GCW  was the only feature independently associated with CTRCD−BP+. Myocardial work is superior to GLS in the serial assessments in patients receiving cardiotoxic chemotherapy. The impairment of GLS in the presence of an increase in GWI and GCW indicates the impact of elevated afterload on LV performance in the absence of actual myocardial impairment.The load dependence of global longitudinal strain (GLS) means that changes in systolic blood pressure (BP) between visits may confound the diagnosis of cancer-treatment-related cardiac dysfunction (CTRCD). We sought to determine whether the estimation of myocardial work, which incorporates SBP, could overcome this limitation. In this case–control study, 44 asymptomatic patients at risk of CTRCD underwent echocardiography at baseline and after oncologic treatment. CTRCD was defined on the basis of the change in the ejection fraction. Those with CTRCD were divided into subsets with and without a follow-up SBP increment >20 mmHg (CTRCD+BP+ and CTRCD+BP−), and matched with patients without CTRCD (CTRCD−BP+ and CTRCD−BP−). The work index (GWI), constructive work (GCW), wasted work (GWW), and work efficiency (GWE) were assessed in addition to the GLS. The largest increases in the GWI and GCW at follow-up were found in CTRCD−BP+ patients. The CTRCD+BP− patients demonstrated significantly larger decreases in GWI and GCW than their CTRCD+BP+ and CTRCD−BP− peers. ROC analysis for the discrimination of LV functional changes in response to increased afterload in the absence of cardiotoxicity revealed higher AUCs for GCW (AUC = 0.97) and GWI (AUC = 0.93) than GLS (AUC = 0.73), GWW (AUC = 0.51), or GWE (AUC = 0.63, all  Cancer-related mortality has declined substantially over recent decades . HoweverCurrent guidelines primarily recommend the left ventricular ejection fraction (LVEF) to monitor LV systolic function and to identify cardiotoxicity ,6. ObserStudy subjects. The population of this case–control study was derived from participants in the prospective randomized SUCCOUR trial, which assessed the usefulness of GLS in the guidance of cardioprotective treatment in at-risk patients undergoing potentially cardiotoxic chemotherapy [2 of doxorubicin . The third was an increased risk of heart failure . We excluded patients with heart failure or LV dysfunction at baseline (EF < 50%), valvular stenosis or regurgitation of more than moderate severity, a history of previous heart failure (baseline NYHA > 2), systolic BP < 110 mmHg, a heart rate <60/min, an inability to acquire interpretable echocardiographic images, contraindications for/intolerance to beta-blockers or ACE inhibitors, existing therapy with both beta-blockers and ACE inhibitors, and an oncologic (or other) life expectancy < 12 months.otherapy . We incli.CTRCD+BP−: cardiotoxicity and no increase in afterload  at a follow-up examination;ii.CTRCD+BP+: cardiotoxicity with a concomitant increase in afterload at a follow-up examination;iii.CTRCD−BP+: no cardiotoxicity in the presence of an increase in afterload at a follow-up examination;iv.CTRCD−BP−: no cardiotoxicity and no increase in afterload at a follow-up examination.Echocardiographic assessment was performed at baseline and repeated on a 3-monthly basis during the first year after recruitment. CTRCD was defined by a 10% asymptomatic fall of LVEF to <55% . To test“Follow-up examination” denotes echocardiography at the time of cardiotoxicity recognition and/or SBP elevation during examination (groups i–iii), or at the routine follow-up echocardiographic study in group iv.Based on 11 individuals eligible for the CTRCD+BP+ group, we used individual matching based on sex and age (±6 years), forming 11 compatible quadruplets.The SUCCOUR trial was designed in accordance with the Declaration of Helsinki, and was approved by the institutional review boards of the participating institutions. The patients were informed of the purpose of the study and provided written informed consent. This work represents an unplanned substudy of the trial, using site measurements of GLS and EF, independent of randomization to strain-guided or usual care.Echocardiography. Echocardiographic imaging was carried out using Vivid E9 and Vivid E95 equipment  with phased-array 2.5 MHz multifrequency transducers. Multiple consecutive cardiac cycles of standard echocardiographic views were acquired and stored digitally for subsequent analysis. Each baseline and follow-up assessment of LV function was performed by a single expert observer who was blinded to the study data.Conventional and tissue Doppler imaging. The measurements of cardiac dimensions and wall thicknesses were performed according to the recommendations of the American Society of Echocardiography [iography . The LV iography . The mitSpeckle tracking imaging. Longitudinal myocardial deformation was assessed using semi-automated 2D speckle tracking  in the three apical views with typical temporal resolutions of 50–70 frames/s. The timing of the aortic and mitral valve opening and closure was obtained using pulsed-wave Doppler traces. After the manual tracing of the endocardial border and selecting the appropriate wall thickness, the software automatically identified 6 segments in each view and tracked the motion of acoustic markers. Segments with inadequate tracking were readjusted manually, and, if this was unsuccessful, they were excluded from further analysis. After measuring the greatest negative value on the strain curve, GLS was calculated as the average from all the LV segments interrogated. All the echocardiographic parameters were averaged over 3 consecutive cardiac cycles.Myocardial work evaluation. Myocardial work was assessed by the combination of LV strain data and a non-invasively estimated LV pressure curve, as previously described [escribed . Based oBlood pressure was measured in the supine position immediately before the echocardiographic study after a 5 min rest using an appropriately sized cuff according to the arm circumference.Statistical analysis. Data are presented as means ± SDs Between-group comparisons were performed using analysis of variance (ANOVA), with the Scheffe post hoc test for continuous variables and the chi-square test for categorical variables. The homogeneity of the variances was evaluated using the Levene test. Logistic regression analysis was used to assess the associations of the GLS and MW indices with the LV response to increased afterload. A receiver operator characteristic (ROC) analysis was used to examine the ability of the GLS and MW indices to identify the LV response to increased afterload. Differences in the area under the ROC curves (AUCs) were analyzed using the z-test. Changes in particular parameters during follow-up were calculated by subtracting the baseline value from the follow-up value and were expressed in the units of their measurements. All the analyses were performed with standard statistical software . The level of statistical significance was set at a two-sided p-value < 0.05.Participant characteristics. The oncologic diagnosis was breast cancer in 40 and hematologic malignancies in four patients. The chemotherapy included two different drug regimens—one based exclusively on anthracyclines, and the other, on a combination of anthracyclines and trastuzumab.CTRCD was detected in seven patients at 3-month follow-up, in eight at 6 months, in five at 9 months, and in two at 12 months. The demographic, clinical, and echocardiographic characteristics of the subsets separated according to the development of cardiotoxicity and increase in blood pressure at follow-up are presented in Changes in metrics of LV function at follow-up. A significantly greater decrease in GLS at follow-up was noted in the CTRCD+BP+ group as compared to the subsets without cardiotoxicity. Larger increases in the GWI and GCW were found in CTRCD−BP+ than in the other three groups. Patients from the CTRCD+BP− group demonstrated significantly larger decreases in the GWI and GCW than their peers from the CTRCD+BP+ and CTRCD−BP− groups. The other parameters of myocardial work—the GWW and GWE—did not differ among the subsets. By definition, the decrease in the LV ejection fraction at follow-up was significantly greater in both groups with cardiotoxicity  than changes in the GLS, GWW, and GWE .Reproducibility. The intraobserver variability of measurements assessed in 15 randomly selected examinations and expressed as coefficients of variation was 5.2% for GLS, 5.3% for the GWI, 3.3% for GCW, 15.8% for GWW, and 1.7% for GWE.This study shows that the measurement of the MW might be helpful in the assessment of cardiotoxicity, especially when there is a BP change >20 mmHg. An increase in the GCW and GWI, even with decreased GLS, indicates the impact of elevated afterload on LV performance in the absence of actual myocardial impairment. From a practical point of view, the evaluation of MW may be a useful adjunct to GLS in patients with significant BP fluctuations during follow-up.The strategy of the early detection of cardiotoxicity consists of serial echocardiographic imaging to identify LV dysfunction. The adopted definition of cardiotoxicity requires a 5% symptomatic or 10% asymptomatic reduction of EF to <55% . HoweverA growing body of research supports the incremental value of GLS over EF for monitoring the safety of chemotherapy . In partIn this study, we demonstrated a difference in the ability of MW and GLS in the recognition of blood-pressure-elevation-induced LV systolic function decline in the absence of the current definition of cardiotoxicity. This clinical scenario is recognized as a substantial increase in GCW and GWI, which is uncommon for cardiotoxicity. The lower decrease in the GWI and GCW in the CTRCD+BP+ patients as compared to the CTRCD+BP− subset may indicate some degree of LV contractility reserve in response to the elevation of LV afterload. Conceivably, a pattern of more profoundly decreased myocardial deformation and less-impaired GWI and GCW might be a marker of this group.Limitations. Several study limitations should be acknowledged. The numbers of patients in each subcategory were small, and the case–control design might have provided a selection bias. Anthracyclines and trastuzumab—the two major cardiotoxic drugs used in this study—are characterized by different myocardial pathophysiology. However, the combined use of these medications in the majority of patients and sample-size limitations precluded the possibility of testing the utility of MW for each individual drug. We did not use biomarkers in this analysis; however, their usefulness for the detection of subclinical myocardial dysfunction  is still controversial. Although a brachial cuff pressure was used to estimate the LV pressure in the calculation of the MW, which may not precisely reflect the hemodynamic profile during LV ejection, this method has been used in previous studies [ studies ,30. FinaClinical implications. Our results have potential clinical implications for the cardioprotective management of patients undergoing oncologic treatment. The distinction between true cardiotoxicity secondary to chemotherapy and alterations in LV function resulting from afterload variations may be of prognostic significance. By providing a measure of myocardial performance independent of LV afterload, MW may be an important advance in the diagnostic workup in patients receiving anticancer treatment. The increasing role of GLS in the cardiac monitoring of chemotherapy might be complemented by the use of MW in some situations.


