Our results showed that both healthy and diseased geometries consistently displayed an increased WSS in the RVOT relative to the rest of the RV. We found that increases in cardiac output may lead to increases of mean kinetic energy (MKE), laminar viscous dissipation and WSS at the RVOT. Furthermore, higher peak WSS magnitudes were found for the diseased cases. The identified high WSS regions may correlate with the common site of RVOT ventricular tachycardia in athletes and patients with ARVC/D. Our results imply that exercise, as well as anatomical and functional remodeling might alter RV wall shear stress both in magnitude and spatial distribution, leading to increased hemodynamic stresses in the RVOT.The rationale of this paper is to investigate right ventricular (RV) hemodynamics in relation to changes in cardiac output, and in particular to study exercise-induced stresses at the RV outflow tract (RVOT), which is a common site of ventricular arrhythmias in the athlete’s heart. We hypothesize that the thin-walled RVOT is exposed to high wall shear stresses (WSS) during physiological states associated with high cardiac output such as exercise, and therefore, may be particularly prone to substrate formation leading to ventricular tachyarrhythmias. 3D Particle Tracking Velocimetry (3D-PTV), an optical imaging method, has been performed in a novel anatomically accurate compliant silicone right heart model derived from a high resolution MRI heart scan of a healthy male proband. RV and RVOT flow patterns at resting conditions were obtained from two healthy athletic male proband’s hearts and two patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) via phase contrast magnetic resonance imaging (PC-MRI). The healthy case was used as a reference for validating the  During exercise, cardiac workload, oxygen uptake and carbon dioxide output increase, which go along with an increase in cardiac output4. Hence, exercise may cause a distinctive stress on the cardiopulmonary circulation4. Most of the previously reported studies on endurance exercise have focused on the left heart6. However, it has been shown that endurance exercise predominantly affects the right ventricle (RV)7. Therefore, RV dimensions and function are clinically important parameters, which may provide an insight into exercise-induced alterations of myocardial function9.Regular physical exercise reduces cardiovascular morbidity and stimulates a number of beneficial physiological changes in the human body, i.e. it improves insulin sensitivity, increases serum high density lipoprotein, coronary flow reserve and myocardial capillary density, and reduces the progression of atherosclerosis10. The extent of these alterations seems to be associated with the type, intensity and duration of exercise12. Scharhag et al. suggested that endurance training induces RV hypertrophy representing a physiologic adaptation13. Moreover, long-term endurance exercise training may cause dilatation of the RV and right atrium, RV diastolic dysfunction, and cardiac fibrosis, which may provide a substrate for right-sided ventricular arrhythmias, RVOT ventricular tachycardia in particular, and increase cardiovascular risk14. Furthermore, it has been demonstrated that the development of an arrhythmogenic substrate in the RV in athletes heavily relies on the intensity of physical activity16. Interestingly, regular intense endurance exercise may promote a differential segmentary remodeling between the RV base and RV apex, potentially leading to differences in wall stress at rest15.Recent data suggests that regional structural alterations in the RV may not only be found in patients with ARVC/D, but also occur in apparently healthy endurance athletes in the absence of desmosomal mutationset al.17 suggested high TKE levels for the complications seen in Tetralogy of Fallot (ToF). Gulan et al.18 proposed a novel approach, which relies on TKE and dissipation of MKE for the assessment of aortic valve stenosis severity. Zajac et al.19 used TKE for determining diastolic dysfunction in the left ventricle of patients with dilated cardiomyopathy. Similarly, Dyverfeldt et al.20 utilized total kinetic energy levels to estimate the severity of mitral regurgitation. Binter et al.21 showed that TKE may provide complementary information to echocardiography, assisting to distinguish within the heterogeneous population of patients with moderate to severe aortic stenosis. Recently, Gulan et al.22 showed that vortex rings develop in the right atrium correlating with WSS, which may help to understand the formation of right atrial thrombus. It is also known that low WSS may lead to intimal wall thickening and hence promotes atherogenesis23.Fluid mechanics parameters such as mean kinetic energy (MKE), turbulent kinetic energy (TKE) and wall shear stress (WSS) in the cardiovascular system have been proposed as potential markers for predicting the development of different cardiovascular pathologies. Fredriksson 25 but can also occur in athletes with subtle structural heart disease and patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D)26. It has been shown that exercise may provoke RVOT tachycardia27, yet the mechanisms for these observations have not been fully understood. The human RV has a complex geometry, which introduces challenges for echocardiographic analysis13. With the improvements in magnetic resonance imaging (MRI) on space and time resolved kinetic energy measurements, it is now possible to investigate flow patterns in the RV29. To the best of our knowledge, the effects of exercise training on blood flow patterns and associated shear stresses in the right heart have not yet been studied. We hypothesize that the RVOT free wall is exposed to high WSS during physiological states associated with high cardiac output, such as exercise, and therefore this region of the RV may be particularly prone to substrate formation leading to ventricular tachyarrhythmias. Since it is challenging to study cardiac output effects in vivo, we performed 3D-PTV flow measurements in an anatomically accurate compliant silicone right heart model. The results are validated and complemented by in vivo flow MRI measurements for two healthy and two pathological (ARVC/D) geometries.RVOT tachycardia can be a primary electrical disease in the absence of structural heart diseasein vivo blood flow characteristics at resting conditions. A qualitative representation of the in vivo blood flow patterns in the RV at peak systole and mid diastolic phases are shown in Fig. This section focuses on In the peak systolic phase (left), high velocity regions develop in the vicinity of the RVOT, particularly at the RVOT free wall. The RV forwards the ventricular blood volume into the pulmonary artery via contraction when the tricuspid valve closes and the pulmonary valve opens. Local recirculation regions arise distal to the RVOT, i.e. in the proximity of the subtricuspid region. In the ventricular filling phase (right), high velocity regions develop in the vicinity of the subtricuspid region as the tricuspid valve opens and the pulmonary valve closes. The RV expands as the atrial blood volume fills the RV. At the RVOT, retrograde flow zones arise with slow velocity. It is noted that recirculation regions develop in the proximity of the tricuspid valve, which are associated with a diastolic vortex present in that region. A major portion of the RV flow is directed towards the RVOT and a small portion of the volume is trapped in the recirculation zone.The time variation of MKE averaged over the RVOT and RV Fig. , left, iin vitro  wall as compared to the septal RVOT and other RV regions for the highest cardiac output investigated. An increase in cardiac output leads to a relative shift of WSS from the septal RVOT to the RVOT free wall, and a relative increase in WSS at the RVOT free wall as compared to the septal RVOT and other RV regions. The identified regions of elevated hemodynamic stresses at resting and exercise conditions correlate with the common site of RVOT ventricular tachycardia in athletes and diseased regions in patients with ARVC/D. Next to RVOT, also the subtricuspid region was associated with elevated WSS. Although WSS did not linearly increase in this region with increasing cardiac output, WSS was hightest at maximum heart rate. These interesting findings may be associated with the clinical observation that the subtricuspid region and the RVOT are the first RV sites to be involved by the pathophysiologic process in ARVC/D26. With regard to this, peak systolic velocities were measured in the RVOT, and peak diastolic velocities in the subtricuspid region. Furthermore, our results indicate that even at resting conditions, WSS, disease stage of ARVC/D and ventricular arrhythmia burden as indicated by Holter-ECG monitoring are correlated, i.e. higher WSS regions develop at the RVOT in patients with ARVC/D as compared to the healthy proband.RVOT tachycardia is the most common form of idiopathic ventricular tachycardia, which may occur in the absence of structural heart diseaseWe also showed that the spatial distribution of the WSS along the RV is different for the healthy and diseased ARVC/D cases although higher WSS zones are located at the RVOT region for both healthy and diseased cases. This finding is interesting as it shows that the hemodynamics of the RV in patients with ARVC/D or the athlete’s heart change as RV remodelling progresses. It is suggested that WSS could be utilized as an indicator for analyzing disease severity in patients with ARVC/D and the athlete’s heart. Based on the results presented in this study, we therefore propose that a relative increase in wall shear stresses in the RVOT, particularly in the RVOT free wall, may contribute to adverse remodelling, scar formation and arrhythmia origin in this region in athletes and patients with ARVC/D.4. It is well known that large scale structures e.g. diastolic filling vortices exist in the RV34. However, studying RV hemodynamics in detail has been challenging as a consequence of its complex geometry. In this study, we found that highly vortical regions develop along the lateral wall of the RVOT with increasing cardiac output, and a relative shift of increased WSS occurs from the septal RVOT at baseline to the RVOT free wall at increased cardiac output. These observations may be linked to the physiologic structural adaptations of the athlete’s hearts, i.e. increased volumes28, but also pathologic processes such as scar formation in the athlete’s heart and ARVC/D32.The pulmonary circulation is a low pressure system, which allows the RV to operate at minimal energy costin vitro observations help to understand the susceptibility of the RVOT for structural changes and ventricular arrhythmias in athletes and patients with ARVC/D. Based on this preliminary data and the linear increase of WSS in the RVOT, we cannot make any recommendations regarding a certain cut-off for maximum exercise intensity (e.g. heart rate nor cardiac output) that can be considered safe in patients with ARVC/D. However, we have to acknowledge that the three groups investigated  have been characterized exclusively from a single individual each, and therefore biological variability has not been taken into account and formal statistical analysis was not possible. In the future, there is a need to reproduce our findings in a larger sample size and the effects of variations in cardiac output on RV hemodynamics in vivo.The pump used in this study has a technical limitation, which limits studying higher cardiac output levels. We were limited to moderate exercise conditions and it was not possible to study intensive exercise conditions with a cardiac output above 20 L/min. It would be worth extending the analysis to this regime in future work since the hemodynamic parameters may become non-linear at a higher cardiac output. Nevertheless, even at a cardiac output of 5.3 L/min equaling a 32% increase from baseline, we observed a substantial and relatively larger increase in wall shear stresses in the RVOT as compared to other RV regions. We can therefore assume that at even higher cardiac output levels such as in endurance athletes, this relative increase would substantially rise further in the RVOT. Therefore, our We confirm that all methods were carried out in accordance with relevant guidelines and regulations. This study was conducted in full agreement with the principles of the “Declaration of Helsinki” and current Swiss law. It has been approved by the Ethics Committee of the Canton of Zurich . All probands signed an informed consent form for prospective inclusion.in vitro, an optical imaging tool, 3D-PTV, has been applied to an anatomically accurate compliant silicone phantom  of the human RV and RA derived from a high resolution MRI heart scan of a healthy male proband. The experimental setup, which is similar to the one used in the study of Gülan et al.22, comprises a physiological silicone model, a high speed camera , a diode-pumped Nd-YLF laser , an image splitter, a data acquisition system, and a wave generator . The high-speed camera was synchronized with the heart pump system to trigger the recordings at the beginning of every cardiac pulse. A 100 W laser power was used for illuminating the fluorescent rhodamine particles  with a diameter of 200 μm. A mixture of glycerine, water and sodium chloride was used as working fluid, which matches the refractive index of silicone (n = 1.41) and the kinematic viscosity of blood (4.85 × 10−6m2/s)36. The position accuracy of the particles was 0.17, 0.17 and 0.35 mm in x, y and z directions, respectively for all cardiac output measurements. The velocity uncertainty of the raw PTV data, as obtained from the calibration, was 0.038 m/s. The Lagrangian data points were indexed onto a homogenous Eulerian grid system with a voxel size of 3.2 × 3.2 × 3.2 mm3. A total of 40 cycles were recorded to obtain a phase averaged flow field which corresponds to 120 k images allowing obtaining converged statistics for both phase averaged flow fields and velocity fluctuations. The heart rate was varied from 60 bpm to 150 bpm. A summary of conditions studied in this study is shown in Table We performed our experiments at four different cardiac output levels, namely 4.05 In vivo 4D-PC MRI measurements were performed with a 3 T Philips Ingenia System  to extract the physiological phase averaged velocity field in two healthy athletic male probands’ RV, and 2 additional patients with different stages of ARVC/D, namely early and moderate stages, which were assigned by RV dimensions and ventricular arrhythmia burden as assessed by ECG/Holter-ECG. The imaging parameters were as follows: spatial resolution 2.5 × 2.5 × 2.5 mm3, field of view 250 × 160 × 50 mm3, TR/TE 5,8/3,4 ms, and temporal resolution 35 ms. The velocity encoding (VENC) values are 40, 100 and 200 cm/s per direction. The phase contrast sequences were synchronized with the electrocardiography (ECG). A 3D-gradient echo phase contrast sequence with multi-point velocity encoding was applied to obtain 10x k-t undersampled data37. Subject characteristics and flow parameters obtained in vivo are summarized in Table Ui is the phase averaged velocity vector.Mean kinetic energy (K), which is the square of the phase averaged velocity magnitude, is defined asμ is the dynamic viscosity of the fluid. The maximum viscous shear stress is calculated ase1 and e2 are the eigenvalues of the stress tensor.Viscous shear stresses are defined asν is the kinematic viscosity of the fluid and The viscous dissipation of MKE due to mean shear, i.e. gradients of the mean velocity profile is defined as,The viscous WSS at a certain time instant is a tensor calculated as22. We achieve a resolution of O(1 mm) in our measurements and use a cubic spline to interpolate the wall-normal velocity profile and estimate its gradient.We use the L2 norm of the WSS tensors to quantify WSS magnitudes. The wall shear stresses are calculated using a velocity interpolation to positions with fixed normal distance to the detected boundaryin vivo and in vitro conditions, strain measurements were performed both in the silicone phantom and in the in vivo heart. 3D-PTV data was used to extract strain in the silicone phantom. The strain is calculated asL0 is the initial length of interest and L is the length at a certain time instance.To further compare In vivo strain measurements were performed using 2D transthoracic echocardiography from the apical four-chamber view at rest . Deformation imaging by speckle tracking is a technique, which is an angle-independent method avoiding limitations related to translational cardiac motion. The endocardial border was traced and the region of interest was adjusted to the myocardial wall. Wall motion was tracked over the cardiac cycle. Myocardial speckle tracking was digitally analyzed using Echo Pac Work Station .in vitro model, we investigated the influence of various cardiac output levels on RV hemodynamics. RVOT flow patterns at resting conditions were obtained in a athletic healthy proband’s heart  via PC-MRI, which is used as a reference for validating the in vitro flow patterns.In an in vivo and in vitro (Case IV) measurements. There is qualitatively good agreement in the RV flow patterns at the peak systolic phase. High velocity zones occur in the proximity of the RVOT, whereas the velocity magnitudes are comparatively lower at the RV subtricuspid region and the RV apex . Phase averaged flow parameters obtained both in vivo and in vitro are summarized in Table in vivo results. There is a slight difference in peak systolic values.The boundaries of the RVOT and RV were defined according to clinical practice (cardiac MRI). Figure pex Fig. , left. Sin vivo conditions, time evolution of the in vivo and in vitro longitudinal strain normalized by peak systolic strain along the RV free wall is shown in Fig. The physiological RV contraction in human begins with activation in the septum, extending to the RV free wall. To validate the presented model may produce similar hemodynamics to the in vitro and in vivo measurements, i.e. the temporal trend of the strain shows a negative kink during systole and two peaks in the diastole. In the early systolic phase the strain is negative representing the contraction of the RV, while pressure in the RV increases. At peak systole the strain reaches the maximum magnitude. In the deceleration phase the RV relaxes and the pressure decreases. In the early diastolic phase, pulmonary valve closes and tricuspid valve opens leading to a further decrease in pressure and an increase in positive strain, i.e. the RV starts expanding as the fluid flows from the right atrium towards the RV. During the isovolumetric contraction phase, the RV again starts to contract and the cardiac cycle restarts. The agreement between in vitro and in vitro strain is better during the systolic phase, whereas some discrepancies arise during the diastolic phase.There is a good qualitative agreement in the temporal variation of the longitudinal strain between


To demonstrate the potential for differentiating normal and diseased myocardium without Gadolinium using rest and stress T1-mapping. Patients undergoing 1.5T magnetic resonance imaging (MRI) as part of clinical work-up due to suspicion of coronary artery disease (CAD) were included. Adenosine stress perfusion MRI and late gadolinium enhancement (LGE) imaging were performed to identify ischemic and infarcted myocardium. Patients were retrospectively categorized into an ischemic, infarct and control group based on conventional acquisitions. Patient with both ischemic and infarcted myocardium were excluded. A total of 64 patients were included: ten with myocardial ischemia, 15 with myocardial infarction, and 39 controls. A native Modified Look-Locker Inversion Recovery (MOLLI) T1-mapping acquisition was performed at rest and stress. Pixel-wise myocardial T1-maps were acquired in short-axis view with inline motion-correction. Short-axis T1-maps were manually contoured using conservative septal sampling. Regions of interest were sampled in ischemic and infarcted areas detected on perfusion and LGE images. T1 reactivity was calculated as the percentage difference in T1 values between rest and stress. Remote myocardium was defined as myocardium without defects in the ischemic and infarcted group whereas normal myocardium is found in the control group only. Native T1-values were significantly higher in infarcted myocardium in rest and stress [median 1044 ms (interquartile range (IQR) 985–1076) and 1053 ms (IQR 989–1088)] compared to ischemic myocardium [median 961 ms (IQR 939–988) and 958 ms (IQR 945–988)]. T1-reactivity was significantly lower in ischemic and infarcted myocardium [median 0.00% (IQR − 0.18 to 0.16) and 0.41% (IQR 0.09–0.86)] compared to remote myocardium [median 3.54% (IQR 1.48–5.78) and 3.21% (IQR 1.95–4.79)]. Rest-stress T1-mapping is able to distinguish between normal, ischemic, infarcted and remote myocardium using native T1-values and T1-reactivity, and holds potential as an imaging biomarker for tissue characterization in MRI. Cardiac magnetic resonance imaging (cardiac MR) is currently the reference imaging technique for the evaluation of cardiac function and myocardial viability. In clinical practice, the visual assessment of first pass perfusion of gadolinium-based contrast agents is used to assess the presence of perfusion defects. However, cardiac MR also provides the unique possibility to assess tissue relaxation times, which can potentially be used for tissue characterization. Native T1-mapping can potentially be used to detect myocardial perfusion defects by quantifying myocardial water content without the use of gadolinium as a contrast agent. The water content is correlated to the myocardial blood volume (MBV) . Due to However, T1-mapping remains a challenge due to the high variability of reference values that result from differences in magnetic field strength, manufacturer, the type of mapping sequence, and inter-patient differences such as age and gender , 4. One A proof of concept study by Liu et al. showed that T1-reactivity was able to differentiate between normal, ischemic, infarcted and remote myocardium in a small group of healthy controls and patients with known coronary artery disease (CAD) . HoweverAll subjects gave written informed consent to participate in the study and the local ethical committee granted approval for the study procedures. Symptomatic patients with suspicion of CAD underwent adenosine myocardial perfusion MR as part of their clinical work up. All patients avoided potential adenosine agonists for at least 24 h prior to the cardiac MR, and all anti-angina medication was stopped 4 days before the examination. The use of Dipyridamole had to be stopped; yet, when this was not an option, it was considered a contraindication. From this prospective study, we retrospectively selected patients with no perfusion defects, and patients with only ischemic defects or only infarcts. A total of 64 patients were included: ten patients with ischemic myocardium, 15 patients with infarcted myocardium, and 39 control patients.All patients were scanned with a 1.5 T MR system . After the standard cine images were taken, a native Modified Look-Locker Inversion Recovery (MOLLI) based T1-mapping acquisition  was performed in short-axis views at both rest and stress. A 5(3)3 sampling scheme of the heart was performed, including eight images in 11 heartbeats. For the MOLLI acquisition, an initial inversion time of 110 ms was used with an 80 ms increment.2; slice thickness, 8 mm; acquisition matrix, 192 × 128; in plane spatial resolution, 1.4 × 1.4 mm2; bandwidth, 1085 Hz/pixel; flip angle, 35°; TR, 279 ms; TE, 1.1 ms; and parallel imaging acceleration factor, 2. Pixel-wise T1 maps of the myocardium were generated with inline motion correction. T1-maps were acquired at rest and at peak dose adenosine stress (140 µg/kg/min) in three short-axis slices . The mid-ventricular slice was used for analysis.A single-shot steady-state free-precession readout T1 sequence (i.e. MOLLI) was used to acquire the images. Other parameters used in the image acquisition included the following: field of view, 300 × 256 mm2; slice thickness, 8 mm; acquisition matrix, 192 × 144; in plane spatial resolution, 1.77 × 1.77 mm2; bandwidth, 1085 Hz/pixel; flip angle, 565°; TR, 2.6 ms; TE, 1.1 ms; and parallel imaging acceleration factor, 2.Stress-only perfusion imaging was performed as previously described in accordance with conventional methods . A nonseThe T1-maps, generated on the imaging console, were analyzed on commercially available software . Short-axis T1-maps were manually contoured using conservative septal sampling; specific sampling was used in ischemic or infarcted regions of interest (ROI) based on perfusion images and LGE images . T1-reacPatients were assigned to the control, ischemic, or infarcted group based on the results of their perfusion and LGE imaging. Patients were assigned to the control group if they presented no defects in both the perfusion series and the LGE series. Patients with a clear perfusion defect on the perfusion series, but without any defects on the LGE images, were assigned to the ischemic group.To avoid partial volume effects of the blood pool, all samples were located in the core of the ROI. All infarcted and ischemic ROIs were placed away from the endocardial and epicardial borders. Remote myocardium was defined as myocardium without defects in the ischemic and infarcted group. Remote myocardial ROIs were placed carefully outside of the ischemic or infarcted region and if possible in the septal area were the normal myocardium was sampled.Continuous values were presented as mean value ± standard deviation (SD), or median with interquartile range (IQR). Categorical data were presented as numbers with a percentage. A Mann Whitney-U test was used to compare groups regarding data that was not normally distributed. Statistical analysis was performed using SPSS Statistics 23 . A p-value < 0.05 was considered statistically significant.The baseline characteristics and hemodynamics during the cardiac MR evaluation of all included subjects are presented in Table In Fig. An overview of T1-reactivity values for the different groups is given in Table Figure This study demonstrates the possibilities for tissue characterization in cardiac MR using native T1-mapping at rest and stress among a population with intermediate-high risk for CAD. We show that T1-reactivity can discriminate between normal and diseased regional myocardium (ischemic and/or infarcted). However, there was no significant difference in T1-reactivity between ischemic and infarcted myocardium. Furthermore, native T1-values were significantly higher in infarcted myocardium at both rest and stress compared to ischemic myocardium; and could potentially be used to differentiate between ischemic and infarcted myocardium.Native T1-values in normal and remote myocardium were within previously published ranges . The T1-A previous study by Liu et al. reported on the ability of native T1-mapping to differentiate between normal, ischemic and infarcted myocardium . An impoA study by Messroghli et al. showed similar native T1-values in infarcted myocardium, while Liu et al. showed much higher values . Native Since T1-values are representative for the water content of the tissue, it is expected that they are associated with MBV. The T1-reactivity reflects the underlying increase of MBV during stress, while the native T1-value is influenced by multiple other factors, such as edema and interstitial fibrosis. Studies on dynamic CT myocardial perfusion imaging have shown that MBV is not only able to discriminate between normal and diseased myocardium, but also between ischemic and infarcted myocardium. Myocardial blood flow (MBF) is decreased in both ischemic and infarcted myocardium; whereas, MBV is only decreased in infarcted myocardium .In this study, compared to values at rest, we saw an increase in native T1-values during stress in normal and remote myocardium among all three groups. No increase was observed in ischemic and infarcted myocardium possibly because the capillary recruitment in these diseased areas is already maximized to compensate for the reduced MBF. As a direct consequence, the absence of T1-reactivity in diseased myocardium could be explained by the fact that inducing stress does not result in an increased capillary recruitment; as a result, the water content stays equal between rest and stress. Our results show that native T1-values in infarcted myocardium are higher than in normal/remote and ischemic myocardium. This represents the fibrotic tissue in infarcted myocardium, where the extracellular space is larger than in normal myocardium, allowing for an increased extravascular blood accumulation , 13. TheThe use of gadolinium has been a big discussion point considering recent studies demonstrated that intravenous administration of gadolinium is associated with deposits in the brain , 15. AckT1-values and T1-reactivity were evaluated in specific regions of interest that were identified based on visual analysis of the perfusion and LGE series. Liu et al. showed that segmental analysis of T1-reactivity is feasible, and that there were no significant differences between interslice and intersegment T1-reactivity values. In our study and in the study of Liu et al., ischemic and infarcted areas were also identified based on manually drawn ROI’s within perfusion and LGE scans . FurtherThis study has several limitations. We used data from patients that were prospectively enrolled in the PARAMETRIC study. However, the perfusion, LGE and native T1-mapping acquisitions were retrospectively analyzed for the purpose of this study. We introduced a selection bias by excluding patients with a combination of ischemia and infarction. However, this decision was based on the secondary outcome in order to be able to investigate the differences of native rest-stress T1-values and T1-reactivity in the remote myocardium of patients with normal, ischemic, and infarcted myocardium. The T1 mapping protocol we used was optimized to meet the acquisition requirements at all heart rate levels, however, this resulted in suboptimal image quality (192 vs. 256 acquisition matrix) in lower heart rate patients (< 90/min). Finally, our study population is relatively small and future research should focus on validating our results in a larger cohort of patients.In conclusion, native T1-mapping using a MOLLI 5(3)3 sequence during rest and stress can replicate the prior findings of ShMOLLI of the ability to distinguish between normal, remote, ischemic and infarcted myocardium using absolute and relative T1-value parameters and holds potential as an imaging biomarker for tissue characterization in MR without the use of gadolinium.


Impaired myocardial deformation has been sporadically described in cardiac asymptomatic systemic sclerosis (SSc). We aimed to study myocardial deformation indices in cardiac asymptomatic SSc patients using cardiac magnetic resonance feature tracking (CMR-FT) and correlate these findings to the phenotypic and autoimmune background.Fifty-four cardiac asymptomatic SSc patients , with normal routine cardiac assessment and CMR evaluation, including cine and late gadolinium enhancement (LGE) images, were included. SSc patients were compared to 21 sex- and age- matched healthy controls . For CMR-FT analysis, a mid-ventricular slice for LV peak systolic radial and circumferential strain and a 4-chamber view for LV/RV peak systolic longitudinal strain were used.Twenty-four patients had diffuse cutaneous SSc and 30 limited cutaneous SSc. Thirteen patients had digital ulcers. Median disease duration was 3.6 years. LV ejection fraction was higher in SSc patients compared to controls . Four patients had no LGE examination; in the remaining patients LGE was absent in 74%, while 18% had RV insertion fibrosis and 8% evidence of subendocardial infarction. LV longitudinal strain differed in those with insertion fibrosis (-18.0%) and infarction (-16.7%) compared to no fibrosis . Patients with SSc had lower RV longitudinal strain and strain rate compared to controls . All other strain and strain rate measurements were non-significant between patients and controls.In cardiac asymptomatic SSc patients with normal routine functional indices, CMR-FT identifies subclinical presence of insertion fibrosis and/or myocardial infarction by impaired LV longitudinal strain. RV derived longitudinal indices were impaired in the patient group. CMR FT indices did not correlate to the patients’ phenotypic and autoimmune features. The heart is a major target organ in systemic sclerosis (SSc), appearing to be involved in 12–80% of autopsy studies , 4. MyocCardiovascular magnetic resonance (CMR) is an accurate method for non-invasive, non-radiating assessment of ventricular volumes, function, myocardial perfusion as well as tissue characterization . While eIn the setting of SSc, there is only limited data  examininThe study was conducted at Skåne University Hospital, Lund, Sweden and Onassis Cardiac Surgery Centre, Athens, Greece and patients were included from both hospitals. Patients fulfilling the American College of Rheumatology criteria  and/or LMedical records were reviewed to collect clinical characteristics of the patients. Detailed history, physical examination, routine laboratory investigations, autoimmune screening as well as screening for atherosclerotic disease risk factors were assessed in all patients. For subgroup analyses, patients were divided based on the observation time from SSc diagnosis to CMR examination (disease duration), skin involvement (lcSSc vs dcSSc), presence of digital ulcers and autoimmune profile . SSc patients were compared with sex-matched healthy controls that underwent cine CMR evaluation during the same period. Controls were prospectively enrolled in previous study from the Lund group  and wereThis study was approved by the ethics committees of Skåne University Hospital, Lund, Sweden and Onassis Cardiac Surgery Centre, Athens, Greece in accordance with the ethical guidelines of the 1975 Declaration of Helsinki. Informed written consent was obtained from patients and healthy controls.CMR was performed on a 1.5 Tesla scanner using ECG-triggered cine steady-state free precession breath-hold cine long-axis planes and sequential 8 mm short-axis slices including the atrioventricular ring to the apex to assess ventricular function. Typical image parameters were: echo time (TE) 1.4–1.6, repetition time (TR) 2.8–3.2 ms, flip angle 60° and gap 0 mm , 2 mm  and 3 mm .To assess for fibrosis, late gadolinium enhanced (LGE) images were acquired 10–15 minutes after intravenous administration of gadolinium-DOTA  in identical short-axis planes using an inversion-recovery gradient echo sequence for fibrosis detection. Inversion times were adjusted to null normal myocardium.42 5.3.4 Tissue-Tracking Plugin  in a random order blinded to the patient clinical characteristics (A.L.). Cine short axis was used to evaluate LV and RV ejection fractions (EF). Analyses of myocardial deformation from two-dimensional strain and strain rate data were performed using feature-tracking imaging. Peak systolic LV and RV longitudinal myocardial deformation were measured in the left 4-chamber view . TRVmax ≤ 2.8 m/s was considered normal estimated pulmonary pressure, while TRVmax > 2.8 m/s giving rise to suspected elevated pressure . PatientAll data are reported as mean ± SD. Statistical analysis was performed using SPSS software . Correlation analysis was assessed using Pearson’s correlation. Volumetric measurements were normalized to the body surface area. Chi-square and unpaired student t tests were used to compare groups. ANOVA was used to test differences among groups. Mean ± SD was calculated to study the variability of the measurements. Inter-observer variability was assessed using intra class correlation coefficient. Results with a p-value of < 0.05 were considered statistically significant.Fifty-four cardiac asymptomatic SSc patients  with no known cardiac involvement were retrospectively enrolled into the study. Twenty-one age- and gender- matched healthy controls were used for comparison . DemograTwenty-four patients were diagnosed as having dcSSc and 30 as having lcSSc. Digital ulcers were registered on 13 patients and 41 did not have digital ulcers. Nineteen patients had anti centromere antibodies (ACA), 18 had anti topoisomerase I antibodies (ATA), 4 had anti RNA polymerase III antibodies (ARA), 10 had anti-nuclear antibodies without ACA, ARA or ATA (ANA+) and 3 were ANA-negative (ANA-). Patients had mean disease duration (time of observation from SSc diagnosis to CMR examination) of 43 months (range 6.6–311 months).Four patients had LGE pattern consistent with myocardial infarction  of which only one had prior suspected ischemic heart disease and 9 had fibrosis at RV insertion, leaving 37 patients without visually localized fibrosis and scar. Four patients had no gadolinium administration due to impaired kidney function (n = 1), anxiety/claustrophobia ending the examination (n = 2) or declining to receive gadolinium (n = 1).Patients with SSc had lower RV longitudinal strain and