Intimal sarcoma of the heart is a sporadic disease, which involves symptoms of cardiac insufficiency due to a fast-growing intraluminal mass. Tumor resection is the first-line treatment, although its location precludes excision with wide uninvolved margins. Despite the aggressiveness of this neoplasm and a high risk of recurrence even after removal by microscopically radical surgery, no standard adjuvant therapy has been established. Chemotherapy is used either as an adjuvant treatment or in cases of advanced disease. In contrast, the use of radiotherapy is rare and usually considered in a palliative setting because the risk of radiation-induced heart disease after high-dose radiotherapy to the heart is significant. Herein, we present the cases of two patients, both diagnosed with cardiac intimal sarcoma, who received irradiation after tumor resection. In both cases, radiotherapy was effective, providing long-lasting local disease control. We regularly monitored cardiac function in both patients to assess the impact of radiotherapy on tumor-free heart structures. The excellent local control of the disease with only mild long-term cardiac dysfunction in both patients suggests that radiotherapy can be a useful treatment modality in this indication. The incidence of primary cardiac tumors ranges from 0.02% to 0.25% as reported in autopsy studies . ApproxiThe main concern associated with using RTH for heart sarcoma is the risk of radiation-induced heart disease (RIHD). Therefore, heart tolerance is usually the dose-limiting factor . Herein,A 47-year-old man was admitted to the University Clinical Center of the Medical University in Gdansk in December 2017 due to worsening exercise tolerance, leg swelling, dizziness, and fainting during physical activity. In October 2017, he was diagnosed with pulmonary embolism, for which he received oral anticoagulants (dabigatran), with short-term improvement. Otherwise, the patient’s medical history was unremarkable. ECHO on admission revealed a tumor filling the right ventricle. The patient underwent an immediate surgical resection of the tumor followed by the reconstruction of the right ventricle (RV) with a BioIntegral patch  and tricuspid annuloplasty using the De Vega technique.th edition)  scanning for RTH planning performed just 7 weeks after the surgery revealed a recurrence in the RV wall. Therefore the patient received RTH with curative intent at a dose of 66 Gy in 30 fractions. Subsequent heart imaging with magnetic resonance (MR) and CT showed radiation-induced abnormalities with no evidence of local recurrence. At 32 months after the initial surgery, the patient was disease-free. He was diagnosed with a second malignancy during the follow-up period, which was radically resected and confirmed as renal clear cell carcinoma (stage pT1b according to TNM 8edition) .In September 2016, a 57-year-old man underwent surgical removal of a left atrium (LA) mass that resembled myxoma on ECHO, with pericardial patch reinforcement of the LA. The diagnosis was made after several months of dyspnea, decreasing exercise tolerance, and fainting. Histopathological examination led to the diagnosis of CIS, with microscopically positive resection margins. The patient’s medical history was unremarkable, apart from well-controlled hypertension and hypercholesterolemia. His overall clinical status was good; therefore, adjuvant CTH consisting of four cycles of doxorubicin with dacarbazine was administered.In December 2017, after the diagnosis of a local recurrence 9 months after the last CTH cycle, the patient underwent another surgery, during which tumor resection was incomplete. Due to the high risk of further progression, postoperative RTH at a total dose of 66 Gy in 30 fractions was administered, leading to complete remission of the LA tumor. After a year, the patient was diagnosed with a metastatic lesion in the retroperitoneal space. Radical resection of metastasis (in January 2019) was followed by the second-line CTH (gemcitabine and docetaxel). In July 2019, due to further disease progression, the patient was offered oral pazopanib, which he continued for 47 months, achieving reasonable control of the disease.RTH planning and treatment were conducted according to the institutional protocol of internal use. The treatment plan for Patient 2 with small residual mass was prepared using a 4-dimensional CT (4D-CT) scan. On the contrary, in Patient 1, 4D-CT did not add any benefit; therefore, we chose a conventional CT scan. Gross tumor volume (GTV) was contoured on the non-contrast-enhanced CT series fused with contrast-enhanced scans and preoperative imaging with the help of an experienced cardio-radiologist. The clinical target volume (CTV) encompassed the GTV with a 20-mm margin adjusted for anatomical structures and areas preoperatively involved by the tumor. Planning target volume (PTV) was created by adding an 8-mm isotropic expansion to CTV, and PTV-boost was created by adding 8-10-mm margin to GTV. The volumes of the target areas are summarized in ® SN1403 accelerator, Varian Medical Systems Inc., Palo Alto, California, United States).Treatment was planned using intensity-modulated radiation therapy with simultaneous integrated boost technique at a dose of 54 Gy for PTV and 66 Gy for PTV boost. Each RTH plan was evaluated by two medical physicists and two specialists in radiation oncology. The RTH plan for Patient 2 met institutional dose constraints. Patient 1 was informed about the high risk of RIHD due to heart dose violation; he accepted this therapy as his only treatment option. RTH was delivered using a linear accelerator , RA (25 cm2), and mild RV free wall hypertrophy (8 mm). Global LV systolic function was mildly reduced, with LV ejection fraction (LVEF) of 50%, and LV global longitudinal strain (LV GLS) of -15.5% . In addition, the hypokinesis of the LV anteroseptal segments was