The role of dobutamine during septic shock resuscitation is still controversial.The aim of this prospective multicentre study was to comprehensively characterize the hemodynamic response of septic shock patients with systolic myocardial dysfunction to incremental doses of dobutamine .n = 21, 66%) at any dose and half of patients  at low-dose (5 μg/kg/min). Poor tolerance to low-dose dobutamine was more frequent in case of acidosis, was associated with lower vasopressor-free days and survival at day-14.Thirty two patients were included in three centers. Dobutamine significantly increased contractility indices of both ventricles [crude and afterload-adjusted left ventricular (LV) ejection fraction, global LV longitudinal peak systolic strain, tissue Doppler peak systolic wave at mitral and tricuspid lateral annulus, and tricuspid annular plane excursion) as well as global function indices (stroke volume and cardiac index) and diastolic function . Dobutamine also induced a significant decrease in arterial pressure and cardiac afterload indices . Oxygen transport, oxygen consumption and carbon dioxide production all increased with dobutamine, without change in the respiratory quotient or lactate. Dobutamine was discontinued for poor tolerance in a majority of patients (In patients with septic myocardial dysfunction, dobutamine induced an overall improvement of echocardiographic parameters of diastolic and systolic function, but was poorly tolerated in nearly two thirds of patients, with worsening vasoplegia. Patients with severe acidosis seemed to have a worse response to dobutamine. Circulatory failure is one of the hallmark alterations in septic shock and involves a variable combination of hypovolemia, vasoplegia and myocardial dysfunction. Septic myocardial dysfunction was first described by Parker et al. in 1984 . DiastolThe surviving sepsis campaign recommends the use of dobutamine in patients who show evidence of persistent hypoperfusion despite adequate fluid loading and the use of vasopressor agents . HoweverThe aim of this study was to comprehensively characterize the response of patients with septic myocardial dysfunction to incremental doses of dobutamine in terms of macrocirculation, cardiac function , microcirculation (mottling), and tissue hypoxia .Patients who met septic shock criteria (as defined according to the Sepsis-3 definition) , either Patient's severity was evaluated by the Mac Cabe and Jackson score for underlying diseases , the SAPTests to predict fluid responsiveness included: i) a “clinical” variable (either pulse pressure or stroke volume variation with a threshold of 12%)  and an “An infusion of dobutamine was started at a rate of 5 μg/kg/min, and was sequentially increased to 10 μg/kg/min and 15 μg/kg/min after 30 min intervals, in case of good tolerance. Poor tolerance of dobutamine was defined as one of the following: (i) worsening hypotension ; ii) severe tachycardia . Hemodynamic measurements were performed before dobutamine start and at the end of each step and included: arterial pressure and heart rate, diastolic shock index =   (mmHg) , mottlin  (mmHg) , echocar  (mmHg) . Ventilan = 6). All measures were averaged over a minimum of three cardiac cycles (five to ten in case of non-sinus rhythm).Serial transthoracic echocardiographies were performed by trained operators  with a standard procedure . In casee') diastolic wave velocity at the lateral mitral valve annulus. LV filling pressures were also assessed using E/A and E/e ratios from pulsed-wave Doppler early (E) and late (A) and tissue Doppler early (e') wave velocities at the lateral mitral valve annulus  systolic arterial pressure ;  ii) systral load) =0.9*SysLV systolic function was assessed using indices obtained by two-dimensional echocardiography (LVEF), tissue Doppler imaging , speckle tracking imaging  . An aften et al. , 27.We measured the velocity time integral in the LV outflow tract and the LVOT diameter, which allowed us to calculate LV stroke volume and cardiac index.*systolic arterial pressure (mmHg)*stroke volume (ml), ii) potential energy (PE)SW+PE iiii) Left ventricular work efficiency  We also assessed i) Stroke work (SW) = 0.9This study was approved by an Institutional Review Board (CPP Ile de France-V), as a component of standard care. Written and oral information about the study was given to the patients or families as per French law.post-hoc paired Wilcoxon test with the Benjamini-Hochberg's correction. Continuous data were expressed as medians [25th−75th percentiles] or mean (± standard deviation), as appropriate, and were compared using the non-parametric Kruskal-Wallis test followed by pairwise Mann-Whitney test. Categorical variables, expressed as percentages, were evaluated using the Chi-square test or Fisher exact test. Two-tailed p-values < 0.05 were considered significant. Using tissue Doppler early (e′) diastolic wave velocity at the lateral mitral valve annulus as the primary measure of outcome focused on diastolic function, we calculated that a sample size of at least 33 patients would have a 90% power to detect a 20% decline in that variable with dobutamine titration, considering a baseline e' of 8 cm.s−1 with a standard deviation of 2 cm.s−1 in our previous cohort  and IBM SPSS Statistics Version 24). Normal distribution was checked using the Kolmogorov-Smirnov test. The global effect of dobutamine was assessed by the Friedman test  followed by 4. Normals cohort . The reps cohort . This con = 1), already receiving an inotropic agent , moribund state (n = 2), unavailability of trained operators or echocardiography system (n = 5), heart rate >130 bpm (n = 9), mean arterial pressure <65 mm Hg despite norepinephrine infusion (n = 1), and final diagnosis of cardiogenic shock without evidence of sepsis (n = 5). Thus, the present study comprises 32 patients (19 men and 13 women), with 28, three and one patient included in each center. Clinical characteristics, comorbidities and organ failures are shown in From June 2015 to April 2019, among 57 patients screened for myocardial dysfunction during septic shock, 25 were excluded because of one of the following reasons: chronic heart failure , while all afterload parameters were decreased . Dobutamine also improved diastolic function  and global cardiac function (with increased cardiac index), but with non-significant change in ventricular–arterial coupling and decrease in LV efficiency.There was a trend toward decreased mottling score with dobutamine titration, but few patients had significant mottling. Arterial blood gases and lactate levels did not change during dobutamine titration, whereas oxygen transport, oxygen consumption and carbon dioxide production both increased, with a stable respiratory quotient. Energy expenditure increased with the maximal dose of dobutamine.n = 18, including 14 at 5 μg/kg/min, two at 10 μg/kg/min and two at 15 μg/kg/min), severe sinus tachycardia in two patients (at 10 μg/kg/min), and worsening hypotension with new-onset atrial fibrillation in one patient (at 5 μg/kg/min).During dobutamine titration, 21 (66%) patients had a poor tolerance leading to discontinuation in 15 patients at 5 μg/kg/min, four patients at 10 μg/kg/min, and two patients at 15 μg/kg/min. The reasons for discontinuation were worsening hypotension in the majority of patients  than in their counterparts with poor tolerance  than their counterparts. However, ICU mortality was not significantly different between groups .At day-14, patients with a good tolerance to low-dose dobutamine had more vasopressor-free days  dobutamine improved echocardiographic parameters of diastolic and biventricular systolic function, while it decreased afterload; ii) nearly half and two thirds of patients had a poor tolerance to low-dose and to any dose of dobutamine, respectively; the inotropic effect was prominent in patients with good tolerance to low-dose dobutamine, while poor tolerance was enhanced by acidosis, and associated with deteriorated vasoplegic response and a worse short-term prognosis.Dobutamine is a synthetic catecholamine that was developed as an inotrope for use in congestive heart failure. It consists of two composite enantiomers, which explains its mixed action on α1, α2, β1, and β2 receptors . VariabiMyocardial cyclic adenosine monophosphate (cAMP) is increased by dobutamine's β-adrenoreceptors stimulation. Intracellular calcium increases secondary to elevated cAMP concentrations and could exacerbate diastolic dysfunction . The tacPrevious findings suggested beneficial effects of dobutamine on microcirculation . We onlyIn our study, dobutamine was discontinued because of worsening hypotension or tachycardia in nearly two-thirds of patients at any dose (5 to 15 μg/kg/min) and in nearly half of patients at low-dose (5 μg/kg/min). This result is in accordance with a previous monocenter study with dobutamine incremental doses . PatientIn our study, a poor tolerance of dobutamine was associated with a worse outcome. A favorable response to dobutamine infusion (in terms of oxygen delivery to the tissues or whole body oxygen consumption) has been associated with a better outcome . A recenThe strengths of our study include its prospective and multicentre design, the careful selection of patients with septic myocardial dysfunction, the comprehensive hemodynamic phenotyping of cardiac function .2 gap as a marker of cardiac output adequacy as many patients had the central venous catheter in femoral position. In our study, LV end systolic volume was not directly measured, but derived from ejection fraction and stroke volume, which may induce errors in LV efficiency assessment. Our finding of LV efficiency impairment with dobutamine warrants confirmation, as a previous small sample size study showed no effect of dobutamine on LV efficiency . Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.KR had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. KR and AMD contributed to initial study design, analysis, interpretation of data, drafting of the submitted article, critical revisions for intellectual content, and providing final approval of the version to be published. VL, LL, AB, GC, NP, FBo, and FBa contributed to study design and analysis, interpretation of data, drafting of the submitted article, critical revisions for intellectual content, and providing final approval of the version to be published. All authors contributed to the article and approved the submitted version.This trial was supported by French intensive care society (SRLF), for financial support of a fellow.Author VL receives advisory board fees from Amomed and grant from Leopharma, unrelated to the present study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Doxorubicin-induced cardiotoxicity (DIC) is a common side effect of doxorubicin chemotherapy, and a major mechanism of DIC is inflammation. However, no effective method exists to prevent DIC. In the present study, we investigated the cardioprotective effects of nicorandil against DIC using multiparametric cardiac magnetic resonance (CMR) imaging and elucidated the anti-inflammatory properties of nicorandil in rat models.Male Sprague-Dawley rats received four weekly intraperitoneal doxorubicin doses (4 mg/kg/injection) to establish the DIC model. After treatment with or without nicorandil (3 mg/kg/day) or diazoxide (10 mg/kg/day) orally, all the groups underwent weekly CMR examinations, including cardiac function and strain assessment and T2 mapping, for 6 weeks. Additionally, blood samples and hearts were collected to examine inflammation and histopathology.ATP channel opener diazoxide.According to our results, the earliest DIC CMR parameter in the doxorubicin group was T2 mapping time prolongation compared with the DIC rats treated with nicorandil (doxorubicin+nicorandil group) at week 2. Subsequently, the left ventricular ejection fraction (LVEF) and global peak systolic myocardial strain in the doxorubicin group were significantly reduced, and nicorandil effectively inhibited these effects at week 6. Our results were confirmed by histopathological evaluations. Furthermore, nicorandil treatment had a protective effect against the doxorubicin-induced inflammatory response. Interestingly, similar protective results were obtained using the KCollectively, our findings indicate that nicorandil application ameliorates DIC in rats with significantly higher cardiac function and myocardial strain and less fibrosis, apoptosis and inflammatory cytokine production. Nicorandil prevents T2 abnormalities in the early stages of DIC, showing a high clinical value for early nicorandil treatment in chemotherapy patients.The online version contains supplementary material available at 10.1007/s10557-021-07252-5. Doxorubicin is a highly effective and frequently used chemotherapeutic agent . HoweverATP) opener [Nicorandil is an ATP-sensitive potassium channel (K) opener  that has) opener . Nicoran) opener , 7. In a) opener . To dateThe early detection and treatment of cardiotoxicity are critical to recover cardiac function and reduce the incidence of associated adverse cardiac events , 10. TheThe use of animals in this study was reviewed and approved by the Institutional Ethics and Animal Care Committee of West China Hospital, Sichuan University. The study design is summarized in Fig. All rats were imaged weekly using a 7.0-T small animal preclinical system . The magnetic resonance imaging system was equipped with a dedicated rat cardiac coil. The preparation work before scanning and specific operating procedures were performed as previously described . The CMRFor the analysis, the image was reconstructed in 2,4-chamber long-axis and short-axis views with a slice thickness of 1.5 mm using cardiac image analysis software . The cardiac function parameters, including the left ventricular myocardial mass (LVM), left ventricular end-systolic volume (LVESV), left ventricular end-diastolic volume (LVEDV) and LVEF, were calculated using semiautomated endocardial and epicardial contour tracing based on a short-axis cine stack. The left ventricular global peak longitudinal strain (GLS), left ventricular global peak radial strain (GRS) and left ventricular global peak circumferential strain (GCS) were semiautomatically tracked based on 2- and 4-chamber long-axis cine images and short-axis cine images. The specific operation was also manually drawn on the short axis and long axis of the cardiac cavity. T2 mapping values were automatically generated by drawing the endocardium and epicardium border. LGE was analysed by visual determination with no visible artefact .Blood samples were collected into 3-ml heparinized tubes and then were centrifuged at 3000 rpm for 15 min to obtain plasma. The plasma levels of creatine kinase isoenzyme (CK-MB), creatine kinase (CK), lactate dehydrogenase (LDH), interleukins IL-1β and IL-18, and tumour necrosis factor-alpha (TNF-α) were detected using chemical kits  according to the manufacturer’s instructions.Rats were euthanized via pentobarbital sodium injection after CMR at 6 weeks. Each heart was extracted immediately and fixed in a 4% paraformaldehyde solution. After fixation for 48 h, the heart was serially sectioned along the short-axis plane. Haematoxylin and eosin (H&E) staining was used to pathologically assess cardiac tissue. Masson’s trichrome staining was used to visualize the development of cardiac tissue fibrosis, which was subsequently examined by a pathologist (H.S. P.) blinded to the MR results.Cardiac apoptosis was detected using terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling (TUNEL) and counterstainedusing 4′,6-diamidino-2-phenylindole (DAPI). The percent apoptosis was calculated by dividing the number of TUNEL-positive cells by the total number of cardiac cells viewed in the section.Paraffin-embedded cardiac tissue sections were routinely prepared and then deparaffinized. Next, the sections were incubated with anti-NLRP3 antibody  at 4 °C for 15 h. Subsequently, the sections were incubated with secondary antibody at 37 °C for 30 min. The proteins were stained with 3,30-diaminobenzidine (DAB) for 1 min and counterstained with haematoxylin. Finally, the stained sections were photographed under a microscope.p < 0.05. All the data were analysed using SPSS Statistics version 27.0 (IBM), and graphics were created using GraphPad Prism software 8.0 .The variables are expressed as means ± SD or medians as appropriate. The normality of the data distribution was assessed using the Shapiro–Wilk test, and the homogeneity of variance was assessed using Levene’s test. One-way ANOVA with the LSD post hoc test was used for multiple groups, and two-way repeated measures ANOVA with Bonferroni correction was used to analyse the changes in the imaging variables across time. Differences were considered statistically significant at n = 15), 40% (7/15) of the doxorubicin-treated animals died during the experiment. However, in the control group (n = 5), the Dox + Nic group (n = 10), and the Dox + DZ group (n = 10), no rats died, with a survival rate of 100%  (p < 0.05) but were significantly increased in the Dox + Nic and Dox + DZ group  ; Fig. 4Boup Fig. . Moreoveoup Fig. .Fig. 4Np < 0.001) , while no significant difference was found at the other time points  Fig.  (Supplem01) Fig. , which dnts Fig. .Fig. 5Np < 0.001). Nicorandil or diazoxide treatment increased these values   Fig. . The str01) Fig. .Fig. 6NMasson’s trichrome staining results showed that the degree of myocardial fibrosis was significantly increased in the Dox group compared with that in the control group and was clearly reduced by nicorandil or diazoxide treatment Fig. . The medWe next examined the effects of nicorandil on the inflammatory response induced by doxorubicin in rats. IHC staining showed that compared with that in the control group, the protein expression of NLRP3 was markedly increased in the Dox group, but nicorandil inhibited this expression Fig. . AdditioIn the present study, we demonstrated the cardioprotective effect of nicorandil in a rat model of DIC. Serial multiparametric CMR evaluation showed that nicorandil significantly attenuated cardiac dysfunction, global strain reduction and markers of myocardial injury associated with DIC. Hearts from the Dox + Nic group showed significantly less myocardial fibrosis and cardiomyocyte apoptosis and a significantly reduced inflammatory response. Furthermore, doxorubicin caused significant T2 prolongation after administration: at subclinical DIC stages (before overt cardiac dysfunction), the increase in the T2 relaxation time was significantly smaller in the Dox + Nic group. These findings demonstrate the beneficial effects of nicorandil in a DIC rat model regarding CMR.Doxorubicin, a DNA topoisomerase II inhibitor, has been used clinically for more than 50 years and remains the first-line therapy for many cancer types . Approxi+ATP) channel opener applied clinically as a new vasodilator treatment [The current clinical approach for DIC includes the early detection of LVEF and use of nonspecific heart failure (HF) therapies such as beta-blocker inhibitors , 31. Howreatment , 33, hasreatment –36. Nicoreatment . Su et areatment . Howeverreatment  revealedreatment  publishereatment  found threatment , but nicreatment . In our reatment ; howeverreatment . Additioreatment . The difAlthough accumulating evidence indicates that iron metabolism, calcium disorders, topoisomerase inhibition, sarcomere disruption, mitochondrial damage, oxidative stress, and apoptosis underlie the toxicity of doxorubicin –47, mostOur study provides the first demonstration that nicorandil protects the heart against DIC in a rat animal model based on CMR. In our model, doxorubicin has a clear cardiocytotoxic effect, and we can detect differences in cardiac function and cardiac strain between animals receiving nicorandil or no treatment. We also found differences in T2 mapping values implicated in DIC . At the T2 mapping is an accurate technique to detect and quantify myocardial oedema . We haveATP channel opener diazoxide. Our results further demonstrate that T2 relaxation time increases at an early disease stage and that early administration of nicorandil is effective in reducing myocardial oedema and subsequent myocardial dysfunction, indicating that nicorandil is a promising cardio-oncological drug to prevent DIC in clinical applications.In conclusion, our study supports previous findings , 41 on tOne potential limitation of the present study is the intraperitoneal doxorubicin administration route, in contrast to the intravenous route used in cancer patients. A further limitation in this study is the use of healthy rats, which are free of the comorbidities that are common in cancer patients who develop DIC, many of whom are elderly individuals. Additionally, this study only comprised a few animals, which may limit the statistical power of the heart weight to body weight ratios.ESM 1Supplemental table. CMR in vivo data for all the time points represented by groups as means ± SD. (DOCX 19 kb)


