased success rate .All these systems are approved in the United States (US) for adult use; despite this, randomized trials are still lacking. If the Bi-Pella approach presents encouraging outcomes in cardiogenic shock probably due to its capacity for biventricular unloading compared to ECMO, a recent meta-analysis  seems toIn patients under short-term support the question of the evaluation of systemic and cardiac recovery becomes crucial, in order to decide if weaning is possible or if a shifting towards a long-term assistance program or OHT is required. Different protocols of progressive decrease of the support are available and they vary among centers. In every step of weaning, systemic perfusion must be maintained  with normal levels of lactate and liver enzymes. In parallel, echocardiography must assess the recovery of LV function  and of RV function , which must remain stable or improve during the flow reduction trial  and to manage, two characteristics which render ECMO the current more suitable assistance when compared to a double Impella, which requires a complex anticoagulation protocol, a strict echocardiographic monitoring of the device position and the contemporary management of a right and of a left pump with different settings.Nevertheless, ECMO presents the negative side of representing a machine which “supports the organs and not the heart”; we can describe it as a temporary tool to preserve the vital organs while waiting for cardiac recovery. This means that, for instance, it can be deleterious if used without a parallel device unloading the left ventricle in case of profound cardiac dysfunction. Obviously, hemolysis and long-term complications including platelet count fall and dysfunction and systemic inflammation are common persisting defects of all currently available short-term devices.1.Syncardia CardioWest : TAH.2.Berlin Heart EXCOR : paracorporeal BiVAD.3.LVAD + Right Ventricular Assist Device (RVAD): two HeartMate 3 : intracorporeal BiVADs.Several devices have been added to and taken off the market over the years: so far, available options are:All biventricular devices are approved for Bridge To Transplantation (BTT) treatment only .Currently, the only device approved for adult use in the US is the Syncardia, while the Berlin Heart is reserved for pediatric use in the US and for patients of all ages in Europe. The third option of two HeartMates 3  is feasible but off-label.Differently from paracorporeal or intracorporeal BiVADs, Syncardia TAH and HeartMate 6 require the excision of both ventricles, thus preventing the possibility of removing the devices in case of cardiac function recovery.The Syncardia  is a pne2 and a ≥10 cm distance between the tenth thoracic vertebra and the sternum) (The TAH is indicated in biventricular HF patients eligible for OHT in INTERMACS class I–II–III with certain thoracic dimensions (Body Surface Area 1.7–2.5 msternum) . Syncardsternum) . Anothersternum) .-Ventricular excision, pulmonary artery and aorta transection.-Anastomosis of atrial connectors and of outflow conduits.The principal steps are :-VentriWhen the patient's thoracic size is on the borderline of the acceptable range, various technical tips have been suggested to find progressive device accommodation suitable for a correct hemodynamic status.1.Left and right air activation pressures: they must allow aortic-pulmonary valve opening .2.Cardiac rate: between 120 and 130/min .3.Systole length percentage: in contrast to a normal heart where diastole is longer than systole, a length of 50% length is usually optimal to achieve adapted filling and emptying.4.Drivelines aspirating pressures (filling help).The following parameters need to be set :1.Left The device automatically calculates filling volumes and bilateral cardiac output (with the right-sided one still 700–800 cc lower).Syncardia works correctly when there is uncomplete filling followed by full emptying. Objectives of management consist of joining the theoretical cardiac output with a central venous pressure <15 mmHg (for avoiding hemorrhagic complications too).The first publication on TAH outcomes in BTT therapy was the multi-center American trial by Copeland , which sMultivariate analysis reveals that risk factors for death with TAH support are age, smoking and preoperative mechanical ventilation, while a prothrombin time of ≥16 s and smoking are associated with a higher mortality rate after transplantation , 28.The main complications following Syncardia implantation are stroke, infections, thromboembolic events, renal failure and chronic multi-factorial anemia. The largest TAH trial  reports Severe postoperative renal impairment is quite frequent (10%) and is due to a sudden fall in Brain Natriuretic Peptide levels secondary to ventricular excision which may interrupt its physiologic compensatory role . Device 2. This device is comparable to the 