noticed. Analysis of the mitral inflow parameters and pulsed tissue Doppler early diastolic velocities showed preserved LV diastolic function. RV systolic function remained significantly impaired, as indicated by a decrease in the tricuspid annular plane systolic excursion (TAPSE) of 8 mm (norm: >19 mm) and low tricuspid annulus systolic velocity in tissue Doppler (S’RV) of 5 cm/s (norm: >9.5 cm/s). As shown in The first ECHO examination revealed a large tumor (82 mm × 63 mm) with irregular borders in the RV, filling the RV outflow tract, and penetrating the pulmonary artery with only the peripheral flow preserved. In addition, significant RV enlargement and impaired RV systolic function, right atrial (RA) enlargement, and severe tricuspid valve regurgitation were found Table 2.2) and docetaxel (60-75 mg/m2), administered at distant recurrence, were uneventful. Subsequently (May 2019), the patient developed paroxysmal atrial tachycardia (PAT), requiring electrical cardioversion to restore sinus rhythm. A complete RBBB was recorded on the ECG. Pharmacologic therapy was changed; bisoprolol dose was increased to 5 mg QD, and perindopril 5 mg QD was added. During therapy with pazopanib, amiodarone was added due to PAT exacerbation. The patient was free of local sarcoma recurrence and clinically stable, with only the slight worsening of exercise tolerance compared to the pre-disease period. ECHO at 45 months after the diagnosis of sarcoma (27 months after cardiac radiotherapy) showed persistent mild enlargement of the RV (4.5 cm), LA (23 cm2), and RA (20 cm2), mildly decreased LV systolic function (LVEF 50%), normal LV diastolic function, and preserved RV systolic function. Of note, LV GLS was -16.7%, and peak longitudinal strain was significantly reduced in the basal anterior, lateral, posterior, and  in the mid-ventricular segments  Table 3.In large cohort studies, patients with primary cardiac sarcomas constitute a heterogeneous group that includes a variety of subtypes and primary locations of sarcomas. As primary cardiac sarcomas are rare and treated with a variety of modalities, any retrospective analyses of the impact of either CTH or RTH on outcomes are precluded. In the French Sarcoma Group Study, in which 24 of 124 enrolled patients received radiation, adding RTH was associated with improved progression-free survival . Wu et aHerein, we report on two patients with CIS treated with RTH and undergoing regular cardiological control. Based on scarce retrospective reports, the prognosis of patients with primary cardiac sarcoma is dismal, with median overall survival (OS) about 17 months  , 8. In oAs expected, both patients showed a gradual but slow worsening of LV systolic function (LVEF 50%). STE revealed a significantly reduced LV peak longitudinal strain in the basal and partially mid-ventricular segments, with only mildly reduced global LV strain. The reduction in LV peak longitudinal strain developed within the highest radiation dose (>50 Gy) area. LV diastolic function remained normal. RV enlargement was observed after cardiac surgery, but RV systolic function was normal in the patient with LA sarcoma. In Patient 1, RV systolic function was significantly reduced before surgery, likely due to cancer infiltration and the history of pulmonary embolism. In addition, surgery was more extensive in this patient, and the postsurgical RV defect required the use of a pericardial patch. The regional peak longitudinal strain impairment in the region of the highest RTH dose resembled that seen in Patient 2. However, in this case, the effect of RTH on RV function was unclear. We noted RV hypertrophy in this patient, which could be the result of radiation-related myocardial fibrosis or the sign of compensatory RV remodeling. We did not observe pericardial complications  in either of our patients; however, both patients developed RBBB.Most previous studies on RIHD involved patients treated with RTH for hematological malignancies or breast cancer; however, no data on the effects of irradiation of the heart sub-volumes have been published to date. It has been shown that radiation causes long-term tissue changes. In the early phase, ionization leads to inflammatory changes with extravasations, edema, and thrombotic state –13. ThisPrevious studies have shown that the volume of the heart receiving >30 Gy, the mean heart dose of >20 Gy, and the dose per fraction of >2 Gy, is associated with an increased risk of cardiovascular complications –17. MeanLV strain changes after RTH have been previously described; however, their prognostic impact remains unclear . Some auOne of the RIHD manifestations is RV wall thickening, which is considered a late complication (observed at least 5 years after thorax irradiation) . FindingRTH might be a feasible treatment for cardiac sarcoma, as it is highly effective and relatively safe even at high doses delivered to the heart. However, it remains associated with the risk of RIHD. Due to high-dose radiation delivered directly to the heart, we anticipate that both our patients develop RIHD earlier than suggested by the literature. Therefore, both patients remain under onco-cardiological supervision. Periodic control and transthoracic examinations with modern ECHO techniques (including STE) and CMR continue in both patients.The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.Ethical review and approval were not required for the retrospective study on human participants in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.Research concept and design—AR and RZ. Data collection—AR, HJ, EL, and GS. Data analysis and interpretation—all authors. Writing the first draft of the manuscript—AR. Writing the section on cardiac function—EL and GS. Critical revision of the article—RZ. Final approval of article—all authors. All authors contributed to the article 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.