Background: Two-dimensional volumetric exercise stress echocardiography (ESE) provides an integrated view of left ventricular (LV) preload reserve through end-diastolic volume (EDV) and LV contractile reserve (LVCR) through end-systolic volume (ESV) changes. Purpose: To assess the dependence of cardiac reserve upon LVCR, EDV, and heart rate (HR) during ESE. Methods: We prospectively performed semi-supine bicycle or treadmill ESE in 1344 patients  referred for known or suspected coronary artery disease. All patients had negative ESE by wall motion criteria. EDV and ESV were measured by biplane Simpson rule with 2-dimensional echocardiography. Cardiac index reserve was identified by peak-rest value. LVCR was the stress-rest ratio of force . Preload reserve was defined by an increase in EDV. Cardiac index was calculated as stroke volume index * HR (by EKG). HR reserve (stress/rest ratio) <1.85 identified chronotropic incompetence. Results: Of the 1344 patients, 448 were in the lowest tertile of cardiac index reserve with stress. Of them, 303 (67.6%) achieved HR reserve <1.85; 252 (56.3%) had an abnormal LVCR and 341 (76.1%) a reduction of preload reserve, with 446 patients (99.6%) showing ≥1 abnormality. At binary logistic regression analysis, reduced preload reserve , chronotropic incompetence , and abnormal LVCR  were independently associated with lowest tertile of cardiac index reserve at peak stress. Conclusions: Heart rate assessment and volumetric echocardiography during ESE identify the heterogeneity of hemodynamic phenotypes of impaired chronotropic, preload or LVCR underlying a reduced cardiac reserve.  The goal of the heart during exercise is to increase cardiac output (CO) to metabolizing tissues . Cardiacn = 1241) or near normal  resting LV EF [In this prospective study, we evaluated 1344 patients  63 ± 8%, mean ± SD) recruited from 1 September 2016 to 1 September 2018 by 21 laboratories in eight countries  [n = 1217, 90.6%) or a motorized treadmill using the Bruce protocol . Exercise testing procedures outlined by the American Heart Association were followed for all assessments [All exercise tests were performed on a semi-supine bicycle ergometer  or post-treadmill exercise, according to the recommended protocols . ElectroLeft ventricular (LV) EDV and ESV were measured from apical four- and two-chamber views, using the biplane Simpson method. When the biplane apical views were not available, a single plane 4-chamber view area-length method was used . Only reHeart rate reserve (HRR) was calculated as the peak/rest HR ratio from 12-lead EKG [LV volumes were evaluated by the biplane Simpson and area-length methods. The SV (mL) was calculated as EDV-ESV . The CO Results of each test were entered in the digital data registry at the time of testing by each recruiting center and sent monthly to the coordinating center with the electronic case report form including clinical data. After checking for internal consistency by trained technical staff, and double-checking with the center for data verification on possibly inconsistent input, the data were added to the data registry.p < 0.1 level in these initial models, were simultaneously entered in a summary binary logistic regression model. Statistical significance was set at p < 0.05. Statistical Package for the Social Sciences ver. 22.0  was adopted for analysis.Statistical analyses included descriptive statistics . The Pearson chi-square test with Fisher’s exact test for categorical variables and the Mann-Whitney test for continuous variables for intergroup comparisons were performed to confirm significance. Based on CI reserve from rest to peak exercise stress, study patients were assigned into low, medium and high tertiles. One-way analysis of variance was used to analyze differences between hemodynamic parameters at each stage of exercise between three groups. When homogeneity of variance was not present, the Kruskal-Wallis test for nonparametric independent samples was used. An intergroup comparison was performed with Scheffé and Tamhane post hoc tests, respectively. Multivariable factors associated with reduced (lowest tertile) CI reserve during ESE, expressed as a binary variable, were investigated using a Binary Logistic regression model. The initial set of clinical covariates selected included age, sex, diabetes, hypertension, resting EF and wall motion score index. The stress covariates included: chronotropic incompetence, abnormal contractile reserve, reduced preload reserve as categorical variables and peak LV EF, as continuous variable. All variables were included in the model without any transformation. The significant variables at the Patients in the middle and highest tertiles were younger, more often male, with less diabetes, hypertension, history of dyspnea and previous myocardial infarction, and lower prevalence of beta-blocker therapy . Highest tertiles compared with the lowest tertile had higher SV index reserve, higher peak HR, and greater increase of EDV index at peak stress .Patients in the middle and highest tertile of CI reserve (Group 1) showed one or more of the following abnormalities: altered HRR in 327 patients (36.5%); altered preload reserve (with peak EDV index < resting EDV index) in 467 patients (52.1%); altered LVCR in 455 patients (50.8%) ; 451 patp < 0.001 vs. Group 1); altered preload reserve in 341 patients  with peak EDV index < resting EDV index; altered LVCR in 252 patients  (p < 0.001 vs. Group 1). In the overall group of 1344 study patients 559 patients (41.6%) showed one abnormality, 557 (41.4%) two abnormalities, 157 (11.7%) three abnormalities, and 71 none (5.3%). Patients in the lowest tertile of CI reserve (Group 2) showed one or more of the following abnormalities: altered HRR in 303 patients  ; 108 patThe integration of HRR, preload reserve and LVCR allowed to identify different groups clustered on the basis of the hemodynamic pattern for CI reserve  and for We identified four main subgroups: normal heart ; abnormal heart (with impaired chronotropic preload and contractile reserve); a group with two abnormalities and a group with 1 abnormality. At binary logistic regression analysis, independent variables associated with the lowest tertile of CI reserve at peak stress were the following: the reduced preload reserve with an odds ratio of 5.6; chronotropic incompetence with an odds ratio of 3.9; and reduced LVCR with an odds ratio of 1.6 .A multi-parametric approach instead of a single parameter approach can be used to exploit at the fullest the unique versatility of ESE. Patients with a normal cardiac reserve show a preserved chronotropic, preload and contractile reserve, but patients with abnormal cardiac reserve have heterogeneous alterations in chronotropic, preload or contractile reserve . This inPrevious studies have shown the possibility and usefulness of extracting information on chronotropic incompetence, preload reserve and contractile reserve from EKG and 2-dimensional echocardiography to characterize the hemodynamic response of the heart under stress. HRR is an imaging-independent parameter that helps to identify a subset with reduced sympathetic reserve and worse outcome, as shown in the pre-stress imaging era by Ellestadt et al.  and LaueThese three mechanisms have been described in the past, assessed with varying techniques and in different populations. The novelty of our approach is that they can now converge conceptually, logistically, and methodologically in the 2-dimensional volumetric ESE combined by simple EKG and exploiting information already present in the SE minimum image and data set. This allows to partially overcome the well-known limitations of EF, which has gained widespread acceptance due to its ease of application and wealth of clinical data supporting its use, yet is highly dependent on loading conditions and gives no information on the hemodynamic mechanisms underlying the development of heart failure and a reduced cardiac reserve. The proposed approach uses clinically available information  for identification of different phenotypes of exercise response which can be theoretically be targeted by SE-driven tailored therapeutic intervention.The current recommended protocol of ESE includes evaluation of HR and EF, derived from EDV and ESV. These same data can be used for a more comprehensive reconstruction of the cardiovascular adaptation to exercise including HRR, LVCR and preload reserve. Due to missing evidence, this information finds no place in current recommendations for diastolic stress echo, which are based only on estimation of E/e’ and systolic pulmonary artery pressure through tricuspid regurgitant jet velocity . Yet, thThis hemodynamic characterization during stress might pave the way to personalized treatment of heart failure by a novel phenotype-driven therapy. Insufficient cardio-acceleration because of reduced HRR could be a therapeutic target with rate-adaptive pacing  or beta-We measured left ventricular volumes with 2-dimensional echocardiography, which is highly feasible and accurate, especially when rest-stress variations are assessed in the same patient ,11,13. IVolumetric ESE can be used to identify and quantify preload and contractile reserve during exercise, while the simultaneous EKG assesses the chronotropic reserve. An impairment of cardiac reserve is associated with impairment of one or more of these three contractile, preload and chronotropic reserves. The detection of the heterogeneity of hemodynamic phenotypes underlying the final common pathway of a reduced cardiac reserve is the prerequisite for a targeted and personalized treatment with a phenotype-guided approach .