70 cc TAH, apart from the 29% reduction in its size. It has two 50 cc ventricles and 25 mm-inflow and 23 mm-outflow valves  technology , 32 Fig. It consThe pump chamber has a flexible three-layer polyurethane membrane separating the air side connected to the driving unit and the blood one connected via the cannulae to the patient's circulation. The blood is propelled by cyclically changing the internal volume of the compression chamber through a pneumatically-driven expansion of the membrane, directing the flow with one-way valves. The energy source is an external smaller and portable compressor. The transparent housing allows for immediate detection of thrombi formation and malfunctions. By that, pump exchange can be performed easy without the need for lysis therapy. To avoid friction, a graphite lubricant powder lies between the layers. The blood-contacting surfaces of the pump are coated with heparin (Carmeda®). It is available in several sizes with different pump volumes  and cannula sizes in order to support patients of all ages. Initially, adult sizes were furnished with mono-disc mechanical prostheses; since August 2004 they have been replaced by heparinized bileaflet valves. This evolution has resulted in a reduction of pump noise and in simpler preparation and de-airing processes. The driver-console, provided with rechargeable batteries, is portable.Step-by-step EXCOR cannulation process consist of: left ventricle apex, right atrium, pulmonary artery trunk, and ascending aorta . Direct Basing on BSA and theoretical cardiac index, patient's adapted pump size is chosen. To obtain the required flow, an appropriate rate on the driving unit is set . Systolic and diastolic pressures must be set and dynamically adapted to change in pre- and afterload for allowing a complete deflection of the blood pump membrane. A systole percentage set between 30% and 40% should allow a complete filling and emptying of the pump. Management goal are a central venous pressure around 10 mmHg and mean arterial pressure around 70–80 mmHg.A recent trial  on BerliContinuous-flow devices are efficacious and safe for the left heart and significantly extended patients' mean survival by up to 7.1 years after implantation . TechnolAncient LVADs were burdened by pump thrombosis and strokes which encouraged the industries to improve the hemocompatibility of these devices . The mosClassic LVAD requires placement of the inflow cannula in the left ventricular apex and of the outflow cannula in the ascending aorta .1.LVADs are designed for systemic circulation: the right outflow graft diameter is surgically reduced to increase right afterload for avoiding pulmonary edema .2.Inflow cannulas are too long for the average RV and need shortening.3.The optimal anatomic placement  for the right pump allowing for the lowest risk of pump thrombosis  is stillIn off-label use of two continuous-flow pumps for total assistance , three pAn alternative surgical technique consists of biventricular excision achieving an arrangement resembling the Syncardia-TAH with the sewing rings sutured to the atrial cuffs; although such a strategy should avoid problems related to correct right device orientation, it still remains off-label and requires further validation .Rotations per minutes are set in order to obtain the theoretical left cardiac output  and a right one 500–1,000 cc lower with classical left speed being between 5,000 and 5,500 rpm.Available trials on continuous-flow BiVADs are based on small cohorts: in 13 implanted patients (50% in a ventricular configuration), Shehab  reportedThe review by Farag  summarizSo far, more than 400 continuous-flow BiVADs have been implanted worldwide.Several papers have compared the results of each approach: a recent meta-analysis  evaluateInterestingly, a retrospective study  on a preAll BMCS require the coupling of anticoagulation and antiplatelet drugs therapies with variable protocols. As for short-term devices, the degree of anticoagulation needs to be adapted to every patient, especially in the first hours after the implantation of the device, considering the individual perioperative bleeding state and risk.Usually, the standard of care is represented by an initial treatment with unfractioned heparin, followed by vitamin K antagonists such as warfarin with the adjunct of acetylsalicylic acid for long-term maintenance. Nevertheless, bivalirudin is gaining space due to its short half-life, lack of dependence on antithrombin, and more stable pharmacokinetics; thus, at present, its use is not limited to situations wherein heparin is ineffective or contraindicated. Especially in children assisted with continuous flow devices or Berlin Heart, outcomes with direct thrombin inhibitors  are encouraging with lower major bleeding and stroke event rate than that reported with unfractioned heparin .Concerning long-term anticoagulation, preliminary