strain rate compared to controls . All other strain and strain rate measurements were non-significant between patients and controls .When evaluating skin involvement, all strain and strain rate measurements were non-significant between patients with lcSSc, dcSSc or healthy controls .When evaluating severe microvascular involvement of the skin, all strain measurements, except LV mid circumferential strain (p = 0.02), were non-significant between patients with or without digital ulcers .LV longitudinal strain was lower in patients with insertion fibrosis (-18.0%) and even lower in patients with infarction (-16.6%) compared to those without fibrosis . LVEF, LV radial and circumferential strain as well as RV longitudinal strain did not differ among the groups. However, RVEF was lower in patients with fibrosis and infarction .In disease duration correlation analysis, all correlations between disease duration and strain and strain rate measurements were non-significant .All strain and strain rate measurement, except LV longitudinal strain rate (p = 0.04), were non-significant when comparing groups of autoantibodies ACA, ARA, ATA, ANA+ or ANA .Intra-class correlation in inter-observer variability was <0.5 for LV longitudinal strain, RV longitudinal strain, LV radial strain and LV circumferential strain.In this CMR study, early cardiac involvement in cardiac asymptomatic SSc patients was documented in the RV but not in the LV. SSc patients had smaller LV/RV volumes as well as higher LVEF, but no difference in radial, circumferential or longitudinal indices, compared with age- and gender-matched healthy controls. Thirteen out of fifty SSc patients had insertion fibrosis and/or infarction, detected due to lower LV longitudinal strain, compared with those without. Finally, LV circumferential strain and LVEF were higher in SSc without, compared with those with digital ulcers.The finding of smaller LV and RV volumes and higher LVEF could be related to heart rate. Interestingly, LV mass was not significantly different between patients and controls. SSc patients have higher heart rate than normal controls, and autonomic dysfunction with altered diastolic function and cardiac remodeling in SSc has been suggested . FurtherGlobal longitudinal strain has an important role in identifying early myocardial dysfunction in patients with non-ischemic cardiomyopathies , 34. HowRight ventricular deformation indices were significantly impaired in the patients’ group. SSc patients are prone to develop pulmonary hypertension and early RV involvement should always be suspected in this population. Our results are in agreement with previous echocardiography derived ones identifying early-stage impaired myocardial deformation.  DefiningWe aimed further to examine the potential correlation of myocardial deformation to the underlying SSc clinical status and autoimmune profile. It has been documented that cardiac manifestations occur earlier and more frequently in patients affected by dcSSc than with lcSSc . PatientThere were no major differences in strain among patients with different autoantibody profile. So far, there has been conflicting data in the literature whether strain is altered in patients with different phenotypes of autoantibodies , 39, 41.From a technical perspective, our strain measurements were expressed as the fractional change in the length (as a percentage) from the resting state (end diastole) to the state following myocardial contraction . Strain Both echocardiography and CMR currently offer reproducible measurements of global strain values that can be applied in different clinical scenarios to assess LV and RV function . CMR hasLimitations of the study were:The use of multiple scanners and effects on variability of CMR measurements. From echocardiography, examining the same patient with two echo machines from different vendors can generate different strain values even when images are interpreted with the same software  and analOur study included mainly long-term SSc cardiac asymptomatic patients with a median time of 3.6 years from diagnosis. Therefore, part of the included patients had already received potentially cardiotoxic disease-modifying agents.Our CMR protocol included only functional assessment as well as visual detection of focal replacement fibrosis. Parametric imaging, which is currently the most sensitive index for detection of diffuse myocardial fibrosis, irrespective of LGE, was not included in the protocol. Perfusion imaging has been the subject of previous studies by some of the authors. The sample size of the patient group is small but comparable to number of patients traditionally used in similar studies, given the rare nature of the entity. The control group was matched with the patient population for sex and age, although LV strain with CMR has been shown to be only sex dependent, in order to achieve the maximal accordance between the two groups.A comprehensive biventricular myocardial deformation study with CMR feature tracking and LGE reveals early subclinical cardiac involvement in cardiac asymptomatic SSc with normal routine cardiac evaluation. CMR-FT contributed to differentiate the patients with silent myocardial necrosis as well as identified early RV involvement. The clinical significance of CMR deformation abnormalities for outcome and treatment goals remains to be elucidated through multicenter longitudinal studies.


The authors used interchangeably the terms “transthoracic echocardiography”, “focus echocardiography”, and “focus cardiac ultrasound”(FoCUS) without the clear distinction required by the potential major clinical implications ; the scrThe authors state: “A diagnosis of NSTEMI was based on the combination of ACS symptoms, lack of ST-segment elevation, and RWMA. Myocardial infarction was excluded in the absence of the latter.” Non-transmural infarctions compromising a small amount of necrotic myocardium may not be detectable on 2D-echo. It has been shown that RWMA detectable by echocardiography occur if resting coronary flow is reduced by > 50%, if > 20% of myocardial thickness is jeopardized by actual ischemia/necrosis, or if at least 1–6% of the left ventricle mass is involved [Previous myocardial infarction is indicated as an exclusion criterion. But a screening for myocardial scars or signs of pre-existing left ventricle disease was omitted from the exam, and a subsequent re-reading of the images by a blinded expert was omitted too, which may have led to potential false positives in non-ST-segment myocardial infarction (NSTEMI) diagnosis.We read with interest the manuscript by Bergmann et al.  but beliIt remains obscure how the authors can conclude that “No evidence of myocardial infarction was found in any patient with NSTE-ACS without RWMA in the pre-hospital TTE” and later state that NSTEMI was conclusively diagnosed in two patients without RWMA . We agre


Previous studies highlighted the usefulness of integrating left ventricular (LV) deformation (strain) and hemodynamic parameters to quantify LV performance. In a population sample, we investigated the anthropometric and clinical determinants of a novel non-invasive index of LV systolic performance derived from simultaneous registration of LV strain and brachial pressure waveforms.Three hundred fifty-six randomly recruited subjects  underwent echocardiographic and arterial data acquisition. We constructed pressure-strain loops from simultaneously recorded two-dimensional LV strain curves and brachial pressure waveforms obtained by finger applanation tonometry. We defined the area of this pressure-strain loop during ejection as LV ejection work density (EWD). We reported effect sizes as EWD changes associated with a 1-SD increase in covariables.P ≤ 0.0084). In both men and women, EWD increased independently with augmentation pressure (effect size: + 59.1 Pa), central pulse pressure (+ 65.7 Pa) and pulse wave velocity . In men, EWD decreased with relative wall thickness (− 29.9 Pa) and increased with LV ejection fraction . In women, EWD increased with left atrial (+ 76.2 Pa) and LV end-diastolic (+ 43.8 Pa) volume indexes and with E/e’ ratio .In multivariable-adjusted analyses, higher EWD was associated with age, female sex and presence of hypertension  contains supplementary material, which is available to authorized users. The performance of the left ventricle (LV) is determined by its intrinsic contractility (inotropy), by the tension on the LV wall at end-diastole (preload) and by the load against which the LV needs to eject blood (afterload) . If myocIn line, community-based studies demonstrated the detrimental impact of increased afterload on LV structure and function –7. IndeeEchocardiographic techniques such as two-dimensional 2D) speckle tracking allow quantification of the relative myocardial deformation (i.e. strain) . FurtherD speckleIn fact, EWD might better reflect LV systolic performance than peak LV deformation, as it integrates the instantaneous deformation as well as the instantaneous afterload against which the myocardium has to shorten , 11. Hown = 14), atrial fibrillation (n = 4) or symptomatic heart failure (n = 1), or because of insufficient quality of the echocardiograms (n = 6) or finger pressure waves (n = 24). In total, we thus analysed data from 356 participants.The Flemish Study on Environment, Genes and Health Outcomes (FLEMENGHO) was approved by the Ethics Committee of the University of Leuven. We randomly recruited a family-based population sample in northern Belgium as described before . All subData Supplement.Echocardiography and arterial phenotyping were performed after the subject had rested for at least 15 min in supine position. Details on the echocardiography, arterial phenotyping and other measurements are provided as Data acquisition - Briefly, one experienced physician (T.K.) did the ultrasound examination using a Vivid E9  interfaced with a 2.5- to 3.5-MHz phased-array probe, in accordance to recommendations [ndations  and prevDuring echocardiography, we recorded continuous finger pressure waves at the subject’s right middle-finger using a Finometer Pro , which were converted to brachial pressure curves by a validated transfer function implemented in the Finometer software .Off-line analysis - One observer (TK) analyzed the echocardiograms using EchoPac software (GE Vingmed). End-diastolic LV dimensions were used to calculate relative wall thickness (RWT) and LV mass. We measured transmitral peak early (E) and late (A) diastolic velocities as well as early (e’) and late (a’) diastolic peak mitral annular velocities at 4 acquisition sites . The E/e’ ratio, a surrogate of LV filling pressure, was transmitral E peak divided by e’ averaged from the 4 acquisition sites. Two observers (N.C and T.K.) measured LV global longitudinal strain (LS) using myocardial speckle-tracking software  as described before [d before . We usedVAC analysis – We post-processed the simultaneously recorded LV deformation curves and pressure waves using a custom Matlab algorithm . The performance of the software was validated in 50 subjects using intermediate and final quality checkpoints and is available upon request from the corresponding author  linked to a computer running SphygmoCor software . Pulse waves were calibrated by the supine brachial BP measured immediately before tonometry. From radial signals, SphygmoCor software constructed the aortic  pulse wave using a validated generalized transfer function. Central pulse pressure (PP) was central systolic minus diastolic pressure. Augmentation pressure (AP) was the pressure difference between the first and second shoulder of the central waveform. In 157 men and 117 women, we measured aortic pulse wave velocity (PWV), the non-invasive gold standard of arterial stiffness, as the carotid-femoral distance divided by the carotid-femoral pressure transit time .Conventional BP was the average of 5 auscultatory readings obtained with the subject in seated position. Hypertension was defined as a BP of at least 140 mmHg systolic or 90 mmHg diastolic or the use of antihypertensive drugs. Participants on antihypertensive therapy were defined as having either uncontrolled (BP > 140/90) or controlled (BP ≤ 140/90) hypertension. Diabetes mellitus was determined by self-report, a fasting glucose level of at least 126 mg/dL, or the use of antidiabetic agents.P value < 0.05. Using mixed models, we assessed multivariable-adjusted associations of EWD with