Background: Reverse remodeling is a clinically relevant endpoint in heart failure with reduced ejection fraction (HFrEF). Rho-kinase (ROCK) signaling cascade activation correlates with cardiac remodeling and left ventricular (LV) systolic dysfunction in HFrEF patients. Cardiac resynchronization therapy (CRT) is effective in HFrEF, especially when there is a left bundle block, as this treatment may stimulate reverse remodeling, thereby improving quality of life and prolonging survival for patients with this severe condition. Here, we evaluate the hypothesis that ROCK activation is reduced after effective CRT in HFrEF.Methods: ROCK activation in circulating leukocytes was evaluated in 28 HFrHF patients, using Western blot , before and three months after initiation of CRT. LV systolic function and remodeling were assessed by echocardiography.Results: Three months after CRT, LV ejection fraction increased an average of 14.5% (p < 0.001) in 13 patients (responders), while no change was observed in 15 patients (non-responders). End-systolic diameter decreased 16% (p < 0.001) in responders, with no change in non-responders. ROCK activation in PBMCs decreased 66% in responders (p < 0.05) but increased 10% in non-responders (NS). LV end-diastolic diameter was also 5.2 mm larger in non-responders vs. responders (p = 0.058). LV ejection fraction, systolic diameter, and ROCK activation levels were similar in both groups at baseline.Conclusion: In HFrEF patients, 3 months of effective CRT induced reverse myocardial remodeling, and ROCK activation was significantly decreased in circulating leukocytes. Thus, decreased ROCK activation in circulating leukocytes may reflect reverse cardiac remodeling in patients with heart failure. In patients with heart failure and low or reduced ejection fraction, reverse myocardial remodeling or reverse remodeling is generally described as increased left ventricular ejection fraction (LVEF) and reduced LV diameter or volume . ReverseLV reverse remodeling correlates with long-term prognosis in patients hospitalized with decompensated HFrEF and LVEF <40% at hospital discharge . After 42 predicted LVEF normalization after CRT implantation , left bundle branch block and non-ischemic etiology of cardiomyopathy were significant predictors of super-responders to CRT  . Baselinantation .While LV reverse remodeling is critically important in HF management, the factors that predict reverse remodeling, as well as the underlying molecular processes, remain to be elucidated .In HFrEF, activation of the renin-angiotensin aldosterone and sympathetic systems significantly contributes to pathological cardiac remodeling and disease worsening . Both noExperimental HErEF models have been used to explore the role of ROCK as a molecular mechanism regulating cardiac function and reverse remodeling. In the preclinical model of congestive heart failure in the Dahl hypertensive rat, the specific ROCK inhibitor Y-27632, administered from the left ventricular hypertrophic phase to the overt heart failure phase, myocardial contractility was reduced by 47% and it was significantly ameliorated by Y-27632 . MoreoveIn cardiac failure patients with low or reduced ejection fraction (HFrEF), ROCK activation in peripheral blood mononuclear cells (PBMCs) is markedly elevated  and inveThe present study assesses the role of ROCK activation in reverse cardiac remodeling in human HFrEF by comparing ROCK activation levels in PBMCs from patients with and without reverse remodeling 3 months after cardiac resynchronization therapy.This prospective clinical study included 28 consecutive patients with chronic HFrEF and left bundle branch block referred for CRT by their cardiologists. Patients were also evaluated by a cardiologist specializing in heart failure prior to study enrollment.This clinical study complied with the principles of the Helsinki Declaration and was authorized by the Human Research Ethics Committee (Pontificia Universidad Católica de Chile School of Medicine). All participants signed an informed consent form prior to any study procedures.Twenty-eight sequential HFrEF patients with an ejection fraction ≤35% were evaluated. All patients were receiving optimal pharmacological treatment according to the 2012 American College of Cardiology, American Heart Association, and Heart Rhythm Society CRT guidelines. The group included patients with asymptomatic and mildly symptomatic HF . All patExclusion criteria were myocardial infarction within the previous 6 months, clinical indication for coronary artery revascularization, cancer in the last 4 years, active infection within the previous 8 weeks, use of high-dose statins, and other major chronic illness such as renal, respiratory, or hepatic failure.CRT implantations were performed by electrophysiologists using conventional devices, cardiac electrodes, and procedures. One electrode was positioned in the right ventricle and the other in the coronary sinus. No study patients experienced clinical complications during or after the procedure.Venous blood samples were obtained before and 3 months after CRT for standard clinical laboratory measurements and to obtain PBMC samples to determine ROCK activation as previously reported . Twelve-Additionally, in order to assess functional capacity immediately before and 3 months after initiation of CRT, a 6 min walk test was performed in a flat 27-m corridor. Heart rate and oxygen saturation were measured with a pulse oximeter. The Borg Breathlessness Scale was used to assess patient-reported dyspnea during physical activity.Echocardiographic measurements were performed using a Philips iE33 instrument with a 2.5-MHz transducer  to evaluate cardiac size and LV ejection fraction at the time of blood sampling, immediately before and 3 months after the CRT procedure, as previously described . Blind ePBMCs were isolated from five volumes of blood with ethylenediaminetetraacetic acid and poured over 5 volumes of density gradient cell separation medium, as previously described . LeukocyFractions of soluble protein were heated (95°C) for 5 min with sodium dodecyl sulfate (SDS) polyacrylamide, as previously reported . Identicp-MYPT1  were incubated overnight , and anti-vernight . Afterwa4 PBMC cells were collected and washed with phosphate buffered saline (PBS). The cells were then fixed with 4% paraformaldehyde within a 1 cm2 area and air-dried for 24 h. Cells were washed twice (PBS). Cells were incubated with permeabilization solution for 15 min, the solution removed, and TUNEL analysis performed using the In Situ Cell Death Detection Kit, POD . Only cells showing TUNEL-positive nuclei plus chromatin margination were considered apoptotic. 400 consecutive cells  were analyzed (40x). We compared the number of total nuclei and apoptotic nuclei to calculate the percentage of apoptotic cells . A Student paired t-test was used to compare changes within each group 3 months after CRT when data were normally distributed . A p-value ≤ 0.05 was considered statistically significant.According to our previous measurements of ROCK activation in circulating leukocytes measured as MYPT1 phosphorylation  in HFrEF patients, the sample size was calculated assuming a reduction of MYPT1-p/t in circulating leukocytes by one standard deviation after effective reverse remodeling 3 months after RCT . Results are shown here as mean ± SD. In order for testing for normality we used both the Kolmogorov-Smirnov as well as the Shapiro-Wilk tests. Baseline differences between responders and non-responders were analyzed using a 2, heart rate 68.6 bpm, disease duration according to symptoms 40.6 months). Of the total sample, 67.9% were male, 53.6% were in NYHA functional class II HF, and all had a left bundle branch block.This study included 28 HFrEF patients , 14 (50%), 22 (78.6%), 23 (82.1%), 16 (57.1%), 13 (46.4%), and 26 (93%) patients were treated with ACE-Is, ARB, beta-lockers, diuretics, statins, aspirin, and spironolactone, respectively.All patients underwent CRT device placement without clinical complications. Three months after CRT, LV ejection fraction improved in 13 patients (responders), with no change in LVEF in 15 (non-responders). Baseline clinical characteristics, laboratory tests, exercise capacity, and LV systolic function and dimensions were comparable in the two groups , 2.Three months after CRT, both groups showed a similar and significant narrowing of the QRS and a significant increase in functional capacity as assessed by distance walked during the 6 min walk test. Perceived dyspnea during exercise was also significantly reduced in both groups as measured by the Borg scale at 6 min. Baseline heart rate was reduced in responders but not in non-responders .p < 0.001, p < 0.05, Three months after device implantation, end-diastolic LV diameter, end-systolic LV diameter, and left atrial diameter were significantly smaller in CRT responders, with reductions of 8, 16, and 7.8% respectively  . ROCK activation decreased significantly, by 3.3-fold, in responders HFrEF patients  .The main finding of this proof-of-concept clinical study is that in HErEF patients, reverse cardiac remodeling 3 months after CRT is associated with a significant reduction