evidence suggests that new direct oral anticoagulants, which directly inhibit Factor Xa  or Factor IIa/thrombin (dabigatran), may be a valuable alternative to warfarin in adults patients assisted with continuous-flow LVAD, but further investigations are needed .No other specific treatments are needed when biventricular dysfunction is judged irreversible. Otherwise, in case of possible partial or complete recovery  and if biventricular implantation is not in a TAH configuration, all drugs employed in an acute HF setting, such as inotropes and levosimendan, and in the treatment of chronic systolic heart failure, may be administered. More in detail, neurohormonal inhibitors (angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), aldosterone antagonists and beta blockers) could facilitate recovery  and signPositive hemodynamic effects have also been demonstrated with other vasoactive substances, including exogenous natriuretic peptides , the endothelin-1 antagonist tezosentan, cinaciguat (an activator of soluble guanylate cyclase) and serelaxin, but their role in acute decompensated HF remains uncertain .1.Prevalent mono- or biventricular failure?2.Chance of recovery of every ventricle.3.Pulmonary status.4.Eligibility to OHT.In acute cardiogenic shock requiring assistance, no time is available for speculation and ECMO is the preferred MCS for its simple implantation. Once hemodynamic situation is stabilized, patient's evaluation and estimation of MCS perspective are mandatory. Clinicians must answer to the following questions:-Need for longer short-term MCS to allow recovery or bridge-to-decision: shifting vs. CentriMag or biventricular percutaneous assistance combination is conceivable.-Satisfactory RV function: consider LVAD implantation or OHT.-In case of no chance of recovery and no contraindications, OHT remains the best option.-If biventricular failure persists along with temporary contraindications to OHT, long-term MCS are required. Syncardia still remains the gold standard due to its diffusion and proved efficacy; Berlin Heart and, in selected cases, an off-label strategy employing two continuous-flow BiVADs, are two valuable alternatives gaining momentum, especially if more time is needed to evaluate recovery chance.Different scenarios may arise:According to the INTERMACS Registry, 24% of patients implanted with a Syncardia were discharged home with their device after 1.6 months, with this number increasing over time. Even if TAHs improve quality of life for most of the implanted patients, rehabilitation and hospital discharge remain very challenging for patients and their care providers. A 6-kg driver that permits hospital discharge is now available to patients waiting for OHT and supported with the Syncardia. For years, one of the major disadvantages of the use of a TAH was the necessity of keeping the patient in-hospital while waiting for transplantation. Clinical experience with the new small TAH driver has allowed a few centers to discharge patients home .Concerning Berlin Heart Excor, the possibilities of patients' hospital discharge seem more encouraging: adult patients requiring a blood pump size of 60 and 80 ml can be discharged with the EXCOR R Mobil by Berlin Heart GmbH. So far, the only other option for patients requiring smaller blood pump sizes is in-hospital treatment with the stationary IKUS driving unit (Berlin Heart GmbH) that can be used for all EXCOR R blood pumps. Unfortunately, the IKUS has a battery life of only 30 min and thus considerably limits patients' mobility. Focusing on this particular patient group, Berlin Heart GmbH has recently developed a novel electro-pneumatic mobile drive unit called EXCOR R Active, that has been especially designed for the operation of the paracorporeal system EXCOR R VAD and can be used for either univentricular assist or for biventricular assist. The use of the EXCOR R VAD in combination with EXCOR R Active as its driving unit has already been proven to be feasible for internal and external usage within the setting of professional health institutions. Unfortunately, this system, which has a guaranteed battery life of approximately 12 h, has not yet been approved for use in a home healthcare environment .The experience with two continuous-flow BiVADs is currently too limited for drawing any conclusion about its capability to allow a simpler hospital discharge compared to TAH or Berlin Heart. If, on the one hand, the portable console unit is quite small and light, on the other hand, the patient is obliged to carry two consoles with two distinct settings, making it a little more difficult to achieve an independent and satisfying quality of life.ad hoc machine would decrease the number of mistakes and reduce the risk of pump thrombosis.In patients needing long-term biventricular support, the available options are far from optimal despite acceptable