anthropometric and clinical characteristics, hemodynamics, arterial stiffness and echocardiographic indexes of LA volume index (LAVi) and LV structure and function. All models were adjusted for age, sex, heart rate and body height and weight, and accounted for family clusters modelled as a random effect. We reported multivariable-adjusted regression coefficients for EWD per 1-SD increase in the covariable. We repeated regression analyses for men and women separately.We used SAS software v9.4  for database management and statistical analysis. We compared means and proportions using a large sample z-test and χ2-test, respectively. Statistical significance was a two-sided P < 0.0001; Table The 356 participants (44.7% women) included 169 (47.5%) hypertensive subjects, of whom 92 (54.4%) were on antihypertensive drug treatment. Mean age was 53.9 ± 13.7 years. Tables P < 0.0001; Fig. ). Of note, EWD was higher in postmenopausal than in premenopausal women  or uncontrolled (P = 0.0036) as compared to subjects with controlled hypertension , but was not related to the use of ACE-inhibitors/ARBs, calcium channel blockers or diuretics (P ≥ 0.51). In addition, after accounting for sex and age, EWD was significantly higher in obese than in non-obese women  or with smoking (P ≥ 0.22).After full adjustment, EWD decreased with the use of β-blockers .Table P ≤ 0.0003) as well as to higher brachial PP (+ 82.1 Pa) and mean arterial pressure . Moreover, after full adjustment, EWD increased with higher AP (+ 59.1 Pa), central PP (+ 65.7 Pa) and PWV .As expected, in multivariable-adjusted analyses, higher EWD was independently related to higher systolic (effect size: + 95.2 Pa) and diastolic BP , but not with PWV  for EWD associated with a 1-SD increase in echocardiographic indexes reflecting LA and LV geometry Table  and LV d% CI for P ≤ 0.039 for all; Table P ≤ 0.013; Table P ≤ 0.035; Table 4; Fig. In all subjects, EWD significantly increased with LAVi + 41.2 Pa), end-diastolic volume index  and LV stroke volume (+ 27.9 Pa) after full adjustment  and stroke volume .Elevated EWD correlated independently to greater early + 55.3 Pa) and late + 47.2 Pa) diastolic transmitral peak velocities  older age, female sex and hypertensive status are associated with higher EWD; (ii) in both men and women, EWD increased with steady and pulsatile BP components and arterial stiffness; and (iii) EWD decreased independently with LV wall thickness in men, yet increased with higher LAVi and LV filling pressure (E/e’ ratio) in women only.LV performance is determined by its intrinsic contractility (inotropy), by the tension on the LV myocardium at end-diastole (preload) and by the load against which the LV needs to contract to eject blood (afterload) . Within Numerous population studies demonstrated the detrimental impact of a chronically increased afterload on LV structure and function –7. IndeePrevious population studies demonstrated that LV diastolic function, particularly in women, is sensitive to the detrimental effects of increased central pulse pressure and arterial stiffness , 6, 7. TBesides undergoing changes in function, the LV progressively remodels in response to chronically elevated LV afterload , 22. IndRecent interest in constructing and evaluating pressure-strain loops supports the need for a non-invasive clinical tool that integrates LV deformation and loading. Indeed, inspired by Russel and colleagues , GE HealThe present study must be interpreted in context of its limitations and strengths. First, echocardiography is prone to measurement errors. However, one experienced observer recorded all echocardiographic images using a standardized protocol. Moreover, images were post-processed by two experienced observers with good reproducibility. Second, we derived EWD by simultaneous finger tonometry and 2D speckle tracking to overcome the technical challenges linked to simultaneous carotid tonometry and Tissue Doppler Imaging [Older age, female sex and hypertensive status are associated with higher EWD. Integration of the LV pressure-strain loop during ejection might be a useful tool to non-invasively evaluate sex-specific and interdependent effects of preload and afterload on LV myocardial performance. Future studies should investigate the utility of pressure-strain loops in clinical decision-making, particularly in subjects at risk for heart failure.Additional file 1:Area of the pressure-strain loop during ejection as non-invasive index of left ventricular performance: supplemental material. (DOCX 814 kb)


Introduction: In light of previous studies reporting the significant effects of preeclampsia on cardiac dimensions, we sought to evaluate changes in the left ventricular (LV) systolic and diastolic functions in patients with preeclampsia with a view to investigating changes in cardiac strain. Methods: This cross-sectional study evaluated healthy pregnant women and pregnant women suffering from preeclampsia who were referred to our hospital for routine healthcare services. LV strain was measured by 2D speckle-tracking echocardiography.Results: Compared with the healthy group, echocardiography in the group with preeclampsia showed a significant increase in the LV end-diastolic diameter , the LV end-systolic diameter , and the right ventricular diameter . The mean global longitudinal strain was -18.69 ± 2.8 in the group with preeclampsia and -19.39 ± 3.49 in the healthy group, with the difference not constituting statistical significance (P = 0.164). The mean global circumferential strain in the groups with and without preeclampsia was -20.4 ± 12.4 and -22.68 ± 5.50, respectively, which was significantly lower in the preeclampsia group (P = 0.028). Conclusion: The development of preeclampsia was associated with an increase in the right and left ventricular diameters, as well as a decrease in the ventricular systolic function, demonstrated by a decline in global circumferential strain. These hemodynamic changes lead to an increase in the thickness of the LV wall, as well as an increase in the size and volume of the LV through cardiac remodeling. However, the systolic and diastolic functions of the LV during a normal pregnancy remain constant with minimal changes.4 These changes are important for the success of pregnancy, but an additional burden may be imposed on the heart.5 In addition, heart disease is the leading cause of maternal mortality during pregnancy, and the number of pregnant women at risk for cardiovascular complications is on the rise. Therefore, the identification and perception of the structure and function of the mother’s heart is of clinical importance and is essential for the management of cardiovascular patients during pregnancy.7Hypertensive disorders of pregnancy are a group of conditions that include pregestational hypertension, gestational hypertension, preeclampsia, and preeclampsia superimposed on chronic hypertension. Preeclampsia is high blood pressure and protein in urine, occurring after week 20 of pregnancy. Preeclampsia is a condition that can threaten maternal and fetal lives during pregnancy. There are studies that show the direct effects of preeclampsia on the left ventricular (LV) mass and other cardiac functional indices.8 Previous studies have reported conflicting data on the parameters of the systolic cardiovascular function such as the ejection fraction (EF) and Doppler velocity. These parameters are dependent on the load on the heart; their use is, therefore, limited due to the instability of reported pregnancy outcomes.11 Recently, 2D echocardiography has shown a significant decrease in longitudinal strain indicators at the end of pregnancy, while the traditional parameters do not reflect these functional changes.12 In addition, recent technological advances in 3D spectrum echocardiographic technology have made possible the measurement of all the quantitative and qualitative indicators of the cardiac function that are neglected in the current 2D speckle-tracking echocardiography (2D-STE). 13 Accordingly, given the importance of echocardiography in pregnant women and the timely diagnosis of possible risky conditions, we aimed to determine the normal size, the LVEF, the strain rate, and the LV function during normal pregnancy in healthy women and compare them with pregnant women with preeclampsia.Despite many reports of maternal heart compatibility, there are discussions about changes in the LV function. Nonetheless, evidence of enlargement in the size of the chambers, as well as the mass and the thickness of the LV wall, is inconsistent.The present study was a cross-sectional descriptive-analytic study conducted in Shariati Hospital between 2017 and 2018. The study population consisted of healthy and preeclamptic pregnant women who were referred to Doctor Shariati Hospital in order to receive routine healthcare services. In the present study, a healthy pregnancy was considered to be pregnancy in women without any cardiac diseases, preeclampsia, seizure, hypertension, diabetes, or kidney diseases.The criterion for demonstrating mild preeclampsia was the incidence of hypertension > 140/190 mm Hg after 20 weeks of pregnancy with proteinuria > 300 mg per 24 hours or 30 mg of stable proteinuria (1+ with strip papery) in randomized urine samples. The criteria for the diagnosis of severe preeclampsia were comprised of hypertension > 160/110 mm Hg with proteinuria > 2 g per 24 hours, epigastric pain, headaches, blurred vision, liver enzyme crisis, coagulation disorders, and increased creatinine and blood urea nitrogen.The exclusion criteria consisted of low imaging quality, high blood pressure, non-pregnancy diabetes, and other abnormal findings such as 1) abnormal dilation in at least one of the 4 cardiac chambers; 2) a left ventricular ejection fraction (LVEF) < 55%, 3) right ventricular (RV) dilatation or hypokinesia, 4) moderate or worse valvular disorders, 4) pericardial effusion, 5) uncorrected cognitive state, 6) congenital heart disease, and 6) diastolic disturbances.Sufficient information as regards the study objectives was provided to the patients; and if they consented to participate in the study, the following variables were collected through a self-made questionnaire and echocardiography: age, the LV end-systolic size and volume, the LV end-diastolic volume, the E/E’ ratio, the number of parity, global longitudinal strain, global circumferential strain, the RV peak systolic myocardial velocity by tissue Doppler echocardiography (RVsm), the RV diameter, and tricuspid annular plane systolic excursion (TAPSE). In this study, the third trimester of pregnancy was considered a gestational age of 27 to 42 weeks. Following the assessment and collection of the above data, 2D-STE was conducted with automated cardiac motion quantification(aCMQ) Philips Epic 7 device in the 2 groups of healthy subjects and pregnant women with preeclampsia. The tests used in this study to measure the variables were: 1) simple 2D echocardiography, 2) Doppler echocardiography, and 3) changes in myocardial strain including global longitudinal strain and global circumferential strain. For measurement of 2D strain, first 6 gray scale images were acquired and stored on digital media, then offline software was used to generate the strain data. Images were apical 4 chamber, 2 chamber, 3 chamber for measurement of LV longitudinal strain , and short axis view at basal, mid ventricular and apical view for measurement of circumferential strain. Quality of 2D images were optimal and care was taken to avoid foreshortening. Gray scale frame rate was kept between 30 and 70 frame/sec. ECG was gated and 3 cardiac cycle was acquired for each loop. Automated border detection followed the endocardium and subsequently a correction was manually performed  and straAll measurement was done by single expert echocardiographist. To reduce interobserver variability, measurements were repeated in random order by an interval of 1 month. To test interobserver variability, a second skilled echocardiographist analyzed data without knowledge of the measurement of first observer.Descriptive analyses were used to describe the data, including the mean ± the standard deviation (SD) for the quantitative variables and frequencies (percentages) for the categorical variables. The χ2 test, the t-test, and the Mann–Whitney U test were applied to compare the variables. For the statistical analyses, the statistical software IBM SPSS Statistics for Windows, version 