in ROCK activation levels in PBMCs. This finding is consistent with the involvement of ROCK in myocardial remodeling in HFrEF. While small, this is the first clinical study to prospectively address the role of ROCK activation in reverse remodeling in human HFrEF. In a previous study, the ROCK inhibitor fasudil was administered for two weeks to patients with HF with preserved ejection fraction (HFpEF) and passive pulmonary hypertension. That study showed that fasudil improved pulmonary and left ventricular hemodynamics, suggesting that ROCK inhibition may be a promising target for HFpEF patients with a pulmonary hypertension phenotype .In the present study, HFrEF patients with effective CRT 3 months after device implantation (responders) showed reverse remodeling and reduced ROCK activation levels as well as significantly increased LVEF and reduced LV systolic, diastolic, and left atrial diameter. In contrast, the patients who did not show reverse remodeling 3 months after initiation of CRT (non-responders) also showed no change in ROCK activation levels. Interestingly, both groups (responders and non-responders) showed significant narrowing of the QRS complex , significantly increased distance on the 6 min walk test , and significantly reduced TUNEL staining as a measure of apoptosis in PBMCs .In stable HFrEF patients receiving optimal treatment, we have previously observed that ROCK pathway activation in PMBCs is related to adverse cardiac remodeling , elevateCRT enhances sarcomere contraction in cells by increasing calcium levels, enhancing cardiac contractility and systolic performance. Beta-adrenergic responses are increased after CRT by upregulation of the beta receptors on the myocardial cell surface. The above is important as cardiomyocytes in the failing heart generally have a reduced adrenergic response (downregulation) . In a prIn HFrEF patients with a wide QRS complex receiving resynchronization therapy, reverse remodeling is a rather consistent result . A recenReverse myocardial remodeling can be assessed in humans using magnetic resonance imaging, which can characterize the tissue and simultaneously assess the extent of scarring and dyssynchrony . In a clThere are no studies in heart failure patients assessing ROCK activation levels and reverse remodeling. However, in 178 patients with congestive heart failure (mean LVEF 47.5%) followed for 2 years, the combination of ROCK activity in PBMCs and N-terminal pro–B-type natriuretic peptide (NT-proBNP) at baseline provided additional value in assessing long-term survival as compared to levels of this natriuretic peptide alone , suggestROCK activation induces apoptosis in several tissues and cells , and carWe used PBMCs to assess the ROCK cardiac remodeling pathway in HFrEF patients for several reasons. First, PBMCs play a crucial role in the interface between the neuroendocrine and immune systems in response to stress. Second, these circulating cells share gene expression profiles with several tissues . FurtherAs CRT becomes more common, even among patients with wide QRS complexes, nearly 30% of patients do not achieve the desired clinical benefits . We cannThis clinical study has some limitations. The number of HFrEF patients is relatively small. However, the ROCK activation levels were significantly modified in patients with reverse remodeling but not in those without reverse remodeling was consistent within each group. Second, three months is a relatively short time to evaluate reverse remodeling after CRT in HFrEF patients. Nevertheless, the aim was to determine changes in ROCK activation levels before and after CRT in patients with and without reverse remodeling at the same timepoint. Our findings do not preclude the possibility that some non-responders could evolve to reverse remodeling at a later time.Effective CRT in HFrEF patients with reverse cardiac remodeling significantly decreases ROCK activity in PMBCs. Since ROCK activation has been shown to be a marker of cardiac remodeling and possibly a therapeutic target in these patients, reduced ROCK activation in PMBCs could be a marker of reverse cardiac remodeling. Further research is necessary to better assess this possibility.


Evaluation of certain biomarkers could be used to predict left ventricular (LV) and right ventricular (RV) function impairment in children with type 1 diabetes mellitus. The aim of this study was to determine the best cardiac biomarker for prediction of diabetic cardiomyopathy.This study was designed as case-control study. A total of 55 children with type 1 diabetes mellitus (group/G1) and 55 healthy controls (G2) were subjected to echocardiography including 3D-Speckle Tracking Echocardiography and tissue Doppler imaging for assessment of RV and LV systolic and diastolic functions. As well as HbA1c, troponin I, brain natriuretic peptide (BNP), plasma cardiotrophin (CT-1), activin-A, transforming growth factor-β, and human insulin-like growth factor binding protein-7 (IGFBP-7) measurements.Diabetic patients showed RV and LV systo-diastolic dysfunction compared to controls, the best predictor of LV systolic dysfunction was CT-1 . BNP was found to the best predictor of diastolic RV and LV dysfunction (sensitivity: 82% for both).CT-1 has proven to be a diagnostic superiority in LV systolic dysfunction whilst BNP continues to prove every day through our study and through many others that it is the chief marker of diastolic dysfunction and HFpEF. This potential accuracy and the increasing availability of BNP in the outpatient setting make it clear that it should be used as a screening test for diabetic patients. Diabetes mellitus is an established risk factor for cardiovascular events and the development of heart failure. Various independent investigators have shown that in diabetic patients there is extensive impairment in left ventricular (LV) functions before the clinical signs of congestive heart failure become manifest. Diastolic dysfunction has been defined as the earliest sign of diabetic myocardial disease to occur before systolic impairment. This isolated diastolic impairment has been alternatively termed heart failure with preserved ejection fraction (HFpEF) ,2.Although echocardiography is the most useful non-invasive diagnostic method for evaluating systolic and diastolic dysfunction, the prognostic value of echocardiography is much less superior than its diagnostic potency. Heart failure results from a complex interplay between genetic, neurohormonal, inflammatory, and biochemical changes acting on cardiac myocytes. The aforementioned facts point at the possible role of biomarkers in the earliest detection and follow-up of changes occurring at the cellular level even in the absence of any alteration in echocardiographic indices .At the practice level, some biomarkers have established role in daily life; notably, cardiac troponins are the chief markers of myocardial infarction (MI). Brain natriuretic peptide (BNP) has proven a diagnostic accuracy for chronic left ventricular (LV) dysfunction rather than acute. It takes longer time to rise in the context of acute MI and lasts longer than cardiac troponins. Therefore, its use as marker of acute myocardial ischemia would be a part of multimarker strategy incorporating its role together with cardiac troponins .Also, BNP has proven a greater superiority in detection of diastolic dysfunction earlier than systolic dysfunction, which raises the need for other markers of systolic function that can add to the diagnostic accuracy of cardiac biomarkers in the context of prediction of heart failure .The aim of this work is to test several new biomarkers such as BNP, plasma cardiotrophin (CT-1), human activin A (ACV-A), human transforming growth factors β1 (TGF-β1), human insulin-like growth factor binding protein-7 (IGFBP-7) in the early detection of systolic and diastolic dysfunction in the context of diabetes mellitus.This case-control cross-sectional observational study was conducted from September 2018 to September 2019. A total of 60 patients with chronic kidney disease were enrolled from Nephrology unit at Cairo University Children Hospital. Exclusion criteria included arrhythmia, congenital or acquired heart disease as well as obesity that may impair image acquisition, or any known comorbidities from diabetes.We also enrolled 60 age- and sex-matched healthy controls (group 2).Written and informed consent was obtained from all the study participants. The study was approved by the local ethics committee of Cairo University.Patients were subjected to a full clinical history including data from age, sex, onset of diabetes, diabetes duration, daily insulin requirements, and blood and urine readings. Physical examination by endocrinologist included a blood pressure (BP) assessment Anthropometric data were collected including weight, height, and body surface area. Glycated hemoglobin (HbA1C), high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides were retrieved from the patients’ files over the last year  and were averaged to ensure reflecting the continuous monitoring of glycemic and lipidemic control of the patients.Echocardiography: According to the guidelines of the American Society of echocardiography [iography ,7.For diastolic function: Conventional Doppler and tissue Doppler (TDI) have been used to determine the LV E/E′ ratio: the ratio of early mitral inflow velocity to average early diastolic velocities of the basal septum and mitral annulus.For the LV: Full-volume acquisition of the LV will be obtained by harmonic imaging from the apical approach. All datasets were analyzed offline using commercially available software . The software automatically will identify the LV cavity endocardial border in 3D. The operator will perform all the necessary adjustments manually in order to correctly place the endocardial border. After the adjustments, software will provide the LV global longitudinal strain (GLS).For the right ventricle (RV): 3DE RV datasets were digitally analyzed offline using the commercial software TomTec RV Function 2.0  to generate RV GLS.Blood was collected into EDTA tubes and processed immediately and the following biomarkers were tested by ELISA as follows:(1) BNP concentrations were determined by the ELISA Kit  with an assay range of 6–400 pg/mL .