Myocardial infarction (MI) is a major cause of heart failure. Left ventricular adverse remodeling is common post-MI. Several studies have demonstrated a correlation between reduced myocardial strain and the development of adverse remodeling. Cardiac magnetic resonance (CMR) with fast-strain encoding (fast-SENC) or feature tracking (FT) enables rapid assessment of myocardial deformation. The aim of this study was to establish a head-to-head comparison of fast-SENC and FT in post-ST-elevated myocardial infarction (STEMI) patients, with clinical 2D speckle tracking echocardiography (2DEcho) as a reference.Thirty patients treated with primary percutaneous coronary intervention for STEMI were investigated. All participants underwent CMR examination with late gadolinium enhancement, cine-loop steady-state free precession, and fast-SENC imaging using a 1.5T scanner as well as a 2DEcho. Global longitudinal strain (GLS), segmental longitudinal strain (SLS), global circumferential strain (GCS), and segmental circumferential strain (SCS) were assessed along with the MI scar extent.The GCS measurements from fast-SENC and FT were nearly identical: the mean difference was 0.01 (2.5)% (95% CI – 0.92 to 0.95). For GLS, fast-SENC values were higher than FT, with a mean difference of 1.8 (1.4)% (95% CI 1.31–2.35). Tests of significance for GLS did not show any differences between the MR methods and 2DEcho. Average strain in the infarct-related artery (IRA) segments compared to the remote myocardium was significantly lower for the left anterior descending artery and right coronary artery culprits but not for the left circumflex artery culprits. Fast-SENC displayed a higher area under the curve for detecting infarcted segments than FT for both SCS and SLS.GLS and GCS did not significantly differ between fast-SENC and FT. Both showed acceptable agreement with 2DEcho for longitudinal strain. Segments perfused by the IRA showed significantly reduced strain values compared to the remote myocardium. Fast-SENC presented a higher sensitivity and specificity for detecting infarcted segments than FT. Coronary artery disease is a major cause of heart failure worldwide, as more patients now survive myocardial infarction (MI) due to improvements in prevention as well as in the availability of primary percutaneous coronary intervention (pPCI) in the case of ST-elevation MI (STEMI) –4. Left The aim of this study was to establish a head-to-head comparison of myocardial strain assessment, in both longitudinal and circumferential directions between fast-SENC and FT in STEMI patients immediately post-pPCI using echocardiographic speckle-tracking strain as the reference.Patients with STEMI, treated with pPCI were offered CMR and 2DEcho within 2 days, while still in the hospital, between 4 November 2019 and 16 November 2020. In this time span, a total of 250 patients were treated with pPCI for STEMI at our hospital. Forty-two patients were asked to participate, 12 declined, and 30 were finally enrolled in the study after giving written and oral consent, see 3, which was reconstructed to 1.0 × 1.0 × 10 mm3. The acquisition length was one cardiac cycle for each cardiac view, requiring a 1-s breath hold at a heart rate of 60 beats per minute, enabling the images to be reconstructed into 22 phases. The following acquisition parameters were used for fast-SENC: repetition time (TR) = 11 ms, echo time (TE) = 0.7 ms, flip angle = 30°. Fast-SENC strain analysis was performed in the MyoStrain software , the technique utilizes tags parallel to the acquired image and is an adaptation of SENC, enabling the acquisition of cardiac deformation in a single heartbeat. Longitudinal strain (LS) was derived from three different short-axis (SA) views, covering the left ventricle at the basal, midventricular, and apical level. Circumferential strain (CS) was derived from two-, three- and four-chamber long axis (LA) views. The LV 17-segment model of the American Heart Association (AHA) was used, excluding the SA apical segment  and SA  images were obtained, excluding the SA apical segment. CS was derived from the SA segments and LS from the LA image segments according to the AHA model . The fast-SENC acquisition had a voxel size of 4.0 × 4.0 × 10 mm segment . The timHA model . The imaStandard transthoracic 2DEcho was recorded for clinical routine evaluation by clinically experienced technicians with the patient in the left lateral decubitus position. Speckle tracking 2DEcho allows for the evaluation of myocardial deformation by assessing the movements of small natural acoustic markers during a heart cycle. A Vivid E-95 Ultrasound System  equipped with a 4Vc-probe was used for assessment of myocardial function and structure via the parasternal long axis, the apical two-, three-, and four-chamber views and when necessary also the subcostal views. End-systolic global longitudinal strain (GLS) was analyzed offline using the 2DS tool in EchoPAC PC Integrated version 203.74 , by an echocardiographic specialist experienced in speckle tracking.CMR, MI scar, and its segmental extent . The diagnostic performance of segmental circumferential strain (SCS) and segmental longitudinal strain (SLS) was based on individual segments and the regional strain was calculated by assigning myocardial segments to the three major coronary artery perfusion territories according to Cerqueira et al.  and global longitudinal strain (GLS) derived from FT and fast-SENC were compared head-to-head. Speckle tracking end-systolic GLS from the 2DEcho gray scale was calculated for reference. All strains were correlated to LVEFa et al. . Strain p < 0.01. Pearson correlation coefficients  where df = N−2, were calculated to express the degree of linear association between the variables. The correlation hypothesis tested was that ρ = 0 vs. ρ ≠ 0 with a significance level set to p < 0.01. The intraclass correlation coefficient (ICC) was calculated, scatterplot graphs were drawn to depict the linear relationship between the variables and boxplots were created to illustrate the distribution of myocardial strain. Bland–Altman difference plots were presented to evaluate the agreement between the CMR methods.Analysis was performed using SPSS 27 . Continuous variables were presented as mean with SD (in parenthesis). Differences in continuous variables were tested with the analysis of variance non-parametric Friedman's Chi square test, where the level of significance was set to CMR was little affected, LVEFCMR ≥ 50%. Patients with maintained LVEFCMR had smaller scar size 10 (5) % than those with depressed LVEFCMR < 50% whose scar size was 19 (10) %, (p < 0.01). Patient demographics and CMR imaging characteristics are presented in The subjects were enrolled and treated with pPCI after identification of the culprit artery in each case. The cohort displayed a median door-to-balloon time of 67 min. Average scar size was 15 (9) % of LVM with a median Troponin-T of 1,640 ng/l, equivalent to 164 × upper level of normal. LGE revealed scar in 240 out of 510 segments (47%) with 122 segments having scar transmurality < 25%, 78 segments between 25 and 49%, and only 40 segments had a transmurality ≥ 50%. In 13 patients the LVEFp > 0.01). The correlations between GCS or GLS from the two myocardial deformation techniques and MI scar, LVEDVCMR and LVEFCMR are shown together with Bland–Altman graphs in p < 0.001) lower for left anterior descending artery (LAD) and right coronary artery culprits but not for left circumflex artery culprits, p < 0.001). The highest correlation factor was computed for the average SCS and scar in the LAD region . In general, correlations were higher for fast-SENC in both strain directions compared to FT and 2DEcho, except for SLS vs. scar in LAD segments, CMR, and speckle tracking strain from 2DEcho.Strain comparisons are given in terms of “higher” when more negative, and “lower” when less negative, according to Voigt et al. . The GCSFast-SENC had a higher AUC for detecting infarcted segments than FT for both SCS and SLS. SCS derived from fast-SENC detected segments with scar transmurality >50%, with the highest sensitivity (73%) at a specificity of 80% and AUC (0.88). SLS derived from 2DEcho detected scar transmurality >50%, with the sensitivity of 73% at specificity of 80%, and AUC of 0.83, All patients had good image quality for fast-SENC, cine bSSFP, LGE, and 2DEcho. The end-systolic phase was captured at 304 (SD 33 ms) ms after the R-wave for cine images, and at 303 (SD 34 ms) ms for the fast-SENC mages. The fast-SENC acquisition took 120 (SD 30 s) s and its post-processing 213 (SD 17 s) s, CMR to GLS of 2DEcho. This is in line with Bucius et al. who found high global strain correlations between fast-SENC, FT and myocardial tagging but who also presented a considerably greater bias between the methods than shown in our study. Furthermore, Obokata et al. also demonstrated high correlation and fairly wide limits of agreement between FT and speckle tracking echocardiography (We performed a head-to-head comparison of myocardial strain assessment between fast-SENC and FT in post-STEMI patients. We were able to demonstrate good interobserver reproducibility and high correlations between the MR techniques with minor differences comparing GLSiography , 26.The assessment of LV contractile dysfunction after a STEMI has important prognostic relevance . AlthougWe were also able to demonstrate high correlations, with slightly higher absolute values for fast-SENC compared to FT and 2DEcho, in the detection of scar segments in the three perfusion territories. Few gadolinium-free alternatives exist for the detection of infarcted myocardial regions, but GCS has been proposed for this task . In our Both MR deformation methods provide a rapid and objective assessment of myocardial function, which makes them viable alternatives to other time-consuming MR procedures. Additional larger studies with patient follow-up could further identify conditions related to the development of adverse remodeling in subjects with reduced strain values.Fast-strain encoding showed higher sensitivity and specificity for detecting infarcted segments than FT. Segmental strain calculated for the perfusion territory of the infarct-related artery showed significantly lower strain values compared to the remote myocardium and this correlated with infarct transmurality. This study was not designed to explore the reproducibility of segmental strain values, but for global strain measurement, excellent reproducibility was detected. The GLS and GCS did not differ significantly between the two methods. Both MR methods showed acceptable clinical agreement with speckle tracking GLS obtained from echocardiography. The acquisition time of fast-SENC was very short, facilitating the investigation of patients with respiratory compromise.This was a study of STEMI patients early after the pPCI and the results may not be applicable in all situations of reduced systolic LV function. Most infarcted segments had MI transmurality <25% which may result in a very subtle lowering of strain. The relatively low number of participants also limits the conclusions. The participating patients were somewhat younger and the male proportion was larger than average for STEMI patients in our catchment area. The presence of risk factors was typical, but the reporting of a family history of cardiac disease in first-degree relatives was probably underrepresented or forgotten by the patients. Adding tagging or displacement encoding with stimulated echoes would have complemented the assessment of deformation measurements using CMR. The present study was limited to the acute phase of STEMI treatment and did not include patient follow-up. We have used