22.0,  was utilized. A P value < 0.05 was considered statistically significant.P = 0.008), the mean LV end-systolic diameter was also significantly higher in the preeclampsia group , and the mean RV diameter was also significantly higher in the preeclampsia group . However, no differences were observed between the 2 study groups vis-à-vis the LV end-diastolic volume, the LV end-systolic volume, the LVEF, RVsm, and TAPSE.In the present study, 60 pregnant women with preeclampsia and 40 pregnant women without preeclampsia were enrolled. As is summarized in P = 0.164). Nevertheless, the mean global circumferential strain was significantly lower in the preeclampsia group . Based on the results, in the patients with preeclampsia, increased systolic diameters, diastolic termination, increased RV diameters, and also decreased global circumferential strain were all expected.Regarding the status of strain, the mean global longitudinal strain was -18.69 ± 2.8 in the group with preeclampsia and -19.39 ± 3.49 in the healthy group, with the difference not constituting statistical significance  and resulting in an increase in the LV mass. Of course, in severe preeclampsia, hypertrophic changes appear to be due to intravascular resistance and lead to mortality.In their study, Zangeneh et al2 reported that the LV volume and the LVEF in their preeclamptic women were higher than those in their healthy pregnant subjects, which again was more apparent in severe preeclampsia.Simmons et alFinally, in the context of preeclampsia and the rise in the vascular resistance index, an increase in ventricular dimensions and a significant reduction in ventricular function as measured by global strain can be observed. It is clear that the above changes are more pronounced in severe cases of preeclampsia, wherein we can expect more ventricular hypertrophy and possibly more disruption in ventricular function, followed by yet again a further reduction in the LVEF, which can still be sustained long after delivery.The limitations of our study are its small sample size and the lack of the follow-up of the patients postpartum.In the present study, the occurrence of preeclampsia was associated with an increase in the LV and RV diameters, as well as a decrease in ventricular function in the form of a drop in global circumferential strain. Of course, a decrease in the other indices such as global longitudinal strain and RVsm was also observed; these changes, however, were not significant, which may have been due to our small sample size.None.The study was approved by ethical committee of Tehran University of Medical Sciences (No. IR.Tums.MEDICINE.REC.1396.2717).


Congestion  is an important culprit mechanism driving disease progression in heart failure. Nevertheless, congestion remains often underappreciated and clinicians underestimate the importance of congestion on the pathophysiology of decompensation in heart failure. In patients, it is however difficult to study how isolated congestion contributes to organ dysfunction, since heart failure and chronic kidney disease very often coexist in the so-called cardiorenal syndrome. Here, we review the existing relevant and suitable backward heart failure animal models to induce congestion, induced in the left-  or right-sided heart , and more specific animal models of congestion, induced by saline infusion or inferior vena cava constriction. Next, we examine critically how representative they are for the clinical situation. After all, a relevant animal model of isolated congestion offers the unique possibility of studying the effects of congestion in heart failure and the cardiorenal syndrome, separately from forward failure . In this respect, new treatment options can be discovered. Heart failure is a major public health problem affecting over 23 million people worldwide  and is dCongestion is classically explained as the consequence of increased cardiac filling pressures, by activation of the neurohumoral and sympathetic nervous system, to compensate a reduced cardiac output (CO). Cardiac filling pressures increase due to ventricular interdependence or due to chronically elevated left-sided filling pressures transmitted back through the pulmonary system into the right ventricle , resultiThe consequences of congestion are not easy to explore in clinical trials, since concomitant forward failure and underlying chronic kidney disease often coexist in patients. Consequently, a wide variety of therapeutics, shown to be beneficial in heart and kidney failure separately, are administered to patients in an attempt to reduce congestion. However, in the clinical setting, the treatment for congestion remains to be optimized. Therefore, further fundamental research in animal models, realistically representing congestion, is necessary. We are the first to review the existing clinically relevant and suitable animal models for the study of congestion, since adequate experimental modeling of the real-life scenario is crucial to examine disease mechanisms and to develop potential therapeutic strategies. In this paper, we will review the existing animal models of heart failure, induced by backward failure, and more specifically congestion.Numerous animal models are available to discuss the cardiorenal syndrome, as reviewed by Hewitson et al. . HoweverThese backward failure models only qualify as a relevant model of venous congestion, if the following conditions are met; 1) CVP has to increase above the upper limit of normal (> 8 mmHg), since this is the most important characteristic of congestion contributing to a worsening in renal function in patients; (2) edema or a congestive state is required to be present; (3) the experimental method to induce backward failure should not be toxic or affect left ventricular, valvular or pulmonary function, and morphology; and (4) only the right-sided heart and/or venous system should be affected by backward failure  [p < 0.01) and mean arterial pressure . This eminent sign of hemodynamic congestion is positively correlated with increased blood arginine vasopressin concentrations , contributing to sodium and water retention (p < 0.05) [Myocardial ischemia and subsequent left ventricular (LV) remodeling is the leading cause of CHF . In rode < 0.05) , 16, 73. < 0.05)  demonstr < 0.05) . In addi < 0.05)  in which < 0.05) . Howeverp < 0.01) vs. 270 ± 34 g/ml in control group; increase in plasma renin activity from 1.4 ± 0.4 ng/ml/h at baseline to 10.2 ± 2.4 ng/ml/h after 8 weeks of pacing (p < 0.01) vs. 1.7 ± 0.5 ng/ml/h in control group; increase in plasma aldosterone from 124 ± 42 p/ml at baseline to 577 ± 151 pg/ml after 8 weeks of pacing (p < 0.01) vs. 124 ± 43 pg/ml in control group) and the neurohumoral activation returns to baseline levels after resumption of sinus rhythm [p < 0.05) [p < 0.01), and right atrial pressures , and is associated with ascites, pulmonary congestion, and low-output failure  [Arrhythmias are often involved in the CHF process as well . Therefos rhythm , 18. Aft < 0.05) , pulmona < 0.01) . Cessati < 0.01) . Howeverp < 0.01), central venous pressure  and left ventricular end-diastolic pressure  [p < 0.05), and cardiac hypertrophy [Chronic volume overload can be achieved in rats and dogs by the creation of aorta-caval shunt (ACS), also known as an arteriovenous fistula , 23. The < 0.01) , thereby < 0.01) , 26. To  < 0.01) . Usuallyertrophy . Howeverp < 0.01), end-systolic volume , end-diastolic pressure , stroke volume , left ventricular mass , and a decreased CO  and mean aortic pressure  [p < 0.05) was also significantly increased, and hypothetically, this augmented pulmonary artery pressure may also be transmitted back to the venous system [2O (= 4.4 ± 1.3 mmHg) in mitral regurgitation group compared to 4.6 ± 1.4 cmH20 (= 3.4 ± 1.0 mmHg) in control group) [p < 0.05) and demonstrate a reduced contractility [Volume overload can also be induced in a canine model by mitral valve regurgitation by a catheter-based method of chordae disruption . Chronicactility . As a rep < 0.01 and mean pulmonary artery pressure in minipigs; 24.62 ± 1.38 mmHg in MCT vs. 15.19 ± 0.70 mmHg in control group, p < 0.01) and right-sided heart failure [p < 0.01) subjected to MCT treatment [p < 0.0001) [p < 0.0001) [p < 0.01) [p < 0.05) and serum , renal and cardiac tissue  in MCT rats vs. 32,120 ± 4961 AU in control rats, p < 0.01), and neutrophil gelatinase-associated lipocalin (NGAL) levels in rats [Monocrotaline (MCT) injections have been used in rats and minipigs to induce pulmonary hypertension  , mean pu < 0.01) . CVP inc < 0.01) –37. MCT p < 0.05) and diastolic pressures  rise [p < 0.01), right ventricular weight increases up to 100–200%, and hepatic function is affected, as evidenced by increased plasma liver enzymes  [p < 0.0001) and right ventricular end-diastolic pressure  which is transmitted back to the venous system, thereby disturbing venous return and increasing central venous pressure  [Pulmonary artery banding (PAB) causes chronic pressure overload leading to right-sided heart failure and is performed by placing a suture, clip, or inflatable ring around the pulmonary artery proximally to the right ventricle . Consequ05) rise , CO is r < 0.05) , 40. PAB < 0.05) , 40. Hep < 0.05)  showed t 0.0001) .In conclusion, the PAB animal model seems to be the most relevant and appropriate animal model of backward failure to induce congestion, since PAB augments the right ventricular pressure and CVP resulting in a congestive state and right-sided heart failure.In the previous section, we summarized the available animal models of heart failure induced by backward failure. None of the models described above fully qualify as a clinically relevant model of congestion. The most commonly employed surrogate for venous congestion has been central venous pressure (CVP). Current knowledge about CVP contributing to renal dysfunction originates from animal experiments performed in the 1850s. Ludwig (1856) demonstrated that urine output decreases as soon as the CVP is raised above 10 mmHg . Later, Recently, a rat model of acute renal congestion has been described by Komuro et al. . In thisIn the past, efforts have been made to induce isolated venous congestion in animal models by restricting the diameter of the inferior vena cava (IVC) Table . In thisIVC constriction affects the kidneys, heart, and liver, thereby inducing subdiaphragmatic venous congestion. Regarding the impact of congestion on the kidneys, subdiaphragmatic venous congestion in dogs , 52 and Most of the existing animal models of subdiaphragmatic congestion do not meet the criteria to be a clinically relevant animal model of isolated congestion Table . First, p < 0.01); (2) kidney function worsened and renal morphometry was altered in IVCc rats, as indicated by a significantly increased plasma creatinine , plasma cystatin C , urinary albumin , glomerular surface area and with of Bowman’s space (p < 0.05); and (3) cardiac function did not differ between both groups, as a result of abdominal venous congestion induced by thoracic IVC constriction. To summarize, Cops et al. [Recently, the authors developed a new rat model of abdominal venous congestion by addressing these aforementioned limitations . They ops et al.  were abls et al. .In conclusion, this rat model offers the unique possibility of studying abdominal venous congestion in heart failure and by extension in the cardiorenal syndrome , 71. ThiCongestion, as part of backward failure in heart failure, is an important player in the pathophysiology of heart failure and the cardiorenal syndrome. Nonetheless, the exact disease mechanisms remain to be elucidated and further fundamental research is necessary. In the past, different techniques have been described to induce backward failure in animal models. Unfortunately, these models are not truly a model of congestion, as explained before. Since an increased CVP is such a strong determinant of congestion, a whole spectrum of techniques has been described to constrict the IVC in an attempt to increase the CVP, above the upper limit of normal, and in this way qualifying as model of congestion. To date, the rat model in which selective abdominal venous congestion was induced by a permanent surgical constriction with a 20-gauge needle seems to be a clinically relevant animal model of congestion, since the drawbacks of the previous subdiaphragmatic venous congestion models are corrected in the current model.