(2) CT-1 by the ELISA Kit  with an assay range of 0.5–200 ng/L .(3) Human activin A (ACV-A) by the ELISA Kit  with an assay range of 8–350 pg/mL .(4) TGF-β1 by the ELISA Kit  with an assay range of 3.3–200 pg/mL .(5) IGFBP-7 by the ELISA Kit  with an assay range of 0.08–20 ng/mL .r). For construction of interactive dot diagrams, RV and LV diastolic dysfunction were defined as a respective E/E′ratio >12 while RV and LV systolic dysfunction were defined as a respective GLS <18 according to guidelines, to assess the diagnostic accuracy of relevant biomarkers in detection of myocardial dysfunction [Data were analyzed using two-way analysis of variance followed by Dunnett’s test for post hoc multiple comparison. Results were expressed as mean, SDs, percentages, and correlation coefficient  diabetic group (cases group) included 55 child with type 1 diabetes mellitus. They were 26 males (47.3%) and 29 females (52.7%). Their ages ranged between 6 and 12 years with a mean 9.6 ± 2.2. Non-diabetic group (control group) included 55 normal children. They were 28 males (50.9%) and 27 females (49.0%). Their ages ranged between 6 and 12 years with a mean 8.7 ± 1.7.There is no statistical difference between the two groups regarding weight, height, BSA and BMI. HbA1c is statistically higher among diabetic group (Table Regarding echocardiographic measures of LV function: LV E′/A′ is significantly lower among cases compared to control group. LV E/E′ is significantly higher among cases compared to control group. LV Tei index is significantly higher among cases compared to control group. 3D LV GLS (%) is significantly lower among cases compared to control group. There is no statistically significant difference between the two groups regarding the 3D LV EF Table .On the other hand, echocardiographic measures of RV function: RV E′/A′ is significantly lower among cases compared to control group. RV E/E′ is significantly higher among cases compared to control group. RV Tei index is significantly higher among cases compared to control group. 3D RV GLS (%) is significantly lower among cases compared to control group Table .Comparing serum biomarkers between the two groups, BNP, CT-1, TGF-β, and IGFBP-7 are statistically higher among diabetic group. There is no statistically significant difference regarding ACV-A between the two groups Table .The relevant biomarkers which achieved statistically significant difference between cases and controls, namely BNP, CT-1, TGF- β, and IGFBP-7 were compared using NRI, IDI, and AUC Table  for eachInteractive dot diagrams have been designed to illustrate the diagnostic accuracy of each of the relevant biomarkers in diagnosis of RV and LV systolic and diastolic involvement. Figures New echocardiographic tools have offered important insights into the analysis of myocardial functions. They have the ability to detect subtle myocardial dysfunction before the development of overt symptoms and even before the appearance of gross changes in the conventionally used parameters such as M-Mode-derived EF and FS. This fact goes in agreement with results of our study which demonstrated an early affection of both systolic and diastolic functions in asymptomatic diabetic patients. Despite this confirmed accuracy, the performance of tedious and refined echocardiographic techniques such as speckle-tracking echocardiography (STE) and TDI requires experienced operators in image acquisition and subsequent analysis. Also, the scanning and interpretation times are long due to the complexity of the data offered by analyzing software .The aforementioned facts raise the need for readily available and reliable serum markers that can be used as a diagnostic modality till results of echocardiography are available and also for regular follow up of the patient even in the absence of echocardiographic examination.Diabetes mellitus offers a good biologic model for testing the accuracy of several old and new biomarkers against benchmark parameters of advanced TDI and STE. Diabetes mellitus is known to impact the heart due to reliance of the heart on fructose metabolism and subsequent progressive cardiomyocyte degeneration that is independent of glycemic control. This process of progressive myocardial involvement offers a good background to test the cardiac biomarkers not only to test their accuracy but also to understand the possible pathogenesis and cellular mechanisms contributing to the process of myocardial degeneration in this systemic disease .et al. [In our study, CT-1 proven to be the best predictor of LV systolic dysfunction. CT-1 is secreted in cardiac fibroblasts; in acute stress, CT-1 promotes cell survival. However, if stressful signals persist, chronic upregulation of CT-1 leads to cardiomyocyte hypertrophy and, finally, LV dysfunction. The specificity of CT-1 in systolic heart failure has been proven by Freed et al.  in post-et al. .Only one study showed the correlation between CT-1 and newly diagnosed diabetes mellitus in adults from the Chinese population . Our stuThere is scarcity of data regarding RV dysfunction in diabetics. Most of the studies are focused on LV deformation. In our study, patients displayed evidence of RV diastolic and systolic dysfunction in the form of prolonged Tei index and decreased GLS, respectively. The RV is usually jeopardized by volume load. It is increasingly recognized that even non-complicated diabetes is accompanied with a state of increased preload. This is due to overall increase of exchangeable sodium content with subsequent increase in fluid retention in the extracellular fluid .P < 0.0001) with a cutoff predictive value of ≥100 ng/mL (sensitivity 64% and specificity 100%).As per markers of RV systolic dysfunction, statistical multiple regression analysis test for IGFBP-7 was found to have the highest statistically significant predictive factor . Moreover, subjects with higher IGFBP-7 had decreased diastolic function LV E/E′ (P = 0.07) and they suggested that serial measurements of IGFBP-7 provide a prognostic information regarding myocardial remodeling. There is scarcity of data about the usefulness of IGFBP-7 in assessing RV functions. Gandhi et al. [The diagnostic accuracy of IGFBP-7 has been mainly investigated in the context of the LV. Motiwala et al.  assessedi et al.  showed aIn contrast, BNP was found to be a good marker of diastolic dysfunction whether in RV or LV. This goes in agreement with several reports denoting that the release of BNP is linked to LV stretch and raised diastolic pressures of the ventricles. This makes it a better marker for diastolic dysfunction and HFpEF than any of the other tested markers. Its increase in use over the last years has made its availability in the emergency and outpatient setting possible .Many studies were done on BNP and cardiac function in patients with heart failure and renal failure on hemodialysis or patients being prepared for heart transplant. They all found that BNP correlated with LV ejection fraction and LV E/E and it is a good indicator of diastolic dysfunction in asymptomatic patients –24.et al. [P < 0.01) and the impaired diastolic function was related to the control of diabetes. They concluded that asymptomatic diabetics had evidence of subtle RV and LV dysfunction with delayed myocardial relaxation which was related to metabolic control.Similarly, Salem et al.  found prWe are living in the era of cardiac biomarkers, and in this evolving era, it is not only important to use them but to understand which of them can point towards a specific pattern or specific pathogenesis. CT-1 has proven to be a diagnostic superiority in LV systolic dysfunction whilst BNP continue to prove everyday through our study and through many other studies that it is the chief marker of diastolic dysfunction and HFpEF. This potential accuracy and the increasing availability of BNP in the outpatient setting makes it clear that it should be used as a screening test not only in diabetic patients and as part of their regular follow-up but also in every systemic disease predisposing to myocardial involvement.Conflicts of interestThere are no conflicts of interest.