the standard AHA definition of perfusion territories, but variation between left- and right-dominated coronary vessel anatomies may especially affect the partition of segments between the LCX and RCA territories, which could have weakened the associations in our evaluation.walid.el-saadi@liu.se.The datasets presented in this article are not readily available because of privacy concerns of the patients. However, data can be made available through the corresponding author, upon reasonable request. Requests to access the datasets should be directed to The studies involving human participants were reviewed and approved by the Swedish Ethical Review Authority in Uppsala, registration number 2019-00480. The patients/participants provided their written informed consent to participate in this study.JE, JK, TE, MM, and SF participated in the design method and CMR acquisition, to ensure high-quality images. JE included patients, reviewed the manuscript, coordinated, and supported the study with research funding. WE-S, J-EK, and JK analyzed and interpreted the data, performed the statistical analysis, and wrote the manuscript with the assistance of all the other co-authors. JA and SS revised the manuscript for important related content and helped with the interpretation of the data and results. All authors made relevant contributions to the study. Before publication, the manuscript was reviewed and approved by all authors.Financial support for WE-S was obtained from Futurum—the unit for research and education, the academy for health and care in County Hospital Jönköping, and the Research Council of Southeastern Sweden. The study was supported by the Faculty of Medicine and Health Sciences, Linköping University, Sweden. This study was not supported by any specific funding that could have influenced the results.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


This study aimed to explore the outcomes of His-Purkinje conduction system pacing (HPCSP) and to screen the predictors of left ventricular (LV) complete reverse remodeling in patients with true left bundle branch block (LBBB) and heart failure with reduced ejection fraction (HFrEF).Patients who underwent HPCSP for true LBBB and HFrEF from April 2018 to August 2020 were consecutively enrolled. All participants were followed up for at least 1 year. Thrombosis, infection, lead dislodgement, perforation, and other complications were observed after HPCSP. Clinical data, including echocardiographic parameters, electrocardiogram measurements, and cardiac function, were assessed before and after the procedure.P < 0.001). Left ventricular end-systolic volume (LVESV) , left ventricular end-diastolic diameter (LVEDD)  and left ventricular ejection fraction (LVEF)  improved dramatically. Complete reverse remodeling of the LV with normalized LVEF and LVEDD was found in nearly half of the patients (45.24%). A short QRS duration after HPCSP was a strong predictor of normalized LVEF and LVEDD (P < 0.001). The thresholds increased markedly in two patients approximately 6 months after HBP. No patients died during the total follow-up period of 20.07 ± 6.45 months.A total of 46 patients were enrolled. HPCSP was successfully deployed in 42 cases (91.30%), which included 37 cases with His bundle pacing (HBP) and 5 cases with left bundle branch pacing (LBBP). The QRS duration decreased significantly (169.88 ± 19.17 ms vs. 113.67 ± 20.68 ms, Complete reverse remodeling of the LV could be found in nearly half of the patients with HFrEF and true LBBB after HPCSP, and the short QRS duration after HPCSP was a strong predictor. A grSeveral studies have illustrated that His-Purkinje conduction system pacing (HPCSP), including His bundle pacing (HBP) and left bundle branch pacing (LBBP), could be a better option for CRT –8. SinghPatients with true LBBB and HFrEF who underwent HPCSP from April 2018 to August 2020 were consecutively enrolled in our center. The exclusion criteria were recent myocardial infarction or cardiac surgery (<3 months). All patients consented to their treatment, which was approved by the hospital ethics board. LBBP would be the alternative therapy for those patients whose first choice of HBP failed, and BiVP would be the rescue therapy if HPCSP failed. All patients received guideline-directed medical therapy for at least 3 months before implantation.Regular follow-up was conducted 1, 3, 6, 12, 18, and 24 months after the operation. During the follow-up, the 12-lead electrocardiogram (ECG), echocardiography, postoperative complications, and pacemaker parameters were monitored. The events of thrombosis, infection, lead dislodgement, perforation, stroke, rehospitalization due to heart failure, or death were recorded.The left ventricular end-systolic volume (LVESV), LVEDD, and left atrial diameter (LAD) were measured following the guidelines of the American Society of Echocardiography. LVEF was measured using the biplane Simpson’s method, and the maximum mitral regurgitation (MR) and tricuspid regurgitation (TR) were measured by the vena contracta width with color-flow Doppler.1, V2, V5, and V6 (True LBBB was defined as QRS duration > 140 ms in men (>130 ms in women) and the presence of at least 2 mid-QRS notches or slurs in leads I, aVL, V, and V6 . An LVEF1 were the simple criteria for left bundle branch capture.His bundle pacing usually had two independent capture thresholds, including a His-bundle capture threshold and an LBBB correcting threshold in those patients. An abrupt decrease in the Stim-LV active time (LVAT) of more than 10 ms and the morphologies of Qr, qR, or rSR’ in lead VThe HBP and LBBP were performed using the Select Secure pacing lead  and a fixed-curve sheath . His bundle electrograms were mapped in a unipolar configuration and recorded in the system . As described in our previous publications, LBBB correcting thresholds lower than 3.0 V/0.4 ms were accepted .5 for LBBP. All patients accepted a CRT defibrillator (D) or CRT pacemaker (P) device according to the guidelines. The leads were then connected to the left atrium (LA), right ventricle (RV), and LV ports. The LV-RV delay was programmed to ensure the shortest QRS duration. The 3,830 lead was connected to the LV port, and the longer interventricular delay was programmed to ensure ventricular activation via conduction system pacing.The LBBP was further performed when HBP failed to correct LBBB or when the corrected threshold was above 3.0 V/0.4 ms. The sheath and lead were advanced approximately 1–2 cm from the His bundle region. The unipolar-tip paced QRS configuration and pacing impedance were monitored along with the measurement of peak LV activation times in lead Vvia the traditional coronary venous approach. The LV lead was positioned with a standard technique in the lateral or posterolateral LV vein on patients with BiVP if possible. The RV lead was implanted in the right ventricular septum.If HPCSP was unsuccessful, an LV lead was implanted t-test, or Wilcoxon test. Categorical variables were expressed as numbers (%) and were compared using the Fisher’s exact test. Univariate and multivariate analyses were performed using logistic regression to determine the independent predictors of LV complete reverse remodeling after HPCSP. The optimal cutoff of QRS duration was shown on the receiver operator characteristic (ROC) curve with the maximized sensitivity and specificity. P < 0.05 (two-tailed) was considered to be statistically significant.Statistical analyses were performed using SPSS 23.0. Continuous variables were expressed as the mean ± SD or median and were compared with independent two-samples, paired A total of 46 patients were enrolled in this study. The HPCSP was successfully deployed in 42 cases (91.30%), which included 37 cases (80.43%) with HBP and 5 cases (10.87%) with LBBP, and the other 4 patients for whom HPCSP failed accepted BiVP. All patients were implanted with CRT defibrillator (D)  or CRT pacemaker (P) devices. All patients were followed up for at least 12 months, and the follow-up duration was 20.07 ± 6.45 months. The LBBB was corrected in all 42 patients after HBCSP with a correcting threshold of 2.13 ± 0.65 V/0.4 ms, and the His-bundle capture threshold was 1.71 ± 0.87.The baseline characteristics of the patients are shown in P = 0.051). The impedance decreased slightly after the follow-up . The correct threshold of the LBBB in patients with HPCSP was not different from that in patients with BiVP . All the changes are shown in There was a slight trend of increment in the correct threshold after follow-up in patients with HBCSP  approximately 6.03 ± 3.50 months after the operation. Approximately 97.62% of patients responded to HPCSP. The LVEF value was higher than 50% in 23 patients (54.76%) soon after the operation (5.21 ± 3.10 months), and the LVEDD decreased to less than 50 mm in 21 patients (50.00%) approximately 6.84 ± 3.72 months after the operation. The changes in values such as QRS duration, cardiac structure, and cardiac function are shown in P = 0.022), small LVESV before HPCSP (P = 0.008), and short QRS duration after pacing (P = 0.003) were related to LV complete reverse remodeling. Further multivariate regression analysis demonstrated that a short QRS duration was an independent predictor of normalized LVEF and LVEDD in patients with true LBBB and heart failure after HPCSP , which is shown in Univariate analysis showed that a short course of heart failure  with true CLBBB and HFrEF. To the best of our knowledge, this was the first study to demonstrate that a short QRS duration after HPCSP was a strong independent predictor of LV complete reverse remodeling.Although the report showed that the failure rate of BiVP was only 3.6%, it was unfortunate that the suboptimal position was accepted in approximately 20% of patients, which might impair the performance of CRT . We provComplications such as thrombosis, infection, lead dislodgement and perforation, and other implant-related events were not found. Recently, Bhatt et al. reported that 8% of 101 patients with successful HBP implantation required electrode adjustment . In our The distal HBP lead helix, by virtue of being in the septal myocardium, played an important role in the favorable capture threshold and amplitude of the R wave . HoweverAlthough BiVP was effective in reducing desynchronization, it was difficult to achieve complete reverse remodeling for the impaired conduction defect . This diHuang et al. found that HBP obviously improved LVEF, LVESV, and NYHA classification in 74 patients with heart failure and LBBB . In our P < 0.001). It has been proved that the shortening of QRS duration after HPCSP was more obvious compared to BiVP (mean QRS reduction of 20 ms) (P = 0.007)  . But the= 0.007) . It sugg= 0.007) . One of Quite different from BiVP, HPCSP completely corrected the LBBB and resulted in super electrical resynchronization. This means that all heart failures originating from LBBB without other heart troubles would be cured. However, approximately 30% of the patients still suffered from heart failure, indicating that some other factor plays a role in LV reverse remodeling.The course of heart failure was an important factor for LV reverse remodeling , 29. SimCurrent trials demonstrate that factors such as non-ischemic etiology, QRS duration, and morphology can predict BiVP response . It was via classical technology might be that too many “true LBBB” cases were contained, which did not meet the strict physiology-based criteria for “true LBBB” after all. It was reasonable to critically evaluate the definition of “true LBBB” and the physiology behind its ECG signature (One of the reasons for the failure of CRT ignature . Howeverignature . In our ignature . Whetherignature .This was a single-center retrospective study with small sample size. More large-sample and randomized control multicenter studies might be necessary to confirm these results.His-Purkinje conduction system pacing dramatically reversed cardiac remodeling and cardiac function in patients suffering from HFrEF and true LBBB. To the best of our knowledge, this is the first study to prove that a short QRS duration after HPCSP is a powerful predictor of LV complete reverse remodeling after HPCSP.