HSP27 (HSPB1) showed a distinct and characteristic intracellular translocation from the cytoskeletal fraction into the membrane fraction of platelets during acute myocardial infarction that did not occur in the control group. In this study, we could demonstrate for the first time that HSP27 (HSPB1) is upregulated and phosphorylated in human platelets during myocardial infarction on a cellular level ex vivo with a characteristic intracellular translocation pattern. This HSP27 (HSPB1) phenotype in platelets could thus represent a measurable stress response in myocardial infarction and potentially other acute ischemic events.Heat-shock proteins are a family of proteins which are upregulated in response to stress stimuli including inflammation, oxidative stress, or ischemia. Protective functions of heat-shock proteins have been studied in vascular disease models, and malfunction of heat-shock proteins is associated with vascular disease development. Heat-shock proteins however have not been investigated in human platelets during acute myocardial infarction ex vivo. Using two-dimensional electrophoresis and immunoblotting, we observed that heat-shock protein 27 (HSPB1) levels and phosphorylation are significantly increased in platelets of twelve patients with myocardial infarction compared to patients with nonischemic chest pain (6.4 ± 1.0-fold versus 1.0 ± 0.9-fold and 5.9 ± 1.8-fold versus 1.0 ± 0.8-fold;  Heat-shock proteins (HSPs) are expressed in many cells of the cardiovascular system such as endothelial cells, cardiac muscle cells, monocytes, and platelets. They are upregulated in response to inflammation, oxidative stress, or ischemia  and protIn this work, we demonstrate for the first time that HSP27 (HSPB1) is upregulated and phosphorylated in platelets of patients with ST-elevation myocardial infarction compared to control patients with nonischemic chest pain. HSP27 in platelets showed a distinct intracellular translocation pattern that was not observed in the control group. Protein spots that showed differential regulation in platelets during myocardial infarction in two-dimensional gel electrophoresis were sampled and analyzed by mass spectrometry. n = 12 in each group) showed a significant increase of HSP27 protein and HSP27 phosphorylation in platelets from patients with myocardial infarction (MI) compared to controls   B,C.Platelets were stimulated with thrombin (0.5 U/L) for up to two hours, and HSP27 levels were quantified by immunoblotting. After thrombin stimulation, we observed a gradual increase of HSP27 with a peak value at 30 min, which declined with longer stimulation . Heat-shThrombin stimulation of platelets induced an intracellular translocation of HSP27 from the cytoskeletal into the membrane-associated fraction of platelets as illustrated by confocal microscopy A. To quaIn the present study, we used two-dimensional electrophoresis to analyze proteomic changes of platelets from patients with acute myocardial infarction and nonischemic chest pain and observed increased phosphorylation (pHSP27) and upregulation of HSP27 in platelets during myocardial infarction. So far, intracellular modulation of HSP27 has not been studied in human platelets during myocardial infarction ex vivo. Patients with ST-elevation myocardial infarction were treated with aspirin immediately after diagnosis, and additional loading with ADP receptor antagonists such as clopidogrel was initiated immediately after blood was drawn. All control patients were also treated with aspirin by the time of blood sampling due to acute onset chest pain and suspected coronary artery disease. Therefore, there was no difference in antiplatelet therapy between groups at the time of blood sampling to make sure that the observed effects can be attributed to the acute vascular event and not to drug-related effects.Phosphorylation of HSP27 seems to indicate that the protein is in a cell protective, anti-oxidative, and antiapoptotic functional state ,22. The Heat-shock proteins were found in increased concentrations in the plasma of patients with acute myocardial infarction or coronary artery disease although the source remained unknown ,28,29, aAlthough we found a robust HSP27 phenotype in platelets during myocardial infarction, it remains to be determined if this is a result of the ischemic process or whether these changes occur prior to the acute event. Further studies suggest that HSP27 also regulates the cytoskeleton and that phosphorylation of HSP27 is a step that immediately precedes the association of HSP27 with the activated cytoskeleton of platelets [In this study, we consistently observed a distinct intracellular redistribution pattern from the cytoskeletal into the membrane-associated protein fraction in platelets during myocardial infarction, which was not observed in patients with nonischemic chest pain. Previous observations demonstrate that HSP27 translocates between cellular compartments in platelets after thrombin stimulation ,9,10, whSince HSP27 directly associates with the cytoskeleton to execute signaling functions, intracellular translocation of HSP27 during cellular activation or in response to stress signals appears to make sense physiologically. Others have reported that HSP27 interacts with the cytoskeleton through actin fiber stabilization, which has also been associated with decreased migratory capacity of inflammatory cells and anti-inflammatory functions . We haveBesides direct regulatory effects on a cytoskeletal level, HSP27 controls translation factors such as eIF4F through binding of eIF4G, which then results in inhibition of translation . Likely An elegant study by Liu and colleagues demonstrates increased levels of CCL2 (Chemokine CC-motif ligand 2) in plasma, platelets, and thrombus material of patients with myocardial infarction. Activation of platelets with CCL2 in return resulted in increased phosphorylation of HSP27 and other signaling proteins . It is tempting to speculate that increased phosphorylation of HSP27 in platelets from patients with myocardial infarction could be a sign of an ischemic stress response. We do not know however if this phenotype is a direct result of the acute vascular events or a consequence of platelet activation. The question whether heat-shock protein phosphorylation is an anti-inflammatory reaction in platelets while unphosphorylated HSP27 may contribute to accelerated aggregation or if it is a passive result of the stress stimulus remains to be determined in future studies. Further research will additionally be necessary to investigate the regulatory mechanisms of HSP27 protein and its phosphorylation during myocardial infarction. In summary, we observed a significant increase of HSP27 (HSPB1) protein levels and phosphorylation of HSP27 in human platelets during myocardial infarction compared to matched controls with nonischemic chest pain in this study. Supporting previous observations in platelets, a characteristic intracellular translocation of HSP27 from the cytoskeletal into the membrane associated protein fraction was also observed during myocardial infarction. This platelet phenotype was distinctly different in platelets from patients with myocardial infarction compared to controls. It will be interesting to extend the observed characteristics of the HSP27 phenotype in platelets during myocardial infarction to other acute vascular events such as ischemic stroke or peripheral artery disease. Twelve patients with acute ST-elevation myocardial infarction (mean age 62 years) and obstruction of a proximal left dominant or right coronary artery as well as twelve age-matched control patients with acute onset typical chest pain but rule-out for acute myocardial infarction by electrocardiogram (ECG) and cardiac enzymes were enrolled in the study. Due to suspected coronary artery disease, control patients underwent coronary angiography in which coronary artery disease was ruled out. According to guideline recommendations, patients with ST-elevation myocardial infarction were treated with aspirin immediately after diagnosis. Blood for this study was drawn in the cath lab before other antiplatelet agents such as clopidogrel or tirofiban were administered for acute myocardial infarction. All control patients were also on aspirin treatment by the time of blood sampling. Written informed consent was obtained from all patients. The study was approved by the local ethics committee of the University of Tübingen  in accordance with the Declaration of Helsinki. Blood was drawn on admission after indication for coronary angiography had been established and blood samples were processed immediately. 9 platelets was lysed in 100 µL of CHAPS lysis buffer  and stored for two-dimensional gel analysis and immunoblotting at −20 °C.Platelets were isolated according to standard protocols in our lab as previously described ,33. For 9) were lysed in 1 mL Triton X-lysis buffer  for 10 min on ice. The pellet containing the cytoskeletal cell fraction was collected after centrifugation at 15,600× g for 4 min after supernatants had been carefully removed. Supernatants were centrifugated again at 100,000× g, and pellets containing the membrane fraction were collected. Both fractions were resuspended in SDS loading buffer before electrophoresis.Freshly isolated platelets  and purified using a 2D clean-up kit  according to the manufacturer’s instructions. Comparative 2D gel analysis of the proteomes was performed as described previously with slight modifications ,35. FirsPlatelets lysed in Laemmli buffer were separated by SDS PAGE gel electrophoresis and probed for HSP27, phospho-HSP27, and β-actin. After protein transfer to a nitrocellulose membrane, membranes were blocked in 5% nonfat milk in Tris-buffered saline with Tween-20  for 1 h. Afterwards, primary monoclonal antibody to HSP27 or phospho-HSP27  were added and incubated overnight at 4 °C with constant agitation. Membranes were washed in TBS-T repeatedly, and HRP-conjugated secondary antibody (1:10000)  was added for 1 h at room temperature. After washing, chemiluminescent substrate  was added for 1–5 min and bands were visualized on plain film. β-Actin served as loading control . HSP27 and phospho-HSP27 levels were quantified by band densitometry analysis with the help of HSP27- and pHSP27-to-actin ratios. Mean HSP27- and pHSP27-to-actin ratios for the myocardial infarction group were set as 1 and relative increases in HSP27 and pHSP27 levels in the control group were compared accordingly. Relative HSP27 and pHSP27 levels between groups based on actin loading are shown.Immunofluorescence staining was performed as previously described . In briep < 0.05.All data are presented as means ± SEM. Statistical analyses were performed with Sigma Plot 10.0. For comparisons between two groups of normal distributed data, the student´s t-test was used. For the comparison of two groups without normal distributed data, a rank-sum test was performed. For multiple comparisons between groups of normal distributed data, the one-way analysis of variance (1-way ANOVA) was used. Differences were considered significant at an error probability level of We observed a significant increase of HSP27 (HSPB1) levels and phosphorylation of HSP27 in platelets during myocardial infarction compared to matched controls with nonischemic chest pain in this study. Supporting previous observations in platelets, a characteristic intracellular translocation of HSP27 from the cytoskeletal into the membrane-associated protein fraction was also observed during myocardial infarction. This platelet phenotype was distinctly different in platelets from patients with myocardial infarction compared to controls. It will be interesting to extend the observed characteristics of the HSP27 phenotype in platelets during myocardial infarction to other acute vascular events such as ischemic stroke or peripheral artery disease.