Novel therapeutic strategies aiming at improving the healing process after an acute myocardial infarction are currently under intense investigation. The mouse model plays a central role for deciphering the underlying mechanisms on a molecular and cellular level. Therefore, we intended to assess in-vivo post-infarct remodeling as comprehensively as possible using an expedient native magnetic resonance imaging (MRI) in the two most prominent infarct models, permanent ligation (PL) of the left anterior descending artery (LAD) versus ischemia reperfusion (I/R). Mice were subjected to either permanent or transient (45 min) occlusion of the LAD. After 3 weeks, examinations were performed with a 7-Tesla small animal MRI system. Data analysis was performed with the freely available software Segment. PL resulted in a massive dilation of the left ventricle, accompanied by hypertrophy of the non-infarcted myocardium and a decline of contractile function. These effects were less pronounced following I/R compared to healthy animals. Single plane assessments were not sufficient to capture the specific differences of left ventricular (LV) properties between the two infarct models. Bulls-eye plots were found to be an ideal tool for qualitative LV wall assessment, whereas a multi-slice sector-based analysis of wall regions is ideal to determine differences in hypertrophy, lateral wall thinning and wall thickening on a quantitative level. We combine the use of polar map-based analysis of LV wall properties with volumetric measurements using simple CINE CMR imaging. Our strategy represents a versatile and easily available tool for serial assessment of the LV during the remodeling process. Our study contributes to a better understanding of the effects of novel therapies targeting the healing of damaged myocardium. Primary prevention, diagnosis and treatment options of ischemic heart disease have rapidly progressed over the last decades. Particularly timely reperfusion—by both thrombolytic and interventional approaches—reduces myocardial damage dramatically and hence forms the cornerstone of modern therapies for acute ST-segment elevation myocardial infarction (STEMI) patients2. Yet, replacement of necrotic myocardium by scar tissue inevitably results in left ventricular remodeling and can eventually lead to heart failure. Left ventricular (LV) remodeling refers to alterations in ventricular architecture and function in response to a variety of forms of myocardial injury and increased wall stress4. In the context of myocardial infarction, ventricular remodeling is associated with characteristic changes in the early and late post myocardial infarction (MI) phases, respectively. Early LV remodeling results from replacement of necrotic myocardium by fibrotic scar tissue and leads to elongation and thinning of the infarcted zone5. Beyond this early phase, LV remodeling is dominated by mechanisms compensating for the loss of vital myocardium. Myocytes in the non-infarcted zone undergo hypertrophic elongation, leading to an increased wall mass, chamber enlargement and a shift from an elliptical to a more spherical chamber configuration5. Morphological changes, reduced performance of hypertrophied myocytes and interstitial fibrosis within the non-infarcted zone lead to progressive impairment of LV function.Ischemic heart disease is still the main cause of death worldwide according to the World Health Organization and accounted for more than nine million deaths in 20166. The development of dedicated small animal cardiac magnetic resonance imaging (CMR) initiated a new era, providing a tool which enables high-resolution in-vivo assessment of cardiac function and post-MI remodeling in rodents with utmost precision9. CMR has become the gold standard for assessing LV remodeling in patients11 for both clinical studies and optimizing therapy management. Particularly with regards to the development of novel regenerative therapies in translational research, non-invasive assessment of LV remodeling has become an indispensable tool. Preserving cardiac function and anatomical integrity is the ultimate goal of regenerative therapies for ischemic myocardium. Thereby, the mouse is the most important model organism when it comes to testing hypothesized mechanisms of action on a molecular and cellular level12. Despite the availability of highly elaborate protocols for CMR based assessment of left ventricular remodeling, such as MR spectroscopy and T1/T2 mapping13, CMR-based assessment of left ventricular remodeling in studies aiming at modulating myocardial healing are mostly restricted to volumetric measurements. Yet, novel therapies targeting modulation of the post-MI healing processes and long-term LV remodeling require more comprehensive imaging approaches for gauging LV remodeling. We suppose, that a wider application of T1/T2 mapping and MR spectroscopy is hampered by the difficulty of both acquisition and image analyses and the need for expensive software add-ins. Therefore, we intended to develop a straightforward protocol which is based on native CINE CMR only, but still provides additional information about the specific properties of the remodeled LV wall. Polar maps were applied to describe both morphological and functional wall properties on a qualitative and quantitative level by using the freely available software Segment. Thereby, characteristics of the two most commonly used experimental models of myocardial infarction—permanent ligation (PL) of the left anterior descending (LAD) and transient occlusion of the LAD (I/R)—are visualized and assessed. As expected, myocardial damage is significantly more severe in PL compared to I/R resulting in distinct patterns of left ventricular remodeling respectively.Initial pivotal studies on LV remodeling were based on post-mortem techniques, such as histopathological tissue analyses14. All experiments performed in this study were approved by the “Landesamt für Landwirtschaft, Lebensmittelsicherheit und Fischerei Mecklenburg-Vorpommern; Rostock, Germany” (registration no. LALLF M-V/TSD/7221.3-1.1-054/15) and carried out in compliance with the ARRIVE guidelines. Myocardial infarctions were induced by either permanent occlusion (PL) or transient occlusion the LAD for 45 min (I/R) as described previously (n = 6 per group)16. Each animal received an intramyocardial injection of 10 μL PBS mixed with 10 μL Growth Factor Reduced MatrigelTM Matrix. Healthy animals served as a control group (n = 7).129S6/SvEvTac mice were bred in the animal facility of the Rostock University Medical Center according to the German legislation on protection of animals and the Guide for the Care and Use of Laboratory Animals18. Respiration cycles and Cardiac BPM were extracted from the Intragate navigator analysis. Mean heart rates during scanning were 340.8 ± 25.4 bpm in the control group, 327.6 ± 19.6 bpm in the I/R group and 343.1 ± 30.3 in the PL group with no significant difference between the groups (p = 0.53).For MRI imaging the mice were anaesthetised with 1.5–2.5% isoflurane in oxygen. Examinations were performed with a 7-T small animal MRI system  using a water-cooled actively shielded gradient system. The MRI system was equipped with a 1H transmit volume coil  and a two-by-two receive-only surface coil array (both Bruker BioSpin GmbH). Images of the left ventricle for functional and morphological measurements were acquired using a IntraGate gradient-echo cine sequences (Intragate Cine-FLASH) in five contiguous short-axis planes covering the whole left ventricle following the planning sequences for the short axis view. The following acquisition parameters were used: echo time (TE): 2.38 ms, repetition time (TR): 5.89 ms, flip angle: 15°, 14 frames per cardiac cycle, oversampling: 140, averages: 1, field of view (FOV): 29.4 × 25.2 mm, matrix size: 211 × 180, resolution in-plane: 0.14 × 0.14 mm, slice thickness: 1 mm, scan time per slice: 2 min. Body temperature of the animals was maintained by a water filled heating mat during the whole scan. Temperature of the water-filled heating mat was monitored and controlled by water bath with immersion circulator . Body temperature was continuously monitored by a small rectal temperature probe and maintained between 36 and 37 °C throughout the examination as previously describedhttp://segment.heiberg.sehttp://segment.heiberg.se)19 was used for the assessment of cardiac function and morphology. Segmentation of the left ventricle was performed manually. Papillary muscles were excluded when defining endo- and epicardial borders. Definition of end-diastole and end-systole were calculated by the software. Following manual LV segmentation, the software calculated end-diastolic volume (EDV), end-systolic volume (ESV), left ventricular ejection fraction (LVEF), stroke volume (SV) and left ventricular mass (LVM) automatically. Interventricular septal thickness (IVSd), left ventricular end diastolic dimension (LVEDD) and lateral wall thickness (LW) were obtained from the respective end-diastolic mid-ventricular slice. Regional wall analyses were performed on a slice-by-slice basis, according to the user manual. In brief, the left ventricle was covered by 5 short-axis slices from basal (1) to apical (5). Each slice was divided into 6 sectors as visualized in Fig. The freely available software Segment v2.0 R5165 . Post-hoc pairwise comparisons were made by the Student–Newmans–Keuls method. When, the normality assumption had been violated, ANOVA on ranks was applied, followed by the Dunn´s Methods for multiple pairwise comparisons. Values of All experiments performed in this study were approved by the “Landesamt für Landwirtschaft, Lebensmittelsicherheit und Fischerei Mecklenburg-Vorpommern; Rostock, Germany” (registration no. LALLF M-V/TSD/7221.3-1.1-054/15).Not applicable.In healthy animals, end-diastolic volume (EDV) was 52.6 ± 4.0 µL whereas the end-systolic volume (ESV) measured 25.7 ± 2.3 µL. Left ventricular ejection fraction (LVEF) was 50.9 ± 1.8% and the stroke volume (SV) 26.9 ± 2.3 µL. Values from healthy animals served as control.p < 0.001 vs. control; ESV: 67.5 ± 12.1 µL, p < 0.001 vs. control). These changes in chamber geometry resulted in a dramatic decline of the ejection fraction . Yet, the stroke volume remained preserved   . Similar to the observation in the PL group, the stroke volume remained preserved   of the LAD lead to similar, but less severe changes of left ventricular geometry three weeks after MI induction compared to the healthy control group . The lateral wall thickness (LW) is significantly reduced . Yet, LV hypertrophy of the non-infarcted myocardium can only be hypothesized from this single slice assessment of the interventricular septum   . Similar to the PL group, the thickness of the interventricular septum was not significantly increased .Visual and qualitative inspection of the scar area Fig.  reveals 26) Fig. . LikewisWhereas single slice assessment of the IVSd did not sufficiently depict LV hypertrophy, left ventricular mass (LVM) as calculated from all slices covering the left ventricle was significantly increased in the PL group. Yet, the increase of LVM in the I/R group did not reach a level of significance Fig. .For a more comprehensive measurement and visualization of LV hypertrophy of the non-infarcted zone and the wall thinning within the scar area, we performed regional wall analysis of the whole LV Figs.  and 6. Tp < 0.0001) and the I/R group  . Transient occlusion