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.X-MG, D-NL, and F-LZ contributed to the conception and design of the study. F-LZ organized the database. D-NL, Y-NZ, and Y-HY performed the statistical analysis. B-LD and S-YD followed up with the patients. X-MG and D-NL wrote the first draft of the manuscript. L-JG, Y-XD, and Y-LX wrote the sections and proofread the manuscript. All authors contributed to manuscript revision and read and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The present CEUS Cardiac Exam Protocols represent the first effort to promulgate a standard set of protocols for optimal administration of ultrasound enhancing agents (UEAs) in echocardiography, based on more than two decades of experience in the use of UEAs for cardiac imaging. The protocols reflect current clinical CEUS practice in many modern echocardiography laboratories throughout the world. Specific attention is given to preparation and dosing of three UEAs that have been approved by the United States Food and Drug Administration (FDA) and additional regulatory bodies in Europe, the Americas and Asia–Pacific. Consistent with professional society guidelines , these protocols cover unapproved “off-label” uses of UEAs—including stress echocardiography and myocardial perfusion imaging—in addition to approved uses. Accordingly, these protocols may differ from information provided in product labels, which are generally based on studies performed prior to product approval and may not always reflect state of the art clinical practice or guidelines. Contrast-enhanced ultrasound (CEUS) is a safe, reliable, cost-effective, and reliable non-invasive imaging tool that is used worldwide to detect heart disease by enhancing left ventricular opacification, augmenting Doppler signals, and assessing myocardial perfusion –3. DurinImproving endocardial border delineation and regional wall motion analysis for the detection of coronary artery disease and cardiomyopathies;Enhancing Doppler signals for the determination of pulmonary artery pressure and valve gradients;Generating left ventricular opacification to quantify left ventricular volumes and ejection fraction;Generating cardiac chamber and vascular opacification to confirm or exclude intracardiac thrombi and masses; and assist in evaluating aneurysms, dissections, and carotid artery disease.Demonstrating microvascular perfusion.UEAs are used to provide the highest quality ultrasound images of the cardiac anatomy and function. Real-time CEUS images help detect and stratify risk of cardiovascular disease by:These applications apply to both rest and stress echocardiograms.The use and dosage of UEAs will be determined by the cardiologist supervising the procedure, or as per departmental protocol. We recommend that UEAs be administered by a physician, qualified sonographer or nurse.Most echocardiographic vendors have presets for contrast very low mechanical index (MI) imaging, which ensures the optimal pulse sequence schemes are being utilized to detect contrast. The optimal MI is the lowest MI that provides strong enhancement with sufficient penetration (absence of attenuation) and which minimizes background noise. Optimal MI will vary based on the patient and specific ultrasound machine.Fundamental non-linear multi-pulse imaging is preferred over harmonic imaging, and a very low mechanical index (VLMI) of < 0.2 will reduce destruction of the microspheres and improve contrast when compared to harmonic imaging. With more recent industry platform changes, the optimal MI may be even lower at 0.10–0.14. Since the fundamental non-linear imaging is multi-pulse, the frame rate  is less than harmonic imaging.The transmit focus may require adjustment, but in nearly all circumstances should be positioned at the mitral annulus to reduce attenuation in the far field and visualize leaflet insertion site for endocardial tracing required for LV volumes and EF measurements. In certain circumstances, the focus can be moved to the near field to better visualize apical thrombus, morphology, wall motion, or perfusion.The optimal transmit frequency for fundamental non-linear imaging should be 1.6–2.0 Megahertz (MHz), while for harmonic imaging 1.3–1.5 MHz works well in most adults (2.6–3.0 MHz receive frequency). In general, higher frequencies provide less penetration but superior image resolution, and large patients may require relatively higher MI and/or lower frequency.Optimal dosing often represents a compromise between attenuation (indicating the dose is too high) and duration (which may be too short if the dose is too low). The speed of injection/flushing may also impact the quality of the CEUS image; faster injection or infusion rates may create higher concentrations of microbubbles in the apex, resulting in basal attenuation artifact, whereas slower injection rates may result in swirling artifact and incomplete LV opacification.Bolus administration generally reduces imaging and preparation time but, due to higher UEA concentrations, attenuation artifacts may be seen. Very low UEA doses with slow saline flushes  are recommended. Repeat injections may be needed to acquire all image planes, when bolus administration is used. Alternatively, continuous infusions provide more prolonged and consistent enhancement with less attenuation artifacts, and may allow for individual optimization of contrast enhancement by adjusting the infusion rate during imaging. While both bolus injections and continuous infusions can be used to evaluate myocardial perfusion, continuous infusions permit better quantification of myocardial blood flow abnormalities with a high MI “flash” followed by a very low MI replenishment scheme.20 G needles or larger are recommended because the UEA may be degraded by a small caliber intravenous cannula. Similarly, a small lumen tubing should be avoided because it may destroy microbubbles even if a large needle is used. Cannulation of an antecubital or central rather than a hand vein is preferred because the UEA delivery site is into a larger vessel nearer to the heart. The use of a 3-way stopcock with contrast connected to the straight line and saline connected to the T-port may allow for the safe change of syringes.See prescribing information for additional details.http://icus-society.org/resources/product-labels/.Three UEAs are available commercially for enhancement of echocardiograms: Definity/Luminity ; Lumason/Sonovue ; and Optison . These agents may be administered via bolus injection or continuous infusion. Preparation and administration of each UEA differs, and prescribing information is available on the ICUS website: Definity/Luminity is activated by agitating the vial for 45 s in a VIALMIX or VIALMIX RFID device, and then withdrawn from the vented vial. Before activating Definity/Luminity, the refrigerated vial should warm to room temperature. The product may be used for up to 12 h at room temperature after activation, but if not used within 5 min the activated vial should be resuspended by gentle hand agitation for 10 s prior to use. Intermittent slow agitation is recommended to maintain microbubble suspension. The recommended bolus dose is 0.1 ml, with a slow (10 s) normal saline flush. Higher doses can be given if needed to achieve adequate homogenous left ventricular opacification. Definity/Luminity can also be diluted in 10 to 60 ml of saline solution and proportionally larger (more easily delivered) injections (0.5–1.0 ml) may be administered, followed by the same flushing technique. Alternatively, Definity/Luminity can be given as an approximate 3–5% infusion in saline to provide more consistent opacification.Lumason/Sonovue is activated by assembling a plunger and prefilled 0.9% saline injection syringe barrel, and connecting the syringe to a provided mini-spike that is inserted into the rubber stopper of the vial. The mini-spike contains a sterile filter and allows protected ventilation of the vial. The saline is then emptied into the vial by pushing on the plunger rod and shaking vigorously for 20 s, producing a homogeneous white milky liquid. In Europe, VUEJECT, a custom-designed infusion pump that continuously oscillates to agitate the agent, is available to maintain homogenous suspension after infusion. (The VUEJECT pump is not currently available in North America.) The VUEJECT pump continues to oscillate after initial mixing is complete. The infusion rate can be controlled via a touchpad and increased or decreased as necessary. Lumason/Sonovue may be used for up to 3 h after reconstitution; in the event of a delay, the microspheres should be resuspended for a few seconds by hand agitation before the suspension is drawn into the syringe. If given as a bolus, the recommended initial dose for adults should be 0.5 ml followed by a slow five milliliter saline flush over 10 s. The dose can be increased to 1.0 ml to achieve homogenous left ventricular opacification. The optimal dose should be repeated every 30 s to maintain opacification. The recommended initial dose for pediatric patients is 0.03 ml/kg.Optison vials should be inverted and gently rotated to resuspend the microspheres; this process will allow the product to come to room temperature before use. The Optison suspension will be homogeneous, opaque, and milky-white. The vial of suspended Optison should be vented with a sterile vent spike or with a sterile 18 gauge needle before the solution is withdrawn into the injection syringe. The product should be used within 1 min of suspension, and in the event of a delay the product should be resuspended by inverting and gently rotating the microspheres in the