Background: There is an emerging body of evidence that supports the potential clinical value of left ventricular (LV) intracavity blood flow kinetic energy (KE) assessment using four-dimensional flow cardiovascular magnetic resonance imaging (4D flow CMR). The aim of this systematic review is to summarize studies evaluating LV intracavity blood flow KE quantification methods and its potential clinical significance. Methods: A systematic review search was carried out on Medline, Pubmed, EMBASE and CINAHL. Results: Of the 677 articles screened, 16 studies met eligibility. These included six (37%) studies on LV diastolic function, another six (37%) studies on heart failure or cardiomyopathies, three (19%) studies on ischemic heart disease or myocardial infarction and finally, one (6%) study on valvular heart disease, namely, mitral regurgitation. One of the main strengths identified by these studies is high reproducibility of LV blood flow KE hemodynamic assessment (mean coefficient of variability = 6 ±  2%) for the evaluation of LV diastolic function. Conclusions: The evidence gathered in this systematic review suggests that LV blood flow KE has great promise for LV hemodynamic assessment. Studies showed increased diagnostic confidence at no cost of additional time. Results were highly reproducible with low intraobserver variability. The hemodynamic loads exerted on the cardiovascular system—mainly the left ventricle (LV)—are the leading cause of cardiovascular diseases ,2. LV inThe LV intracavity flow patterns change during the cardiac cycle. For example, during diastolic filling, a 3D vortex ring is formed at the base of LV. This vortex ring characteristically adapts during the course of diastole . All theThe aim of this systematic review is to methodically summarize CMR studies evaluating LV intracavity blood flow KE quantification methods and its potential clinical significance.This systematic review was prospectively registered (CRD42019117855) [A comprehensive search was undertaken on the 5th of January 2019. Several electronic databases  were searched individually using the healthcare databases advanced search (HDAS) provided by the National Institute of Clinical Excellence (NICE), United Kingdom . Our seaThe A total of 667 studies were initially identified with the search strategy. After an initial screening by HK, 101 studies were shortlisted and included. Article abstracts were reviewed further by PG to exclude irrelevant studies. This narrowed the screened articles to 25 after further discussions among the three reviewers. Cases of disagreement were discussed between the reviewers to reach a suitable conclusion. The studies that passed this screening, had their full texts evaluated.A meta-analysis was deemed inappropriate for this systematic review as much of the research is exploratory with considerable heterogeneity in the included studies. As a result, a narrative review is provided.After a comprehensive review, 25 studies were considered suitable for the systematic review. Further nine studies  were excluded after having read through the paper carefully. The reason for exclusion was the following: right ventricle (1), used echocardiography , focused on congenital heart disease  and duplicates .The 16 remaining studies were further categorized into six (37%) studies on the topic of LV diastolic function and aging, another six (37%) studies on heart failure (HF) including cardiomyopathies, three (19%) studies on ischemic heart disease or myocardial infarction and finally, one (6%) study on valvular heart disease, namely mitral regurgitation (MR).Of all studies, five ,10,11,12p > 0.9) which is important in clinical translation of this novel imaging biomarker for hemodynamic assessment [In this systematic review, the evidence from the pooled studies highlight that LV blood flow kinetic energy (KE) assessment by 4D flow CMR is an emerging novel technique for the assessment of cardiovascular hemodynamics. LV energetics assessment has demonstrated clinical utility in LV diastolic assessment , predictsessment . The chap < 0.007) and a second dip was observed between 2nd and 4th age quartiles (p = 0.025). Four-dimensional flow CMR is capable of capturing intricacies of blood flow within the heart in three directions whereas two-dimensional (2D) echocardiography and 2D CMR could measure it in one direction only. Compared with children and young adults, older adults had a lower early peak diastolic KE (p < 0.0001 and p = 0.025) respectively. In another study, Crandon et al. [iEDV) E/A ratio and 2D mitral inflow E/A ratio  decreasing progressively with age (p < 0.01). Another important finding was observed by Zajac et al. [p < 0.001) and correlated with LV diameter (p = 0.02) and transmitral velocity (p < 0.01). Thus, TKE measured with CMR in decompensated DCM patients by late diastolic LV TKE values exceed those with normal LV. On the other hand, Steding-Ehrenborg et al. [p < 0.001). Increased LV mass in athletes is not pathologic due to preserved geometry . However, this is called ‘physiological hypertrophy’ as the heart adapts to long term endurance. The peak KE at early diastole in LV is higher in athletes  while the mean KE of LV over the cardiac cycle remains the same and the peak oxygen uptake (VO2max) correlated with mean KE . In addition, the amount of KE needed to meet the metabolic demands at rest, measured as mean LVKE/CI (as indexed by cardiac index) did not differ between athletes and sedentary subjects , due to lower heart rate cancelling increased KE per beat in athletes. Measuring the amount of KE inside and outside the LV diastole vortex further contribute towards determining the kinetic energy blood flow in athletes and sedentary controls. The mean KE of the diastolic vortex contributed  of LV total diastolic KE in athletes and controls, respectively. Moreover, the percentage of ventricular KE made up by vortex KE showed no differences between athletes and controls .Four-dimensional flow cardiac magnetic resonance proved to provide consistent information on the decline in early diastolic kinetic energy with aging . Four-din et al.  suggestec et al. . They asg et al.  demonstrp = 0.004, respectively) LV KE during early diastole was higher in LV than . High early diastolic KE in the LV indicates that LV filling is more dependent on ventricular suction as a result of wall tension.In a study by Carlsson et al.  nine heaiEDV. The results obtained from patients who completed full study showed infarct size was similar in acute and chronic MI patients and the majority had anterior MI. The averaged KEiEDV and minimal LV flow KEiEDV were significantly lower in MI patients (p = 0.02). Similarly, diastolic peak E-wave KEiEDV was significantly lower in MI patients (p < 0.005) and the time difference to peak E-wave KEiEDV was significantly higher in MI group (p < 0.01). Also, diastolic peak E-wave KEiEDV was significantly lower in MI (p < 0.005) and several LV flow KEiEDV demonstrated significant differences between LV systolic impairment groups of patients (p < 0.05). In another study, Garg et al. [p = 0.002), whereas peak late filling KE in end-diastole volume was not different between the three groups (p > 0.05). Patients with LV thrombus demonstrated a significantly higher drop in peak late filling KE from mid to apex compared to LV without thrombus patients (p < 0.01). It is also suggested that during early and late diastole, blood flow into the LV cavity takes very little time due to intraventricular pressure gradients. Increasing time difference from healthy controls to LV without thrombus and further to LV with thrombus patients demonstrated that patients with LV thrombus have a significantly delayed wash-in of the LV. These data also supported that increase in the in-plane flow will reduce the proportion of through-plane flow in the LV cavity and thus less blood will pass through the ventricle per unit time resulting in reduced global wash-in and wash-out of the LV. Another important finding was that of Chan et al. who suggested that vortex KE can be used as an early predictor of LV progressive dysfunction overflow energetic indices e.g., KE fluctuations and energy dissipation index (DI) [p < 0.001) and vortex KE (p = 0.003). Furthermore, the magnitude and spatial distribution of flow–energetic indices were also quite similar in both the healthy and preserved normal EF group in contrast to the reduced EF group. This is largely explained due to the increased KE fluctuation index inside the vortex than outside in the healthy and the preserved EF group.Garg et al.  studied g et al.  compareddex (DI) . Chan etp < 0.001; direct flow KE r = −0.48, p = 0.013 and r = −0.56, p = 0.003). KE and non-ejecting flow volume increased with rising LVEDVI and LVESVI . These results reflect those of Kanski et al. who also investigated HF patients. By looking into 39 patients , they assessed LV KE in heart failure patients and the majority (79%) had left bundle branch block (LBBB) with IHD as the most common etiology. KE was calculated within the whole LV and vortex ring. The study exhibited indexed KE to SV and showed that HF patients compared to controls had higher values for both the systolic average KE/SV  and diastolic average KE/SV . However, when indexed to EDV, HF patients showed lower systolic average KE compared to controls  with no difference in diastolic average KE . There were no statistically significant differences in systolic and diastolic KE peak value between heart failure patients and controls . The most important point highlighted in this study is that despite the dyssynchrony affecting KE, regional wall motion in the presence or absence of septal dyskinesia had no impact on KE in this study. Another study on HF patients was done by Zajac et al. who sought to investigate the impact of mechanical dyssynchrony on diastolic function by comparing 4D flow in myopathic LVs with and without LBBB [p = 0.018). LV Direct Flow KE in presystole was less in patients with LBBB compared to non LBBB patients. Therefore, 4D flow CMR can help as a marker of LV mechanical dyssynchrony in HF. Eriksson et al. demonstrated that HF patients with mild LV remodeling demonstrate altered diastolic flow routes through the LV and impaired preservation of inflow KE at presystole compared with healthy subjects [p = 0.021) and EF was smaller (p < 0.001) compared with healthy subjects; the SV was equivalent  and total LV inflow that passed directly to ejection was smaller in DCM (p < 0.01). However, end-diastolic KE per mL of blood of the direct flow was similar in the two groups. Bolger et al. study, on the other hand, performed CMR 4D flow phase contrast velocity mapping in 17 normal subjects including one with DCM. They measured the relative volume of LV flow components and diastolic changes in inflowing KE. They eluded that in healthy subjects, 16 ± 8% of KE of inflow was conserved to the end of diastole compared with 5% in DCM. The reduction in KE of retained inflow in DCM patients was 18-fold greater than that of blood tracing the direct route. Four-dimensional CMR was used in order to assess LV diastolic function by various methods—phase contrast CMR data acquisition; flow separation and visualization; flow quantification and statistical analysis. Four components  of LV flow were measured in normal subjects against myopathic LV. The original proportions and routes of the inflow components noted to be varied with the phase in the cardiac cycle and vortical flow noted on the ventricular side of the mitral leaflets and LV apical area in all the subjects. The direct flow path consistently runs from the basal half of LV around the edge of the anterior leaflet and then flows toward LV outflow tract, while other flow components run along other regions of LV.Direct flow volume and KE diminishes with increased LV volumes. Svalbring et al. suggested in his paper that subtle or subclinical LV remodeling can be detected by 4D flow CMR particularly in the direct flow phase . Thirty-out LBBB . They resubjects . Twenty p < 0.01). There was a significant decrease in mean KE, systolic and early diastolic KE peaks postoperatively . However, not much change in late diastolic peak KE was observed. The most important finding of their study was that physiological flow conditions did not fully normalize post mitral valve surgery—highlighting much more needs to be done to improve therapeutic interventions in valvular heart disease.In a study done by Al-Wakeel et al. , intracaIn this review, we highlight some of the clinical studies demonstrating mechanistic insight into how LV blood flow KE assessment can offer enhanced and reliable assessment of LV hemodynamics. However, more work needs to be done to establish patho–physiological cascade of LV blood-flow behavior from healthy hearts to disease state. Rise in intracardiac pressure is the hallmark of heart failure. Future studies should also explore the relationship of LV blood flow KE with intracavity pressure throughout the cardiac cycle. This will help develop superior noninvasive LV KE biomarkers of intracardiac pressures which can be applied in clinical setting to inform diagnosis and possibly optimize treatment to improve clinical outcomes in heart disease. LV blood KE in particular may have a role in aortic regurgitation assessment as aortic valve incompetency mainly results in a jet inside the LV cavity. Future studies are needed to evaluate how LV blood flow KE changes in aortic regurgitation and could this be used for informing timing of intervention. Even though aortic stenosis causes blood flow acceleration in out flow tract predominantly, it is affect on the LV blood flow KE remains unknown. To summarize, LV blood flow KE assessment not only has the potential to improve diagnostic strategies for LV diastolic function, but also in many other cardiovascular disorders including valvular heart disease.The evidence gathered in this systematic review suggests that LV blood flow KE holds great promise for LV hemodynamic assessment. Studies showed increased diagnostic confidence at no cost of additional time. Results were highly reproducible with a low intraobserver variability. However, the prognostic role of these novel imaging-based biomarkers of flow remains undetermined. Future clinical studies are warranted to evaluate the prognostic role of using these novel intraventricular flow biomarkers.