potentially resulted in a slight, yet not significant reduction of the lateral wall thickness .Thinning of the infarct zone was assessed by measuring the end-diastolic lateral wall thickness . Permanent ligation of the LAD resulted in a significant thinning of the lateral wall compared to the control group  but preserved wall thickening in the septal region . Similarly, transient occlusion of the LAD resulted in significantly reduced wall thickening in the infarct region  with preserved septal wall thickening   Figs. .Figure 820 in a rat model and eventually been confirmed in patients in the 90s21. LV remodeling is a progressive process, which is closely linked to activation of the renin–angiotensin–aldosterone axis (RAAS) and the adrenergic nervous system. Pharmacological inhibition of these mechanisms has the potential to stop or even reverse pathological remodeling5. The imaging-based parameters EDV, ESV and LVEF proved to be reliable surrogate parameters to both estimate cardiovascular events and the effects of pharmacological RAAS inhibition5. Hence, monitoring infarct size and left ventricular chamber dimensions are well-established surrogate markers for the effect of therapies for the treatment of myocardial infarctions in patients.The size of a myocardial infarction has been correlated with the extent of LV remodeling in the late 70sNovel therapies aiming at reducing myocardial damage or restoring contractile function usually target very specific biological mechanisms. Therefore, pilot proof-of-concept studies are most commonly conducted in animal models. Mere global volumetric and functional parameters will not suffice to capture these effects. From a translational perspective, development of novel therapies targeted at modulating myocardial healing requires methods for sequential and comprehensive in-vivo assessment of the remodeling process.13 have been developed. Yet, studies aiming at modulating myocardial healing are mostly restricted to volumetric measurements. The application of elaborate CMR techniques, e.g. MR spectroscopy, requires elaborate and expensive software and profound expertise in CMR radiology, which might hamper a wider application of these attractive tools. This motivated us to develop a protocol, which is based on CINE CMR only, but still provides additional and highly valuable information about the specific properties of the remodeled LV wall.Interestingly, a variety of highly elaborate protocols for CMR based assessment of left ventricular remodelingTherefore, mice were subjected to permanent occlusion (PL) or transient occlusion (I/R) of the LAD, respectively. Post-infarct ventricular remodeling was assessed after 3 weeks by native CMR. PL resulted in a massive dilation of the left ventricle and thinning of the scar, with consecutive formation of an anterolateral aneurysm. Interestingly, despite dramatic increases in EDV and ESV and an according decrease of the LVEF, stroke volume (SV) remained unaffected (Fig. 24. The observation that SV remains preserved despite LV dilation in both infarct models has also been made by Soepriatna et al. in mice17. Similar findings in patients, namely the fact that SV is commonly not reduced despite enormous LV dilation in patients, has been extensively reviewed by Maciver et al.25 and can most probably be explained by a compensated stage of heart failure in both animals and patients at the time of assessment.Our overall observation, that LV dilation and consecutive impairment of cardiac function parameters caused by PL is more pronounced compared to I/R, is well in line with findings by other groups5. On the other hand, adaptive mechanisms, such as hypertrophic myocyte elongation in the non-infarcted myocardium and a consecutive increase of LV mass have the capacity to compensate for the loss of functional cardiomyocytes to a certain extent5. These adaptive mechanisms retain normal cardiac output in the initial post-MI phase but eventually result in progressive fibrosis of the pathologically hypertrophied non-infarcted myocardium, chamber enlargement and a decline in ventricular performance5.Post-infarct LV remodeling comprises characteristic alterations in both infarcted and non-infarcted myocardium. Fibrotic repair of the necrotic area results in scar formation with consecutive elongation and thinning of the infarcted zone27. In contrast, I/R induces a longitudinal scar layer in the middle of the LV myocardium with non-infarcted endocardial and epicardial myocardium left27. As a consequence, LV wall thickness in the infarct region is maintained. Yet, both infarct models show signs of compensatory hypertrophy of the non-infarcted region measured by histological methods24.PL of the LAD induces a large transmural scar with a thin remaining rim of endocardial-located viable cardiomyocytes resulting in progressive thinning of the fibrous scar29. The evolution of elaborate techniques for qualitative tissue assessment resulted in studies describing differences in LV wall properties between the two infarct models by both echocardiographic-based regional myocardial strain analysis17 and CMR-based T1/T2 mapping23.Differences in regional left ventricular wall properties between PL and I/R in mice had been described mostly in post mortem studies until recentlyHere, we developed a simple and straightforward protocol, based on CINE CMR only, to provide a tool for regional LV wall analysis for scientists in the field of experimental cardiology who are not designated experts in the field of cardiovascular imaging.In our study, we measured changes of LV wall dimensions by both single plane and multiple plane approaches. Thereby, using a clinically well-established single plane view, the mid-ventricular parasternal short axis, only thinning of the infarct wall reached the level of significance. Hence, we used a multi-slice approach for more comprehensive analysis of the LV wall properties in both infarct models Fig. . We used26. In contrast to single plane approaches26, we found I/R to result in LV hypertrophy and a consecutive increase in septal wall thickness in our study. Yet, as supposed, lateral wall thickness was preserved after I/R.We found PL to induce dramatic thinning of the lateral wall accompanied by hypertrophy of septal wall regions, a finding, which is in line with previous reports17. Haberkorn et al. also described distinct differences in T1 values within the infarct region between IR and PL in mice, which they ascribe to fibrotic changes23.For functional assessment of the scarred myocardium, we measured regional wall thickening in both infarcted and non-infarcted regions. As one would expect, the dilated scar in PL mice exhibited a negative thickening value, which might represent the passive systolic expansion of the aneurysmal lateral wall. Interestingly, despite retained thickness of the lateral wall after I/R, wall thickening was dramatically reduced. This finding suggests, that scarring after I/R has significant implications on LV function, despite a lack of changes on lateral wall dimensions. Similarly, Soepriatna et al. who used echocardiography based three-dimensional strain mapping, found significantly higher strain values within the infarcted myocardium of I/R compared PL miceBy the use of multi-plane sector analysis, we succeeded in capturing both morphological and functional differences between PL and I/R regarding post-infarction LV remodeling by native CMR. We believe our approach to offer a deeper understanding of the specific functional implications of both PL and I/R. This will provide an excellent and simple tool for unraveling the effects of novel therapies targeting at healing damaged myocardium.30. Lack of intra- and inter-observer analysis may also have produced some inaccuracy. Finally, the injection of Matrigel matrix into the infarct region of all mice may have contributed to our failure to detect significant wall-thinning in the infarct regions of the I/R mice.We did not apply late gadolinium enhancement CMR, which represents the gold standard for determination of circumferential scar size extent. The scarred area can only be estimated indirectly based on the “thinning” of the infarct region. Furthermore, our approach is based on the repeated assessment of five contiguous 1 mm thick short-axis slices. Hence, the longitudinal increase in LV mass and wall motion properties may have been missed. Also, the heart rates below 400 per minute, as a potential result of anesthesia, may have affected the assessed functional parameters


Severe tricuspid regurgitation remains a challenging heart-valve disease to effectively treat with high morbidity and mortality at mid-term. Currently guideline-directed medical treatment is limited to escalating dose of diuretics, and the rationale and timing of open-heart surgery remains controversial. Emerging percutaneous therapies for severe tricuspid regurgitation continue to show promising results in early feasibility studies. However, randomized trial data is lacking. Additionally, many patients are deemed unsuitable for these emerging therapies due to anatomical or imaging constraints. Given the technical simplicity of the bicaval valve implantation (CAVI) technique compared to other transcatheter devices, CAVI is postulated as a suitable alternative for a wide variety of patients affected with severe+ tricuspid regurgitation. In this review we illustrate the current evidence and ongoing uncertainties of CAVI, focusing on the novel CAVI-specific devices. Severe symptomatic tricuspid regurgitation (TR) is associated with poor short- to medium-term clinical outcomes, representing a leading cause of moderate-to-severe heart valve disease in developed countries ,2. MedicCaval valve implantation (CAVI) emerged initially as an alternative therapy for patients deemed as having ‘no other options’ for treating their severe symptomatic TR; such patients often afflicted with concomitant hepatic congestion and right heart failure . Given tSevere TR is a complex valve disease based on heterogeneous TV anatomy along with variations in its etiology and clinical presentation. Secondary TR, usually associated with pulmonary arterial hypertension or left heart disease, is manifested by significant right ventricle (RV) dilatation in the longitudinal direction  and/or tricuspid annular dilatation towards the RV free wall. These structural alterations result in tethering of the TV leaflets resulting in coaptation gaps. Conversely, in isolated TR (without significant pulmonary hypertension) the RV typically has a normal length and TR is mainly caused by tricuspid annular dilation of the right atrium (RA), mainly in the presence of atrial fibrillation .With the abovementioned anatomical and pathological changes in mind, a range of transcatheter strategies have been developed for targeting severe TR according to the underlying mechanism of disease. Briefly, annuloplasty devices are designed to reduce annular dilatation and help indirectly restore leaflet coaptation; edge-to-edge repair aims to create a leaflet tissue bridge across the regurgitant orifice; direct orthotopic valve replacement can be used in patients with large annuli and significant coaptation gaps where edge-to-edge repair and/or annuloplasty would unlikely to be effective  9,10,11,13,14,15By contrast, compared with other tricuspid devices, CAVI procedures have some inherent advantages owing to the relative simplicity of the caval anatomy relative to the TV and right heart  