syringe. . The IV line should be shaken gently and tapped to prevent Optison microspheres from adhering to the sides or separating. The recommended initial bolus dose of Optison is 0.3–0.5 ml followed by a slow 5 ml normal saline flush over 10 s.Suggested initial doses for each agent are provided above. We recommend small doses for resting or stress echocardiograms.When using VLMI fundamental non-linear imaging, higher doses are rarely necessary. Always start with lower doses to avoid shadowing/attenuation and waste of the UEA. Dosing may be adjusted according to adequacy of visualization of the UEA in the cardiac chambers.Use a very slow saline flush via syringe (approximately 5 ml over 10 s). Stop flushing when the UEA appears in the right ventricle. Alternatively, use a saline drip, adjusting the rate as required to obtain a good image.To prolong the contrast effect, a second dose may be administered, followed by a second saline flush. For most applications, this is typically 30 s after the first dose, but will vary from patient to patient.For pharmacologic stress studies, wall motion images should be acquired at baseline, low dose, and peak stress; additional imaging may be done at pre-peak, and in recovery.For exercise stress studies, the UEA bolus and saline flush should be administered at rest, and then again approximately 15–30 s before termination of exercise, depending in part upon the UEA being administered. For pharmacologic stress studies, the UEA bolus and flush can be administered at rest, and during the infusion through the same IV line as the pharmacological stressor; in general, a flush is not needed when administering in the same line as the stress agent infusion.Avoid flushing vigorously or applying strong pressure to the infusion or injection because doing so may destroy the UEA microspheres.VLMI (< 0.2) fundamental non-linear multi-pulse imaging, such as amplitude modulation or combined amplitude/phase modulation, is preferred for BOTH optimal left ventricular opacification (LVO) and perfusion imaging.Alternatively, second harmonic low mechanical index (LMI) (0.2–0.3) imaging may be used, but is less optimal and will achieve only LVO.Set up the ultrasound system to utilize contrast presets.Caution: Reducing MI in the LVO mode may not achieve the image quality of the dedicated VLMI contrast preset, as the signal to noise ratio is significantly reduced when MI < 0.25. However, recent industry platform changes have included fundamental non-linear imaging as an option for the LVO setting, with the same multi-pulse sequence used for perfusion imaging but with slightly different dynamic range and filtering. This permits taking advantage of a dedicated VLMI setting to improve the signal to noise ratio for LVO and endocardial border delineation of all segments at an MI < 0.20.For LVO: Homogenous left ventricular cavity contrast enhancement without swirling or blooming in the apex or shadowing/attenuation in the basal segments is seen. Contrast should be visible in the left atrium approximately 1–2 cm behind the mitral valve.As previously described, this is best achieved with a fundamental non-linear multi-pulse imaging technique such as amplitude modulation or combined amplitude/phase modulation. Near and far field time gain compensation adjustments may be needed, and transmit focus may need to be adjusted. Repeat UEA bolus and flush as needed to maintain optimal visualization.For perfusion: Proceed as above, with additional step of using high mechanical index (high MI) “flash” impulse, which will destroy the UEA within the myocardium, without reduction in LV opacification. The high MI flash frame number and/or flash frame mechanical index can be adjusted to achieve UEA destruction within the myocardium without causing loss of microsphere signal in the LV cavity. With current two-dimensional transducers, normal myocardial perfusion is indicated by complete replenishment of myocardial contrast within 5 s of the high mechanical index (MI) impulse under resting conditions, and within 2 s under stress conditions. Abnormal myocardial perfusion is indicated by delayed or absent replenishment after flash high MI impulses, and may be subendocardial or transmural in distribution.Myocardial perfusion consists of two elements: blood volume and blood flow velocity. The absence of blood volume at peak enhancement can indicate the presence of a myocardial infarction or severely reduced microvascular perfusion. In addition, delayed replenishment of blood flow following microsphere destruction occurs due to reduced myocardial blood flow and can indicate a hemodynamically significant epicardial coronary stenosis and/or compromised microcirculation.Myocardial perfusion imaging should be combined with wall motion analysis. During stress testing, perfusion imaging is more sensitive and may rule-in high-risk patients, whereas wall motion analysis is more specific and may rule-out low-risk patients.Acquire images when:Make 2 syringes—One for REST, one for STRESS (if stress test is utilized). Use ½ vial of contrast for each setting and dilute in 20–30 ml of normal saline if you are utilizing a continuous infusion.For LVO: Homogenous left ventricular cavity contrast without swirling in the apex or shadowing of basal segments. This is best achieved with a fundamental non-linear multi-pulse imaging technique such as amplitude modulation or combined amplitude/phase modulation. Mechanical index should be < 0.2 for fundamental non-linear imaging and 0.25–0.30 for harmonic imaging.For LVO with perfusion: homogenous myocardial contrast opacification in all segments with normal wall thickening (using near and far field time gain compensation adjustments), and adjustment of transmit focus.Complete disappearance of myocardial contrast following high mechanical index “flash” impulses , 5–20 frames) with minimal evidence of reduced LV opacification [achieved by adjusting the flash frame number and/or flash frame mechanical index (MI)].Normal myocardial perfusion: near-complete replenishment of myocardial contrast within 5 s of the high mechanical index impulse under resting conditions, and within 2 s under any type of stress , is consistent with normal perfusion.Abnormal myocardial perfusion: findings other than this would be considered abnormal perfusion. Attenuation must be ruled out if any delay is confined to just basal segments in apical windows. The apical windows can be purposefully foreshortened to bring these basal segments into the near field for better evaluation should attenuation be suspected. In addition, the image plane can be adjusted to bring the myocardial segments of interest nearer to the center of the image, rather than at the sides of the imaging sector where contrast sensitivity is lower. Near field time gain compensation should be adjusted higher for most systems to avoid the appearance of decreased apical segment contrast enhancement. More recent platforms have built in this adjustment in the near field and no near field upward adjustment in time gain compensation is necessary. This should be optimized under resting conditions.Adjust dose to achieve the following image appearance of the left ventricle from the apical windows:Imaging mode. A fundamental non-linear setting is recommended for both LVO and myocardial perfusion imaging, if available. For both fundamental and harmonic imaging, gain settings should be adjusted and set to provide the most homogenous discernable difference between the left ventricular cavity and endocardial border of the myocardium. This varies from system to system, but should be adjusted so that a high MI reduces the visible myocardial contrast in all segments of the myocardium.Use both overall gain settings and slight position changes in near and far field time gain compensation potentiometers to achieve this objective.The following protocol should be used for continuous infusion of the UEA:UEAs should be stored in a convenient location in or near the echocardiography laboratory or intensive care unit to provide for immediate access. A dedicated medical-grade refrigerator should be provided for agents requiring refrigeration.Serious adverse reactions to UEAs are rare and occur in approximately 1 in 10,000 patients , 10. Prihttp://icus-society.org/resources/product-labels/.For current product labels approved in jurisdictions around the world, please visit the ICUS website: The information and protocols contained in this document do not constitute the offering of medical advice, nor do they create a physician–patient relationship between the International Contrast Ultrasound Society (ICUS) or its directors or members, and any other party. ICUS makes no express or implied warranties regarding the accuracy or completeness of the information and protocols contained in this document, and ICUS shall not be liable to any party with respect to any medical decision made, or any action taken or not taken, in direct or indirect reliance on the information and protocols contained in this document.


This experimental study aimed to determine the dynamic changes in myocardial strain and microvascular perfusion in diabetic rats by comprehensive echocardiography while evaluating the effect of dapagliflozin (DAPA).n = 128) were randomly divided into four groups based on the presence or absence of a high-fat diet and streptozotocin-induced diabetes with or without DAPA treatment (n = 32/group). Serial conventional ultrasound, two-dimensional speckle tracking echocardiography (2D-STE) and myocardial contrast echocardiography (MCE) were performed at 2, 4, 6, and 8 weeks, and left ventricular global longitudinal strain (GLS), myocardial blood flow velocity (MBFV), myocardial blood flow (MBF), and myocardial blood volume (MBV) were determined. All animals were sacrificed immediately after the last echo measurement for histopathological assessment.Male Sprague–Dawley rats (p > 0.05), left ventricular GLS, MBFV, MBF, and MBV were decreased at 8 weeks in diabetic rats (p < 0.05) as detected by both 2D-STE and MCE. These indexes were significantly improved at 6 and 8 weeks after treatment with DAPA for diabetic rats (p < 0.05), reaching similar values observed in non-diabetic controls. DAPA treatment was associated with increased myocardial vacuolization and microvessel density and reduced interstitial fibrosis in diabetic rats.Despite similar conventional Doppler-echo indexes among the groups at 2, 4, 6, and 8 weeks (Combined 2D-STE and MCE is sensitive for detecting left ventricular deformity and impaired microvascular perfusion in prediabetes and the early stage of diabetes mellitus. DAPA exerts a beneficial effect on protecting myocardial perfusion in diabetic rats. It is well recognized that chronic hyperglycemia reduces the self-protective ability of vascular endothelial cells, impairs microvascular perfusion, and decreases cardiac systolic and diastolic function, ultimately