outcomes that are independent of device choice. Syncardia is bulky and noisy, leading to a limited quality of life. The Berlin Heart in biventricular configuration is not approved for adults use in the US; anyway, it has four mechanical valves and two drivelines, although its strong points are that it is less heavy, less loud and is suitable for every patient. With regard to continuous-flow BiVADs, the lack of a right-heart specific device is problematic: an The conclusion is that the ideal long-term biventricular support is far to be found. Engineers and researchers are strongly working on this field, trying to ameliorate all the current defects of the available machines. The most important objective would be to have a device which allows fast patient's hospital discharge, assuring a satisfying and pseudo-normal quality of life. This means that it should be noiseless, with a little and portable controller or, even better, equipped with a transcutaneous charge, a feature which could also greatly reduce the rate of one of the most frequent complications of BMCS represented by drivelines infections. From a surgical point of view, the implantation technique should be simple and standardized ensuring a safe incoming transplantation. An ideal device should also be removable in case of cardiac recovery.Another fundamental issue that needs to be addressed is hemocompatibility: pump thrombosis and its related adverse events  remains the Achilles heel of BMCS despite aggressive antiacoagulant and antiplatelet therapies which may furthermore cause gastrointestinal or cerebral bleeding. Consequently, in order to mitigate the phenomena of thrombosis, future MCS devices must focus their attention on improving the design of pump geometry, the materials, and the blood-contacting surfaces . In thisSome promising trials are underway with the BIVACOR BV System .An alternative line of development concerns CARMAT-TAH device .BIVACOR is a unique pump developed by BIVACOR Inc. . It consists of a single chamber, separated by a dual sided rotor designed to provide centrifugal flow to both the systemic and the pulmonary circulation. There are four ports of attachment to the native circulatory system—an aortic port, a pulmonary artery port and two atrial ports for the left and right atrium, respectively. The rotors have different outer diameters to produce the pressure required of the systemic and pulmonary systems at a common rotational speed. BIVACOR performance has been tested in a simulated pulsatile loop, reproducing an end-stage HF situation: it reestablished a correct flow of 5 L/min starting from 2 L/min .This device is expected to remove many complications of current available BMCS: first, the setting is simpler, since there is no need to separately adjust the parameters of a systemic and of a pulmonary assistance thanks to its ability to alter and adapt the left and right outflow following the changes in vascular resistance or contingent abnormalities occurrence; second, it can operate successfully alongside a functioning RV in case of recovery; third, the double-side impeller configuration of the BIVACOR and its modulable pulsatile flow reduce the potential for thrombus formation by eliminating areas of low flow or stagnation often found beneath single-side centrifugal blood pump impellers. Last, this TAH presents a relatively small size which enables intrathoracic placement: a virtual fitting model showed that it fit well within the chest cavity of all tested patients .Nevertheless, similarly to Syncardia, it requires cardiac excision, resulting in the impossibility of device explant if a sufficient biventricular contraction is restored. In addition, due to the coupled nature of the right and left impeller, the capacity of accommodation of the respective outflow may be impaired in case of contemporary changes in systemic and pulmonary vascular resistance . In this circumstance, medical management becomes mandatory. Finally, differently from Syncardia, no mechanical valves are included in the device, but at least a low level of anticoagulation is still needed.CARMAT's history began in Paris in 1993 . This TAAfter a first implantation in France in 2013 on a 76-years-old patient, CARMAT received Food and Drug Administration approval in 2020 for the recruitment of 10 patients eligible for OHT in the US and then, in February 2021, for initiating a new American feasibility trial. CE mark was obtained on December 2021 for a BTT implantation.Since the PIVOTAL study in 2016, CARMAT's analysis of the first 10 patients demonstrated that 70% survived or were successfully transplanted. The absence of hemolysis or major complications was reassuring, with lighter anticoagulation required compared to Syncardia or LVADs.The ideal BMCS does not yet exist. Available tools (TAH or BiVADs) are exclusively indicated in a BTT therapeutic strategy  and ensu