Despite the pilot nature of this study, statistically significant improvements to the cardiac structure, systolic function, and diastolic function demonstrate that scES combined with task-specific interventions led to beneficial cardiac remodeling, which can reverse atrophic changes that result from spinal cord injury. Long-term improvements to cardiac function have implications for increased quality of life and improved cardiovascular health in individuals with spinal cord injury, decreasing the risk of cardiovascular morbidity and mortality.Cardiac myocyte atrophy and the resulting decreases to the left ventricular mass and dimensions are well documented in spinal cord injury. Therapeutic interventions that increase preload can increase the chamber size and improve the diastolic filling ratios; however, there are no data describing cardiac adaptation to chronic afterload increases. Research from our center has demonstrated that spinal cord epidural stimulation (scES) can normalize arterial blood pressure, so we decided to investigate the effects of scES on cardiac function using echocardiography. Four individuals with chronic, motor-complete cervical spinal cord injury were implanted with a stimulator over the lumbosacral enlargement. We assessed the cardiac structure and function at the following time points: (a) prior to implantation; (b) after scES targeted to increase systolic blood pressure; (c) after the addition of scES targeted to facilitate voluntary  movement of the trunk and lower extremities; and (d) after the addition of scES targeted to facilitate independent, overground standing. We found significant improvements to the cardiac structure (left ventricular mass = 10 ± 2 g,  Cardiac myocyte atrophy and the resulting decreases to the left ventricular mass and dimensions are well documented in spinal cord injury . There iIncluded in this study were four individuals  with chronic, cervical motor-complete spinal cord injury . Individs′) and early diastolic (e′) contraction velocities were measured using tissue Doppler imaging (TDI) in the lateral and septal annulus. Four consecutive cardiac cycles were recorded for off-line analysis.Individuals lay in the left lateral decubitus position and were given sufficient time to acclimate prior to recording. Brachial blood pressure was recorded from the right arm. Individuals did not consume caffeine, alcohol, nicotine, or blood pressure medication the morning of the exam; they did not use scES for at least 12 h prior to acquisition to limit the residual effects of stimulation on the cardiovascular system. Assessments were repeated twice, with 2–4 days in between, to account for changes in volume related to variability in blood pressure. Registered diagnostic cardiac sonographers recorded images on a Philips EPIQ 7 ultrasound system with a Philips X5-1 MHz xMATRIX array transducer or a GE LOGIQ P6 ultrasound system with a GE 3Sp-D phased array transducer. Images were obtained in the parasternal long axis, parasternal short axis, and apical two-, three-, four-, and five-chamber views according to the standards and recommendations of the American Society of Echocardiography . Aortic,∗E/e′ ratio) +1.9  +1.9 . Global A 16-electrode array  was implanted under the T11-L1 vertebrae, spanning spinal cord segments L1–S1, as previously described . StimulaThe stimulation parameters for CV scES were identified specifically to increase systolic blood pressure within a normative range (105–120 mmHg) without activation of the skeletal muscle, demonstrated by the absence of EMG activity ,b. IndivStimulation configurations for the Voluntary scES interventions were selected to facilitate bilateral initiation, termination, and controlled movement of the trunk and lower extremities, including trunk flexion, extension, and rotation; isolated extension and flexion of the hip, knee, and ankle joints; and coordinated extension and/or flexion of the hip, knee, and ankle to move the lower extremities . IndividStimulation configurations for Stand scES were selected to facilitate overground, independent, weight-bearing standing in a custom frame . While tt test. The significance level was set to 0.05 and all tests were two-sided. Statistical analyses were performed in SAS 9.4 .Data were analyzed with mixed linear models in which each measurement was the outcome. The only independent variable was the experimental time point . For each participant, a random intercept and random slope for time point were included. Assessments were repeated at each time point, but measurements were only included for analysis if the images met the standards established by the American Society of Echocardiography; to account for such variability, we included this in the linear model as a random effect nested within time point. To evaluate the improvements over time, linear contrasts were built to compare Post scES time points with Pre CV scES and evaluated with a n = 4) was 30.8 ± 2.7 years. At implant, the duration of injury was 6.5 ± 1.1 years. We found significant increases to the aortic root, left atrial dimension, and left ventricular chamber dimension and mass after scES interventions, associated with statistically significant increases in systolic and diastolic function measurements. After the Voluntary scES intervention, the left ventricular mass , interventricular septum dimension , aortic root diameter , and left atrial dimension  increased significantly compared with the Pre scES time point. Likewise, after the Stand scES intervention, the left ventricular mass  and the aortic root diameter  increased significantly compared with the Pre scES time point (p < 0.001), left ventricular internal dimension during diastole , left ventricular internal dimension during systole , and the interventricular septum dimension  increased significantly (p < 0.001) and left atrial dimension  also increased significantly with each subsequent scES intervention.The mean age of individuals (me point . With eaficantly . The aorp < 0.05) was significantly increased after the Stand scES intervention compared with the Pre scES time point (p < 0.05) increased significantly without changes to the end-diastolic or end-systolic volume, but the VTI  and stroke volume  increased significantly without a change in heart rate (p < 0.05) increased significantly with each subsequent scES intervention.The VTI of blood  after the Voluntary scES intervention compared with the pre scES time point. The mitral valve deceleration slope increased significantly  and the mitral valve deceleration time decreased significantly  after the Stand scES intervention compared with the Pre scES time point (p < 0.05) and the isovolumic relaxation time  decreased significantly and the mitral valve deceleration slope  increased significantly  were thus adaptations to the scES interventions and not just residual effects of stimulation. Long-term improvements to cardiac function have implications for increased quality of life and improved cardiovascular health in individuals with spinal cord injury, decreasing the risk of cardiovascular morbidity and mortality.Measurement of the left ventricle dimensions illustrates preload and afterload within the left ventricle and its ability to generate sufficient force to open the aortic valves against the high-resistance systemic circulation. After scES interventions, the left ventricle dimensions and mass increased significantly in response to increased preload and afterload. Even though these increases were not accompanied by significant increases to the posterior wall thickness, the relative wall thickness did not change after scES interventions. There was therefore no evidence of eccentric  hypertrophy of the myocardium because the geometry of the left ventricle remained the same after each intervention. In four individuals, the myocardium was thus able to strengthen appropriately in response to increased cardiac demand and wall stress