leading to diabetic cardiomyopathy. Cardiac dysfunction in the absence of coronary artery disease, hypertension, and valvular disease is called diabetic cardiomyopathy, which is one of the most common complications of diabetes mellitus (DM). The main pathological changes of diabetic cardiomyopathy includes myocardial interstitial fibrosis, myocardial stiffness and microvascular rarefaction, eventually leading to diastolic and systolic dysfunction. Timely intervention of diabetic cardiomyopathy is very challenging , therefoSeveral randomized trials and observational studies have shown that sodium-glucose cotransporter 2 (SGLT2) inhibitors significantly reduce the risk of cardiovascular adverse events in diabetic patients –7. FurthSince changes in myocardial function and microvascular perfusion in prediabetes and earlyDM have not yet been well studied and whether early intervention with SGLT2 inhibitors can effectively prevent myocardial damage is not clear, in this experimental study, we used conventional ultrasound techniques, 2D-STE and MCE, to evaluate the dynamic evolution of myocardial function and microvascular perfusion and to explore the potential beneficial effect of the SGLT2 inhibitor dapagliflozin (DAPA) in a diabetic rat model.Male Sprague–Dawley rats (120–150 g) aged 5 weeks were obtained from the Laboratory Animal Center of the Third Military Medical University and kept in a constant temperature and humidity environment under a 12-h light/dark cycle with free access to food and water. The experimental protocol was approved by the Laboratory Animal Welfare and Ethics Committee of the Third Military Medical University (No. AMUWEC20224071).n = 32 in each group): the normal control group included rats with 8 weeks of standard diet plus saline followed by citrate buffer; the DAPA-control group consisted of rats with 8 weeks of standard diet plus oral administration of DAPA followed by citrate buffer; the diabetic group comprised rats with 8 weeks of high-fat diet (HFD) plus saline followed by intraperitoneal injection of streptozotocin (STZ), and the DAPA-diabetic group comprised rats with 8 weeks of HFD plus oral administration of DAPA followed by intraperitoneal injection of STZ. In brief, a HFD consists of 79.85% general animal feed, 15% fat (oil), 5% custard powder, and 0.15% cholesterol . DAPA (AstraZeneca) was given orally at a dose of 1 mg/kg/d for 8 weeks. STZ  was injected at a dose of 30 mg/kg under fasting conditions, and diabetes was identified when the fasting blood glucose level was >11.1 mmol/L at day 5  with a linear array probe  was used to carry out conventional transthoracic echocardiography. M-mode images were recorded at the level of the papillary muscles in the best parasternal long axis view. Left ventricular end-diastolic (EDD) and end-systolic diameters (ESD) and end-diastolic posterior wall thickness (PWd) and interventricular septum thickness in diastole (IVSd) were measured, and fractional shortening (FS) and left ventricular mass index (LVMI) were calculated. Left ventricular end-diastolic (EDV) and end-systolic volumes (ESV) and ejection fraction (EF) were determined by two-dimensional echocardiography. An average of three consecutive cycles was used.Spectral Doppler in the best 4-chamber view with the sampling site positioned at the level of the mitral valve was used to measure peak flow velocity (E), isovolumic systolic time (ICT), isovolumic diastolic time (IRT), and LV ejection time (ET). Tissue Doppler imaging (TDI) was applied to determine myocardial motion velocity (e') at the junction between the septum and mitral annulus. The ratio of E to e' (E/e') and the Tei index, (ICT + IRT)/ET, were calculated .Parasternal long- and short-axis images were acquired for at least 3 cardiac cycles with optimal visualization of the LV myocardium. 2D-STE analysis was performed offline using TOMTEC software . Both endocardial and epicardial boundaries of the left ventricular myocardium were manually traced. This software can automatically track the movement of the entire myocardium. All tracked contours were checked, and, when poorly tracked, the data were excluded. Left ventricular global longitudinal strain (GLS), global circumferential strain (GCS), and global radial strain (GRS) were then derived. All values were averaged from 3 cardiac cycles.Real-time MCE was performed using a Philips ultrasound diagnostic system  with a linear array probe . In brief, a commercially available contrast agent  was diluted twice by adding 5 ml of normal saline, and a 24-gauge cannula was placed into the tail vein with continuous infusion (0.3–0.4 ml/min) . All ima2, and each frame was manually checked to avoid partial volume effects from the right and left ventricular cavities. The first frame image after “flash” was set as the background frame, and then the time-signal intensity curve was fitted to an exponential function  workstation. Regions of interest (ROIs) were manually placed on the middle segment of the anterior myocardium with an area of approximately 1.5 mmfunction :*β equals myocardial blood flow (MBF) , β is the rising slope of signal intensity, reflecting myocardial blood flow velocity (MBFV), and Aow (MBF) .After MCE, all animals were anesthetized in an unconscious state, then euthanized with thoracotomy and heart removal. The heart was fixed in 4% neutral buffered formalin and embedded in paraffin, then serially sectioned along the long axis of the left ventricular papillary muscle (4 μm thick), which was similar to the MCE plane. Hematoxylin and eosin (H&E) staining was performed to assess cardiac histomorphological changes. Masson's trichrome staining was performed to visualize the status of cardiac tissue fibrosis, and CD31 (Abcam ab182981) was used to evaluate myocardial vessels, which were subsequently examined by a pathologist who was blinded to the ultrasonic results.post hoc tests. A value of p < 0.05 was considered significant. All statistical analyses were performed by SPSS , and GraphPad Prism  was used to generate statistical figures.The Shapiro–Wilk test was performed to evaluate the distribution of the data. Continuous and normally distributed data were presented as mean ± SD. Differences among groups were determined by one-way ANOVA followed by Bonferroni p > 0.05). The left ventricular EF decreased gradually in the diabetic group but remained stable in the DAPA-diabetic group. However, the difference did not reach statistical significance . At 8 weeks, left ventricular strain parameters were significantly reduced in the diabetic group compared to the normal control (p = 0.011) and DAPA-control groups (p = 0.032). However, no differences were observed among the normal control, DAPA-control, and DAPA-diabetic groups  and 2 and 8 weeks . Compared with the normal control and DAPA-control groups, MBFV, MBF, and MBV were decreased gradually in the diabetic group across 2, 4, 6, and 8 weeks, reaching levels of statistically significant differences at 6 weeks for MBFV and MBF  and at 8 weeks for MBV (p = 0.033). There were no significant differences in these values among the normal control, DAPA-control, and DAPA-diabetic groups (In the diabetic group, the values of myocardial perfusion as expressed by MBFV and MBF decreased stepwise from 2 to 8 weeks, with statistically significant differences between 2 and 6 weeks (c groups .Histopathological changes were found in the diabetic group. The results of this study showed that the combined use of 2D-STE and MCE was a sensitive way to detect left ventricular deformity and impaired microvascular perfusion in prediabetes and earlyDM. DAPA exerts a cardio-protective effect in this setting.Myocardial dysfunction of varying degrees often occurs in earlyDM . With thOne major finding of this study is the advantage of 2D-STE and MCE, in comparison with conventional echo-Doppler techniques, for early detection of left ventricular deformity and abnormal microvascular and myocardial perfusion in prediabetes and earlyDM. In fact, no significant changes in left ventricular geometry or systolic and diastolic function were observed using conventional echo-Doppler parameters in diabetic rats, which is consistent with previous studies . AlthougAnother important finding is that DAPA exerts a beneficial effect on left ventricular function and myocardial perfusion in diabetic rats. SGLT2 inhibitors are a new class of oral hypoglycemic drugs that can lower blood glucose levels by inhibiting sodium-glucose reabsorption in proximal renal tubules and by promoting urine glucose excretion. These agents not only effectively reduce glycosylated hemoglobin but also have a low risk of hypoglycemia. Recent studies have confirmed that DAPA slightly decreases systolic and diastolic blood pressure, improves myocardial energy utilization, and inhibits myocardial fibrosis. Recently, DAPA has been embraced as a drug of choice for the treatment of heart failure with reduced or preserved EF in diabetic and non-diabetic patients , 10. In In addition, our histopathological study demonstrated that myocardial cells were vacuolated and disorganized in prediabetes and earlyDM. Increased collagen fibers deposition and decreased myocardial microvascular density were also seen, which is in line with previous reports . InteresIn conclusion, the findings of this experimental study support the view that the combined use of 2D-STE and MCE is more sensitive than the conventional Doppler-echo technique for detecting impaired myocardial function and microvascular perfusion in prediabetes and earlyDM. DAPA exerts a beneficial effect on protecting left ventricular function and myocardial perfusion in diabetic rats. This information may provide experimental basis for the pathophysiology of diabetic cardiomyopathy and should be useful to physicians who are involved in decision-making for diabetic patients.This study is subject to several limitations. First, the current study focused on the changes in left ventricular strain and microvascular perfusion in prediabetes and the early stage of diabetes mellitus and the effect of DAPA but did not focus on the changes in the late stage and the corresponding role of DAPA. Future studies on the changes in the late stage of diabetes and the role of DAPA will be carried out. Second, in the present study, resting MCE was performed; however, in the future, stress MCE may be used to further evaluate myocardial microvascular perfusion.The original contributions presented in the study are included in the article/The animal study was reviewed and approved by Laboratory Animal Welfare and Ethics Committee of the Third Military Medical University.JL, YW, YSha, and YShe participated in study design, data analysis and interpretation, and drafting the manuscript. JL, JZ, XL, and LT performed experiments. JL, HH, YD, YSha, and YShe revised the manuscript before final approval. All authors read and approved the final manuscript.