Recent clinical trials have shown that pulmonary artery pressure-guided therapy via the CardioMEMS™ system reduces the risk of recurrent hospitalizations in chronic heart failure (HF) patients. The CardioMEMS™ pressure sensor is percutaneously implanted in a branch of the pulmonary artery and allows telemetric pressure monitoring via a receiver. According to the most recent ESC guidelines, this technology has currently a class IIb indication in patients with class III New York Heart Association symptoms and a previous hospitalization for congestive heart failure within the last year, regardless of ejection fraction. Aim of this guided-therapy is multifold, including an early prediction of upcoming decompensation, optimization of patients’ therapy and thereby avoidance of hospital admissions. In addition, it can be used during acute decompensation events as a novel tool to direct intra-hospital therapeutic interventions such as inotropes infusion or left ventricular (LV) assist device monitoring, with the aim of achieving an optimal volume status.We present a case series of three end-stage HF patients with reduced ejection fraction (HFrEF) who received a CardioMEMS™ device as an aid in their clinical management. The CardioMEMS™ system enabled a closer non-invasive hemodynamic monitoring of these patients and guided the extent of therapeutic interventions. Patients were free from device- or system-related complications. In addition, no pressure-sensor failure was observed. Two patients received a 24-h infusion of the calcium sensitizer levosimendan. One patient showed a refractory acute decompensation and underwent LV assist device (LVAD) implantation as a bridge to cardiac transplantation. Switching a patient with recurrent hospitalizations to the Angiotensin Receptor Neprilysin Inhibitor  on top of the optimal heart failure-therapy improved its subjective condition and hemodynamics, avoiding further hospitalization.Our case series underlines the potential impact of CardioMEMS™ derived data in the daily clinical management of end-stage HF patients. The new concept to combine CardioMEMS™ in the setting of an outpatient levosimendan program as well as a bridge to LVAD-implantation/heart transplantation looks promising but needs further investigations.The online version of this article (10.1186/s12872-018-0883-4) contains supplementary material, which is available to authorized users. Heart failure (HF) represents a heterogeneous population of patients defined by multiple etiologies and characteristics sharing, however, a common clinical outcome characterized by disabling symptoms and chronic congestion leading to recurrent hospital admissions –3. The l− 5 vs 1167 and 178 dyn sec cm− 5 respectively, before and after the infusion). These changes were accompanied by an increased cardiac output (4.5 vs 3.8 l/min). Pulmonary artery mean pressure at 1 week dropped after levosimendan infusion  and a history of lymphocytic myocarditis. Her comorbidities included stage III chronic kidney disease (CKD), chronic gastritis and Hashimoto thyroiditis. Because of recurring episodes of sustained monomorphic ventricular tachycardia and repeated pre-syncopal events she had received an implantable cardioverter defibrillator in 2009, followed by a cardiac contractility modulation (CCM) – system in 2012. Despite optimal medical treatment , the patient experienced a severe worsening of dyspnea and quality of life, with a progressive left ventricular ejection fraction (LV EF) reduction and LV dilation during the following years. A coronary heart disease and a recurrence of myocarditis had been excluded by coronary angiography and a repeated endomyocardial biopsy, respectively. For this reason, the patient was enrolled in the waiting list for heart-transplantation and, at the beginning of 2017, a CardioMEMS™ was implanted Fig. . In the A 74-year-old male with a history of dilated cardiomyopathy presented to the outpatient clinic with severe dyspnea at rest (NYHA IV). The patient’s comorbidities included arterial hypertension, dyslipidemia, GOLD stage II COPD, stage III CKD, type II-Diabetes, ulcerative colitis and Barrett’s esophagus. His cardiovascular history started in 2008 with recurrent atrial fibrillation episodes and ventricular ectopies of LBBB morphology. He underwent cardioversion and pulmonary vein isolation procedures. A coronary angiography in 2012 revealed a single vessel coronary artery disease, managed conservatively. In 2014 the patient underwent a MitraClip implantation for severe mitral regurgitation. Given the worsening of the patient’s symptoms, recurrent decompensation events, and a severely reduced LV function (LV EF 27%), an implantable cardioverter defibrillator was implanted for primary prevention in June 2015. In February 2016, a baroreceptor simulator was implanted and, given no NYHA class improvement, his medication was implemented with Sacubitril-Valsartan in April 2016. Another decompensation event followed in January 2017 and subsequently a CardioMEMS was implanted. In early 2017, the patient required a diuretic dose adjustment. As shown in Fig. Additional file 1: 4-chamber-views from the echocardiographic examination before levosimendan infusion. (MP4 195 kb)Additional file 2: 4-chamber-views from the echocardiographic examination after levosimendan infusion. (MP4 454 kb)A 53-year-old male presented to our outpatient clinic with severe dyspnea at rest (NYHA IV) and a history of idiopathic dilated cardiomyopathy. His cardiovascular history included the occurrence of paroxysmal atrial fibrillation and ventricular arrhythmias (non-sustained ventricular tachycardia) that were managed with two previous catheter ablations. In 2015, he underwent a coronary angiography as well as left ventricular endomyocardial biopsy sampling that excluded coronary artery disease and myocarditis, respectively. In the same year, a cardioverter defibrillator was implanted (primary prophylaxis of sudden cardiac death). A year ago, he underwent a mitral valve repair with annuloplasty, and percutaneous patent foramen ovale (PFO) closure. Following recurrent hospital admissions with severe decompensation events poorly responded to optimal medical treatment , a CardioMEMS system was implanted in June 2017.During CardioMEMS implantation a LV end-diastolic pressure of 14 mmHg and a cardiac index of 2.4 l/min were measured. A week post hospital discharge, he had another decompensation event (severe dyspnea and 3 kg weight gain), correlated with a sudden rise in PAP (59/45/35 mmHg) leading to a further hospital readmission. During this hospital stay, his systemic pressure profile and volume status improved on Sacubitril-Valsartan 24/26 mg twice daily and intravenous furosemide 30 mg twice daily respectively, while PAP showed slight improvement (46/33/25 mmHg), Fig. . The mid2. As most of the literature focuses on the out-of-hospital management of these patients, we set out to discuss the potential of PA pressure monitoring as a guidance to intra-hospital therapeutic interventions in end-stage HF patients. We hereby present a case series of three end-stage HF patients that received a CardioMEMS™ device to improve their clinical management.Pulmonary artery pressure-guided therapy is a novel strategy to reduce the risk of recurrent hospitalizations in chronic HF patients, being a class IIb indication in patients with class III New York Heart Association symptoms and a previous hospitalization for congestive HF within the previous yearIn line with the results from the CHAMPION trial , the repTwo out of three patients were admitted to the hospital for a 24-h infusion of levosimendan. A recently discovered novel inotrope, levosimendan, is a calcium-sensitizer shown to combine inotropic, vasodilatory and cardioprotective effects without affecting body oxygen requirements –28. ThisIn the third clinical case, we present for the first-time the telemetric data on the positive impact of the ARNI, sacubitril-valsartan, on our patient’s hemodynamics. The PARADIGM-HF trial , 38 compFinally, one of the patients with refractory acute decompensation despite optimal medical therapy underwent LVAD system implantation as a bridge to cardiac transplantation. LVAD patients carry a high readmission rate after implantation, as a result of incomplete LV compensation or pre-existent right ventricular failure. The potential benefit of CardioMEMS™ in managing volume-status and pump performance in such patients still needs to be investigated. Although CardioMEMS™ was helpful in identifying early critical re-decompensation periods of the described HF end-stage patient, already screened for either LVAD or transplantation listing, it was not anymore possible in this clinical scenario to prevent further re-hospitalization or to postpone the need for LVAD. With respect to the costs, it has to be discussed individually whether under these circumstances CardioMEMS™ should be recommended.Our cases support the universally accepted idea that additional strategies are needed to improve clinical management of end-stage HF patients. CardioMEMS™ was shown to be a safe and effective solution. However, all research to date has been performed within the US healthcare system. Basic differences in HF disease management strategies between countries within Europe as well as between US and Europe might influence the clinical results of haemodynamically guided HF treatment. The ability of HF care facilities in a given health system to provide basic telemonitoring requirements  are essential for the successful management of patients, and might therefore also influence the clinical performance characteristics of the CardioMEMS™ system.In conclusions, CardioMEMS™ represents a significant technology for reducing the burden of HF in real life scenarios, holding the potential for addressing the urgent need for appropriate HF-management strategies in Germany, as well as in whole Europe . However