imposed by the scES interventions. These changes are similar to those reported by other groups that observed improved posterior wall (Δ1.5 mm), interventricular septum (Δ1.6 mm), and left ventricular diastolic (Δ3.2 mm) dimensions in individuals with SCI after functional electrical stimulation. These changes also mirror those observed in non-injured individuals after reversal of left ventricular atrophy (mass = Δ12.4 g) and left ventricular hypertrophy  . This beSystolic function outcomes illustrate the strength of the left ventricle as it pumps blood into the systemic circulation. We found significant increases to the ejection fraction and stroke volume with each subsequent scES intervention, suggesting a long-term adaptation to increased cardiac demand in four individuals with SCI. This observation is similar to other groups that report systolic function increases after body weight-supported treadmill training . These fE/e′ ratio, nor with decreases to e′ velocity. Therefore increased blood velocity through the mitral valve did not result from maladaptive increased left atrial pressure “pushing” blood into the left ventricle, but rather from stretch of the left ventricle “pulling” blood from the left atrium  diastole . This wat atrium . Moreovet atrium .E/e′ ratio, prevents the decrease in pressure required to open the mitral valve (There were also significant decreases to the isovolumic relaxation time after scES interventions, similar to improvements observed after body weight-supported treadmill training, indicating improved coronary perfusion and cardiac health in these four individuals with SCI . Prolongal valve . This deal valve . Signifial valve . This invia vasopressor responses and results in increased wall thickness and mass of the left ventricle without any increase to the internal dimensions or preload – changes to the filling pressure and volume are minimal, but the myocardium thickens in order to generate sufficient force to overcome the increased afterload (While there was no investigation into the mechanism in this research study, animal models may lend insight into the hemodynamic changes that occur upon active stimulation. Research using anesthetized dog models demonstrate that electrical stimulation of the lumbar sympathetic ganglia elicits greater constriction of the hindlimb and splanchnic capacitance vessels than resistance vessels . Becausefterload . Skeletafterload ,b. And efterload .Given the proximity of the stimulator to the lumbar sympathetic ganglia and that the significant increases we found indicate myocardial adaptation to increased preload, it is possible that scES removes blood from the compliant venous circulation to a greater degree than it elicits arterial vasoconstriction, which led to the significant changes in the cardiac structure, systolic function, and diastolic function after scES intervention. However, there were no significant differences between scES intervention, and in order to understand the effects of CV scES alone and compared with Voluntary and Stand scES, more research is needed. Additionally, investigation into catecholamine release, venous compliance, venous flow and velocity, and arterial diameter and stiffness would elucidate the mechanism by which scES increases preload and afterload.The data reported in this study were obtained from a heterogenous, young cohort of four individuals with severe cervical spinal cord injury without a statistical control since each participant served as their own control in this pre- and post-measurement study design. The clinically heterogenous injury characteristics make generalization inappropriate, while the small sample makes discrimination between the effects of each scES intervention difficult. However, the significant improvements are promising and justify expanding the research into a larger cohort clinically representative of the SCI population. This would allow us to investigate the effects of scES interventions on cardiac function in lower-level injury, incomplete injury, and in relation to age-related declines in cardiac function.We found significant improvements to the ejection fraction and stroke volume, diastolic filling times, and left ventricle dimensions after scES interventions, indicating that scES led to restorative cardiac remodeling in these four individuals with SCI. This has the potential to decrease the secondary health consequences of spinal cord injury and improve quality of life, with implications for improving cardiovascular health and attenuating immobility-related declines in cardiac function. Future studies should investigate this in a larger representative group of SCI participants.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by University of Louisville Institutional Review Board. The patients/participants provided their written informed consent to participate in this study.BL: writing – original draft, methodology, visualization, and interpretation. SW: methodology, investigation, and writing – review and editing. BU: formal analysis and writing – review and editing. NS and MS: interpretation and writing – review and editing. SH: conceptualization, methodology, writing – review and editing, resources, and funding acquisition. GH: conceptualization, methodology, interpretation and writing – review and editing. All authors contributed to the article 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.


PA was assessed by the short form of the International Physical Activity Questionnaire (IPAQ), and the body composition was measured by bioelectrical impedance analysis (BIA) instruments. The differences of separate body composition indices  of older participants with different PA levels (below PA recommendation and over PA recommendation) were examined using the one-way analysis of variance (ANOVA). To compare the differences of three body composition indices with six different multiples of PA recommendation , the one-way ANOVA and Turkey’s test was used for the post hoc analysis to identify the upper PA-benefit threshold in different indices of body composition. Results: The LBM and BM are significantly higher and the FM are significantly lower in old adults performing more PA volume than the WHO recommendation, compared with individuals performing less PA volume than the WHO recommendation. There were significant increases in LBM for males in “1–2 REC”, “2–4 REC”, and “>6 REC” groups, compared with the “0–1 REC” group; and there were significant increases in BM for males in “1–2 REC”, “2–4 REC”, compared with the “0–1 REC” group. The best PA volume for LBM and BM in females was the PA volume of “2–4 REC”. Additionally, whether males or females, there was no significant difference in FM between the “0–1 REC” group and other separate groups. Conclusion: The PA volume that causes best benefit for body composition of the elderly occurs at 1 to 2 times the recommended minimum PA for males, while it occurs at 2 to 4 times that recommended for females. No additional harms for old adults’ body composition occurs at six or more times the recommended minimum PA.Purpose: The purpose of this study was to investigate Chinese old adults’ different body compositions in response to various levels of physical activity (PA). To the best of our knowledge, this is the first study to demonstrate the dose–response relationship between PA and body composition in old adults. Methods: 2664 participants older than 60 years (males:  In the last century, people’s life expectancy has increased dramatically, leading to huge changes in the population structure of the world . Aging hThe potential changes of body composition may be one of the most common determinants of frailty and unhealthy state in old ages . SeveralSeveral studies have proved that there is a significant correlation between physical activity (PA) and old adults’ healthy state. It has been consistently believed that regular PA is the most effective non-medicine