Hepatic disease is linked to cardiovascular events but the independent association between hepatic and cardiovascular disease remains unclear, given shared risk factors.This was a retrospective study of consecutive patients with a clinical cardiac MRI (CMR) and a serological marker of hepatic fibrosis, the FIB-4 score, within one year of clinical imaging. We assessed the relations between FIB-4 scores grouped based on prior literature: low (< 1.3), moderate (1.3–3.25), and high (>3.25), and abnormalities detected by comprehensive CMR grouped into 4 domains: cardiac structure ; cardiac function ; vascular structure ; and cardiac composition . We used Poisson regression to examine the association between the conventionally defined FIB-4 category  and any CMR abnormality while adjusting for demographics and traditional cardiovascular risk factors.Of the 1668 patients studied , 85.9% had ≥1 cardiac abnormality with increasing prevalence seen within the low (82.0%) to moderate (88.8%) to high (92.3%) FIB-4 categories. Multivariable analyses demonstrated the presence of any cardiac abnormality was significantly associated with having a high-range FIB-4 ; notably, the presence of functional cardiac abnormalities were associated with being in the high FIB-4 range  and any vascular abnormalities with being in the moderate FIB-4 range .Elevated FIB-4 was associated with cardiac functional and vascular abnormalities even after adjustment for shared risk factors in a cohort of patients with clinically referred CMR. These CMR findings indicate that cardiovascular abnormalities exist in the presence of subclinical hepatic fibrosis, irrespective of shared risk factors, underscoring the need for further studies of the heart-liver axis. Increased cardiovascular morbidity is seen in patients across the spectrum of liver disease, including conditions such as cirrhotic cardiomyopathy in advanced liver disease, and accelerated atherosclerosis and arrhythmia in earlier stages of liver disease –3. DespiAn improved understanding of the consistently observed associations between liver and cardiac disease can be achieved by leveraging sensitive and specific phenotyping methods applied in at-risk populations. Cardiac magnetic resonance imaging (CMR) can identify subtle changes in cardiac structure and function, vascular size and structure, and myocardial composition . AdditioWe assessed all patients who received a clinically-referred CMR from 1/1/2010 to 4/1/2021 within the Cedars Sinai Health System (CSHS), a large quaternary care system which serves a diverse catchment area of over 2 million individuals with 1.66 million registered outpatients in the major metropolis of Los Angeles, California. An automated electronic medical record (EMR) data pull using structured queries by clinical informatics tools  was used to obtain demographic and clinical characteristics and the laboratory values comprising the FIB-4 score, including age, platelet count, aspartate transaminase, and alanine transaminase levels within one year prior to CMR. A sequential subgroup of 20 patients were manually assessed to ensure that lab values and characteristics reflected in the data pull were accurately measured, with no evidence of discrepancy. We excluded patients with insufficient data to generate the FIB-4 score within the year prior to CMR. The study was IRB approved, and a waiver of informed consent was provided for this retrospective study.post-hoc from a prospective cohort of including all clinical patients receiving CMR within CSHS which contained structured measurements recorded during initial clinical read. The measurements were organized into four distinct domains with multiple sub-components. The domains included cardiac structure with sub-components of left and right ventricular end diastolic volumes, left and right atrial 4-chamber dimensions, and septal and lateral wall thickness from steady-state free precession  cine images; cardiac function including left and right ventricular ejection fraction, presence of wall motion abnormalities, and left ventricular cardiac output from SSFP cine images; vascular structure consisting of ascending aortic and pulmonary arterial sizes measured on axial Half-Fourier Acquisition Single-shot Turbo spin Echo imaging  images; and cardiac composition which included late gadolinium enhancement  on gradient echo magnitude and phase sensitive inversion recovery images, T1 times from modified Look-Locker inversion recovery sequences, and T2 times from T2-prepped SSFP sequences. Each sub-component was assessed as within or outside of normal range, as provided by Kawel-Boehm et al. , and we defined the presence of any domain-specific abnormality as the occurrence of an abnormal value detected for any sub-component of each respective domain. For patients with multiple CMRs in a single year, we defined each outcome as the presence of abnormality across any CMR within that year.P-values below 0.05 were considered statistically significant. All analyses were performed using R statistical software version 4.0.3  or mean (SD) as appropriate. Differences in characteristics across FIB-4 groups were assessed using ANOVA for continuous variables and chi-squared tests for categorical variables. We evaluated the association between FIB-4 score and domain-level CMR abnormalities using univariable and multivariable adjusted Poisson regression models with robust standard errors. Models were adjusted for demographics and traditional cardiac risk factors including age, sex, race, body mass index (BMI), hyperlipidemia, hypertension, diabetes, family history of premature coronary artery disease, and smoking. Among domains for which the association between FIB-4 score and domain-level abnormalities was statistically significant, we used univariable and multivariable Poisson regression models with robust standard errors to examine the association between FIB-4 score and sub-component abnormalities using the covariates described above. Additionally, we used further univariable and multivariable Poisson regression models with robust standard errors to examine whether associations between FIB-4 score and sub-component abnormalities were driven by abnormal values above vs. below the normal range. on 4.0.3 .p < 0.001), sex (p < 0.001), hyperlipidemia (p < 0.001), family history of premature coronary artery disease (p = 0.024), diabetes (p < 0.001), and hypertension (p < 0.001).We identified 1,668 patients who underwent CMR and had FIB-4 scores within the year prior to CMR. Among the study population, the mean FIB-4 score was 1.922 ± .70, with 794 (47.6%) were categorized as low FIB-4, 706 (42.3%) as moderate FIB-4, and 168 (10.1%) as high FIB-4 . The meaAmong the study population, 85.9% of patients had at least one cardiac or vascular abnormality detected in the CMR, with the prevalence of abnormalities increasing across low (82.0%) to moderate (88.8%) to high (92.3%) FIB-4 categories. Across domains, structural abnormalities were the most prevalent , followed by functional abnormalities , compositional abnormalities , and vascular abnormalities .In multivariable analyses, patients with high FIB-4 scores had a higher prevalence of any abnormality detected in the CMR when compared to patients with low FIB-4 scores : 1.07, 95% CI:1.01–1.13), though no statistically significant differences were detected for patients in the moderate FIB-4 group  . In domaIn multivariable analyses assessing sub-components of domain-level abnormalities, domain-level findings appeared to be driven by abnormal left ventricular (LV) output and abnormal ascending aortic size in the function and vascular domains, respectively. When compared to patients with low FIB-4, patients with high FIB-4 had a higher prevalence of abnormal LV output  . No statn = 159 patients with abnormal LV output, 79% had LV output values above the normal range. In multivariable analyses, patients with high FIB-4 scores had a higher prevalence of elevated LV output compared to patients with low FIB-4 scores   , but no In our study, we assessed the association between FIB-4 score and abnormalities seen on CMR to elucidate the relationship between hepatic and cardiovascular disease. Our findings were twofold: first, high FIB-4 was associated with CMR functional and vascular abnormalities after multivariable adjustment for standard cardiovascular risk factors in a cohort of patients referred for CMR. Secondly, the abnormalities were driven by an increase in cardiac output in the high FIB-4 category and increased aortic size in both the moderate and high FIB-4 categories.The associations between liver and cardiac disease using CMR have been limited thus far to small studies in cirrhosis and conditions such as NAFLD. Within cirrhosis, small studies have shown alterations in CMR measures of blood flow with elevated cardiac output and the increased presence of late gadolinium enhancement –18. A moOur results are in line with previous results but cover a broader spectrum of potentially subclinical diseases. In general, we observed a stepwise increase in the prevalence of abnormalities across the increasing FIB-4 groups, which gives biological plausibility as a dose response for the abnormalities. Within the multivariable analysis, the increase in cardiac output abnormalities is likely related to the distributive/high-flow state seen in more advanced cirrhosis . This isOur study has some limitations that merit discussion. As a retrospective cohort study of patients clinically referred for CMR, our analysis was focused on individuals who are likely to have a higher prevalence of abnormalities than in an unselected community-based population; thus, while broad generalizability may be limited, the findings are potentially more relevant to individuals encountered in the clinical care setting and more amenable to future interventions that medical providers could facilitate. Similarly, restriction of analyses to patients with available laboratory values sufficient to calculate a FIB-4 may sub-select a cohort more engaged with the medical system due to comorbidities. Finally, although FIB-4 has been validated as a method for screening for hepatic fibrosis, it is not as sensitive or specific compared to the gold standard liver biopsy-based assessments or more specific imaging or serological methods, its individual components (i.e. platelet counts and transaminases) may be affected by acute hepatic injury or non-hepatic conditions which may increase noise within our models, and specific cutoffs may have variable accuracy between different disease or demographic populations. Notwithstanding the limitations, a strength of our study includes the use of validated measures and the inclusion of a much larger cohort than those included in prior reports. Nonetheless, given our study's cross-sectional design, we consider our findings as hypothesis-generating with respect to putative causality or directionality of heart-liver axis associations. Additional studies in separate and more diverse populations using more specific measures of liver fibrosis are needed to validate our findings.In conclusion, we found in a large cohort of real-world patients referred for CMR evaluated in a large healthcare setting that the presence of cardiovascular abnormalities was significantly associated with measures of hepatic fibrosis. These abnormalities were most notable for alterations in cardiac function, driven by cardiac output, and alterations in vascular anatomy, driven by ascending aortic size. These cardiovascular findings appeared related to hepatic fibrosis, even after accounting for the presence of shared risk factors—underscoring the importance of further consideration of and investigations into perturbations of the heart-liver axis and their longer-term clinical implications for affected individuals.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.This study involving human participants was reviewed and approved by Cedars Sinai IRB. Written informed consent for participation was not required for this study due to retrospective nature in accordance with the national legislation and the institutional requirements.AK was involved in conceptualization, formal analysis, investigation, writing—original draft, writing—review and editing, and visualization. NS and MD were involved in methodology, formal analysis, investigation, and visualization. PB and JN were involved in methodology, formal analysis, and data curation. DO was involved in methodology, investigation, and writing—review and editing. SH was involved in conceptualization, methodology, and writing—review and editing. MN was involved in conceptualization, methodology, resources, writing—review and editing, and supervision. DL was involved in resources, writing—review and editing, and supervision. JE was involved in methodology, resources, data curation, and writing—review and editing. DB was involved in resources, data curation, writing—review and editing, and supervision. SC was involved in conceptualization, methodology, resources, writing—original draft, writing—review and editing, visualization, and supervision. All authors contributed to the article and approved the submitted version.AK reports funding support from the Doris Duke Charitable Foundation Grant 2020059, a Smidt Heart Institute Research Grant, and National Institutes of Health 2R01HL131532-06A1. DO reports funding support from National Institutes of Health K99HL157421-01. JE reports funding support from National Institutes of Health K23HL153888.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.