17]. An. An17]. CAVI is intended to alleviate congestive signs for patient affected by severe to torrential TR considered inoperable/high-risk for conventional cardiac surgery. The concept centers in the heterotopic placement of a valve in the inferior vena cava (IVC) and another in the superior vena cava (SVC), at the cavo-atrial junctions ,18. The The SVC is 7.1 cm ± 1.4 long and is formed by the union of the right and left brachiocephalic trunks ; it returns the blood from the upper half of the body to the heart. It courses along the right middle mediastimun, with the trachea and ascending aorta on its left and drains over the anterior roof of the RA. SVC is often irregular in shape. The Azygos vein is a major tributary and drains posteriorly into distal SVC. There are no other major tributaries, however SVC has several patterns of venous collaterals. Neither the SVC nor the brachiocephalic trunk contains valves. They do give rise to the internal, external and subclavian jugular veins, and their valves are usually located at the entrance to the subclavian and jugular veins. These vein valves can hinder the progression of catheters or wires. Other notable anatomical structures of the RA, such as the sinus node, are located in a lower level, in an area where CAVI devices should not be implanted  20,21].,21.20,21The IVC is typically larger than the SVC, it returns the blood from the inferior part of the body to the heart. Its junction with the RA is at its inferior and posterior part, close to the inter-atrial septum. Therefore, junction of the RA-IVC and RA-SVC are not coaxial. In the anterior part of the junction between IVC-RA there is a valve  that it is variable in size and it extends to the lateral/right part of the vein. The Eustachian valve can be easily viewed by transesophageal echocardiography (TEE) in the bi-caval view. Angulations around the RA-IVC and above-below the hepatic veins and RA-junction may be present, which could pose hindrance to CAVI . The dia® system, the Tricento® system, and the TrilliumTM system.The chief concern regarding CAVI is that there is still scarce data published regarding its effectiveness. However, similar to other transcatheter tricuspid devices, initial first-in-man studies also showed promising results in terms of feasibility, safety and device performance . To dateLauten and Figulla initially studied the impact of CAVI to improve TR in an animal model using a self-expandable valve stent. The authors found that the procedure were feasible in 100% of cases, showing a significant decrease in tricuspid regurgitation volume into the cava, coupled with an increment in the cardiac output in both the acute and chronic phase . The samOne of the major concerns of using a non-dedicated device for CAVI is prosthesis migration or embolization, some of which are detected at a late stage. This was the main issue of the TRICAVAL study, which randomized 28 patients to CAVI with a non-dedicated device vs. medical therapy (14 patients each) . In thisAnother unresolved question is whether one prosthesis (only for the IVC) is better than two (treating the SVC as well). Initial studies used only one prosthesis in IVC and showed improvements in the signs/symptoms of congestion. The implantation of a single IVC valve likely reduces the risk of device migration than the implantation of 2 valves. However, it seems that two valves present superior hemodynamic performance than 1 .® system has been granted in 11 countries. To date, 47 patients have been treated within this program, with an implantation success of 98%, with only 1 out of 47 patients suffering from device embolization requiring surgical correction. So far, in hospital mortality is 0% and 30-day mortality is 4% , an early feasibility first-in-man trial; and TRICUS-EURO (NCT04141137), a CE mark trial. End-points also include assessment of the functional status, exercise capacity and quality of life. The 2 trials have single arm-an open label design and have completed patient enrollment. TRICUS included 9 patients from Lithuania, and TRICUS-EURO included 35 patients from Spain and Austria. Besides the global compassionate use program, there are currently 2 ongoing trials with specific protocols assessing the feasibility, safety and performance of the TricValve® is the only CAVI device with CE mark approval obtained in May 2021. The TricValve® implantation system consists of 2 TricValve® self-expanding nitinol structures with leaflets made out of bovine pericardium, one designed for the SVC and the other for the IVC–pre-mounted on a 27.5 F TricValve® Delivery System. The bioprosthetic leaflets are processed with anti-calcification treatment as well as chemical dehydration for preloading in the delivery system  despite optimal medical therapy, and deemed at high or prohibitive surgical risk for conventional tricuspid surgery : 1 right common femoral vein (27.5F) for device deployment and 2 left common femoral vein (5F and 7F) for pigtail control injections and a Swan-Ganz catheter. Optionally a 4th left basilic vein access (5F) can be useful for better identifying the confluence between innominate and SVC. Pre-closure with 1–2 Proglides in the right common femoral vein can be useful for hemostasis, but not mandatory. A Swan-Ganz catheter should be placed at the level of right pulmonary artery for reference. Using the pigtail (+ a multipurpose catheter within the innominate vein), an angiogram of the SVC with special attention to the confluence and the distance between the innominate vein ostium and the SVC at the level where the right branch of the pulmonary artery crosses it is recommended for planning the deployment A,B. A stFor the IVC deployment, a venogram of the hepatic veins centered in the confluence with inferior cava and its junction with the RA is obtained, and serves as a reference for deployment D. The IVCompared to percutaneous left heart procedures, CAVI is typically quite well hemodynamically tolerated during the procedure. However, following implantation there is an abrupt change in physiology characterized by a significant increase in right ventricular afterload due to amelioration of retrograde flow to the cava caused by the newly competent bi-caval valves, an acute increase in RA pressure, and increase in cardiac output if right ventricular function is preserved. This is coupled with significant systemic decongestion, with favorable effects especially seen hepatically. The individual response to these changes is variable and will largely depend up on baseline right ventricular function and its ability to adapt to increased afterload, baseline pulmonary arterial pressures, and left ventricular function.Ventricularization of RA pressure is inevitable to a certain extent, with the concomitant risk of provoking further atrial arrhythmias despite the fact that the majority of these patients already have atrial fibrillation . In patiSpecial attention is required inpatients with baseline right ventricular dysfunction, because the acute increases in right ventricular afterload may cause right ventricular failure. Usually this appears within the first 24 h, manifesting as systemic hypotension and oliguria. The response to low dose inotropes is generally good, with a weaning process instituted over 48 hrs. Prosthesis malfunction can be observed in patients with baseline low tricuspid v-wave as a minimum backflow pressure is required for proper prosthesis leaflet motion. Shoulder pain, likely caused by compression of sensitive branches of phrenic nerve at the level of diaphragm, is a common and usually benign and self-limited symptom following the procedure. The pain seems neuropathic in origin, and it is distributed in the dermatome of the phrenic nerve . In our A temporary platelet count decrease is also frequently observed during the first few days after post-procedure, and may be related with some chemical component of the prosthetic leaflets . This adThere is an inherent risk of device migration since they are fixed upon a non-calcified venous vasculature. Migration usually appears within the first 48 hrs. An adequate anatomical assessment , resulting in a 10% to 40% degree of oversizing, coupled with an accurate and slow deployment technique reduces the risk of migration. Embolization is rare and in general is a consequence of errors in device sizing or secondary to non-accurate implantation technique. To date, there is no case documented of late post-procedural embolization. With the current valve sizes available, the device can be implanted in the vast majority of patients with minimum risk of device migration/embolization. ® studies only recommending oral anticoagulation for 3 months, most of patients are already systemically anticoagulated due to the frequent presence of concomitant atrial fibrillation. The reduction in hepatic congestion also translates into the reduction in diuretic needs, and consequently possible improvement of renal function.The improvement of liver congestion may require a change in the dosage required of vitamin K antagonist (VKA) in patients receiving this therapy, increasing the risk of bleeding due to VKA overdose. There is an inherent risk of valve thrombosis or dysfunction because the low pressure of central venous system, however these issues still require further analysis. Despite TricValve® prosthetic valve is a self expandable bio-prosthesis consisting of a stent graft spanning from the inferior to the superior vena cava and a lateral bicuspid valve element. It is positioned within the right atrium and prevents bicaval backflow. The system is made from porcine peri cardium and Nitinol support structures. The covered stent has a maximum length of 13.5 cm. Anchoring is achieved by oversizing the stent elements in the area of overlap of stent and caval veins. This overlapping area also functions as a sealing zone that prevents blood from flowing back into the cava during systole  is a cross-caval stent graft with multiple covered fenestrations arranged circumferentially around its RA portion. The covered fenestrations allow inflow of blood from the venous system into the RA and prevent backflow into the venous system. The Trillium™ is delivered using a 24 French delivery system in a strictly fluoroscopic procedure with transfemoral venous access. The main characteristics of the device include the multiple circumferential valves, which simplify the rotational positioning of the device, increase the total inflow area, and provide better safety of the technology. Positioning the device over existing pacemaker or implantable cardioverter-defibrillator leads is feasible. Additionally, the Trillium™ has a designated skirt for blocking IVC backflow without blocking supra hepatic vein inflow in patients with very small distance between the supra hepatic veins and the RA cavity C. CurrenInitial data suggest that CAVI procedures with specific-designed devices are feasible and safe for treating severe TR. Procedures with CAVI-specific device are relatively simple and predictable, requiring less anatomical pre-requisites and interventional skills than other percutaneous tricuspid devices. Thus, these devices are a promising alternative for a wide range of patients affected of severe tricuspid regurgitation. However, theirs favorable effects from a safety and efficacy perspective still needs to be corroborated by the currently ongoing pivotal trials, and ultimately in a pivotal randomized trial against optimal medical therapy.