intervention to improve old adults’ ability to carry out activities of daily living , musculaWorld Health Organization recommended old adults aged 65 years old and above should do at least 150 minutes of moderate-intensity PA (MPA) or 75 minutes of vigorous-intensity PA (VPA) throughout the week (at least 10 minutes each), or an equivalent combination  of moderate- and vigorous-intensity PA (MVPA) . HoweverTo the best of our knowledge, this is the first study to demonstrate the dose–response relationship between PA and body composition in old adults. In this study, (1) we quantified the PA volume that could cause the best benefits for separate indices of body composition  and the trend for different body compositions benefited from PA for old adults; (2) and we evaluated and explained whether there were excess harms for old adults’ body composition when conducting as much PA as possible.A cross-sectional health survey design was used in this study. A total of 2664 elderly subjects older than 60 years were recruited through a large information campaign from Jurong Center for Disease Control and Prevention in Jiangsu Province, China. Among these samples, there were 984 males  and 1680 females . Inclusion criteria were as follows: over 60 years of age, absence of contraindication for conducting body composition measurement by bioelectrical impedance analysis (BIA) instruments, absence of clinically significant cardiovascular disease and severe acute or terminal illness, absence of physical disability that hinders PA, capable and willing to provide informed consent. The recorded sociodemographic information in this survey included age, smoking habits , educational level , marital status , occupation . See PA was assessed by the short form of the International Physical Activity Questionnaire (IPAQ). In this study, IPAQ was used to collect the volume of MPA and VPA per week based on the metabolic rate (MET) energy expenditure estimates for the last 7 days. The volume of PA (MET × min/wk) was calculated by multiplying the metabolic rate (MET) and the minutes spent on that activity per week (min/wk). In IPAQ, the MET values and formulas for computation of MET × min/week were derived from a variety of work undertaken during IPAQ reliability studies . The IPAAccording to Formulas (2) and (3) of PA volume based on the IPAQ, we calculated the MPA and VPA volume (MET × min/wk) during the last week respectively for each participant, and added up the “MET × min/week” of these two categories of PA to get the total “MET × min/week” of MVPA in the last week. Then, based on the WHO recommended minimum MVPA volume (600 MET × min/wk), we grouped the elderly participants into five different multiples of this recommendation . The participants who performed more than 600 MET × min/wk of MVPA volume met and exceeded the minimum recommendation, and others were those participants whose MVPA volume was below the WHO recommendation.To measure the body composition, the BCAII  tetrapolar eight-point tactile electrode system was used. This device was based on BIA technique and was an accessible, inexpensive method for estimating total body water, extracellular water, fat-free mass, and body cell mass. With these estimated parameters, this method could allow the quantitative assessment of different body components in the human body . The BCAWhen older subjects agreed to participate in this study, they received a questionnaire of specific information about illness, physical state, or disability to verify whether they met the inclusion criteria of this study. After providing information about the study , an informed consent was signed. All elderly participants in this study completed all measurement protocols on one day.The interviewer read each question of IPAQ loudly to ensure that the subjects could understand the meaning of each item well and then wrote down the old subject’s answer in the questionnaire. After the survey of PA, the subject stood on the footboard of the BCAII device without shoes, metal accessories and in lightweight clothing, and held two handles of BCAII with two hands to measure the body compositions. All BIA data was collected at the similar times of day (from 7:00 a.m. to 9:00 a.m.). All subjects were fasted and restricted from fluid consumption after getting up, and also the vigorous exercise was prohibited. All participants had detailed procedures introduced to them before participating in the study and then signed the informed consent documents. Participants were also clearly informed that they could withdraw from the study at any time for any reason. Any participant’s own PA and body composition measurement results in this study could be made into one’s health report and then provided to each participant. The authors declared that all the experiments of this study complied with the current laws of China in which they were performed. The study was approved by the medical ethics committee of Tsinghua University. p < 0.05. In this study, we also indicated the significance level at p < 0.01. The statistical analyses were implemented by using the SPSS . Results were expressed as Mean ± SD for continuous variables or frequencies (percentages) for categorical variables. We also reported the 95% confidence interval (95% CI) and variable range for the results. The subgroup analysis according to gender was performed in this study. The difference of separate body composition indicators  of older participants with different PA levels (below PA recommendation and over PA recommendation) were examined using the one-way analysis of variance (ANOVA). To compare the difference of these three body composition indicators with five different multiples of PA recommendation , the one-way ANOVA and Turkey’s test was used for the post hoc analysis to identify the upper PA-benefit threshold in different body composition indices. The level of the significance was set at The descriptive characteristics and PA level of 2664 participants are shown in p < 0.01). For the BM, the male participants performing PA volume over PA recommendation (49.2 ± 5.7) had a BM significantly higher than those performing PA volume below PA recommendation , and similar results presented in the female participants . For the FM, there was also a significant difference between participants performing PA volume over PA recommendation and those performing PA volume below PA recommendation .The LBM, BM, and FM of the old participants with five different multiples of PA recommendation are shown in p < 0.05). However, the LBM in the “1–2 REC” group (73.3 ± 9.1) and the “2–4 REC” group (73.0 ± 3.9) was also significantly higher than that in “0–1 REC” group (p < 0.05). For females, the highest mean value of LBM occurred in the “2–4 REC” group (66.4 ± 8.3), which was significantly higher than that in the “0–1 REC” group . For the LBM, the highest mean value of LBM in males occurred in the “>6 REC” group (73.4 ± 8.9), which was significantly higher than that in the “0–1 REC” group . Furthermore, the BM in the “2–4 REC” group (48.6 ± 5.9) was also significantly higher than that in “0–1 REC” group (p < 0.05). For females, the highest mean value of BM occurred in the 2–4 REC group (45.9 ± 4.6), which was significantly higher than that in the “0–1 REC” group . For the BM, the highest mean value of BM in males occurred in the “1–2 REC” group (50.0 ± 5.4), which was significantly higher than that in the “0–1 REC” group  Old people of different genders have a different PA benefit threshold on different indicators of body composition. For old males, the best benefits for the LBM will occur when they perform a PA volume more than six-fold the PA recommendation suggested by WHO (>6 REC); and the maximum BM benefit of PA appears to be probably one to two times the WHO recommended minimum PA (1–2 REC). For old females, the best PA volume that could cause the maximum benefits for the LBM and BM appears to be probably two to four times WHO recommended minimum PA (2–4 REC). (2) There does not appear to be a decreased LBM and BM risk when the PA exceed six times WHO recommended minimum PA, compared with the PA volume below WHO recommended minimum PA. Although there was no significant difference in FM between five groups with different multiples of PA recommendation, there was a downward trend in FM with the increase in PA levels. Hence, it indicated that there were no additional harms for old adults’ body composition when conducting as much PA as possible. p < 0.01) 46], and We also found that a different body composition mass had a different physical activity benefit threshold in different genders, through dividing the participants into five different multiples of WHO PA recommendation. The best benefit in LBM occured among males performing more than six times the recommended minimum PA and females performing 2 to 4 times the recommended minimum PA. While the PA volume of “1–2 REC” and “2–4 REC” also produced remarkable benefit for the LBM in males, after post hoc analysis, no significant difference was found in“1–2 REC”, “2–4 REC”, and “>6 REC”. Therefore, we suggest the PA volume of “1–2 REC” as the best choice for old males to acquire extra benefit, compared with the PA volume of “0–1 REC”. The best benefit in BM occurs among males performing 1 to 2 the recommended minimum PA and females performing 2 to 4 times the recommended minimum PA. Furthermore, for males, the PA volume of “2–4 REC” can cause extra benefit, compared with the PA volume of “0–1 REC”. But the BM of “1–2 REC” is significantly higher than that of “2–4 REC” after post hoc analysis. We found that the best benefit threshold of PA volume for LBM and BM is different in males and females, the PA volume that can produce best benefit for females is more than that for males. This may be because nearly all old female adults aged over 60 years are menopausal women, and due to menopause, there is a loss in the main female sex steroid hormone  ,55, whicIt is worth mentioning that we observed an increased benefit for LBM and BM in individuals performing six or more times the recommended minimum PA, compared with that in participants performing less PA than the recommended minimum PA. It meant that there was no additional harms and risks for old adults’ body composition when conducting as much PA as possible. Our study has several limitations that need to be addressed. First, this study is limited by its cross-sectional design, it precludes any conclusions on causality. Future studies may perform a longitudinal study design to confirm our results. Second, this study estimated the volume of physical activity using IPAQ, and it requires participants to self-report and recall their physical activity of the last week, which can produce recall bias. Some studies have indicated the IPAQ could overestimate total physical activity ,61. ThirPerforming more PA volume than the WHO recommended minimum PA could generate more benefit in BM, LBM, and FM in the elderly. The PA volume that causes the best benefit for body composition of the elderly occurs at 1 to 2 times the recommended minimum PA for males, while it occurs at 2 to 4 times that recommended for females. No additional harms for old adults’ body composition occurs at six or more times the recommended minimum PA. These findings will be useful for updating PA guidelines for Chinese old adults based on the body composition.


Left ventricular mural thrombus (LVMT) is a life-threatening complication in patients with left ventricular dysfunction.A 67-year-old man had a history of penetrating myocardial infarction and left ventricular aneurysm (LVA). The patient was scheduled for a non-cardiac surgery and stopped aspirin for 10 days to reduce the risk of bleeding. Fresh LVMT was revealed via the transesophageal echocardiography (TEE) after the preoperative discontinuation of aspirin.Perioperative repeated evaluation for the thrombosis by echocardiography is essential in cases of patients with cardiovascular disease undergoing non-cardiac surgery. In high risk patient, during temporary interruption of antiplatelets, bridging with perioperative low-molecular-weight heparin is advisable. Over the past decade despite great improvements in prognosis, myocardial infarction remains high rates of morbidity and mortality worldwide. Left ventricular aneurysm (LVA) is a serious complication of transmural myocardial infarction, resulting in lower cardiopulmonary efficacy and poorer quality of life. These patients usually having cardiac stents are strictly advised to continue antiplatelet therapy such as aspirin to prevent any thrombotic events and allow re-endothelialization , 2.However, continuation or stop aspirin before elective surgery has long been in dispute. Perioperative withdraw antiplatelet therapy increases the incidence rate of thromboembolic in patients with left ventricular aneurysm. Continued use of aspirin therapy results in a higher risk of surgical bleeding . In thisA 67-year-old male has a history of old myocardial infarction, cardiac stents, apical LVA for almost 8 years and newly was diagnosed rectal cancer needing surgery. The patient was posted for non-cardiac surgery (Hartmann’s procedure) and stopped aspirin 100 mg QD) for 10 days to reduce the risk of bleeding. The preoperative cardiac troponin-l level stabilized at 0.07–0.078 ng/mL. Electrocardiogram (ECG) showed “persistent” Q-waves and elevated ST-segment with relevant inverted T waves in leads V2–V5, suggesting a remote healed anterior wall myocardial infarction (Fig. 00 mg QD Additional file 1. Video of 3-dimensional TEE showing the left ventricular mural thrombus.Wall motion abnormalities, particularly LVA after myocardial infarction, lead to blood pooling and thrombus secondary formation, put the patient at greater risk for systemic embolization and cardioembolic stroke . In thisFirst possibility, LVMT may have been in the left ventricular all along only because the preoperative TTE failed to identify its presence. As is known to all, echocardiography is one of the most widely diagnostic tests in current era because of lower cost, safer and without traumatic effect. In 2006, Srichai MB et al.  reportedThe troponin-l was stabilized and no new myocardial infarction occurred. It is greatly possible that the mural thrombus is fresh which formed during the period of stopping aspirin. The usage of aspirin as antiplatelet and antithrombotic agent has been for several decades. However, stop or continuation aspirin before elective surgery has long been in debate. The surgeon analyzed the risk of hemorrhage before the open abdominal surgery for the patient and then ordered an aspirin treatment temporary stop for 10 days. Coexistence of wall motion abnormalities, preoperative aspirin discontinuation and without bridging with perioperative low-molecular-weight heparin, physical activity reduction and prolonged fasting are associated with an increased risk of blood hypercoagulability and thrombosis.Current guidelines recommend that vitamin K antagonist is the first choice of treatment for cardiac thrombus . There hPreoperative LAV/LVMT risk assessment is a vital step in reducing perioperative cardiac complications and mortality in patients undergoing non-cardiac surgery, which was operated by surgeons, cardiologists and anesthesiologists. We need to evaluate the pros and cons of preoperative withdrawal of aspirin in patients with cardiovascular disease undergoing non-cardiac surgery. Once patients stop taking antiplatelet agent, it might increase the risk of thrombus and should closely monitor the patient during this period. Furthermore, bridging with perioperative low-molecular-weight heparin is advisable.The first TTE examination is 2 weeks before surgery and no TTE re-examination was applied during cessation of aspirin. We failed to detect thrombosis in time.


Myocardial fibrosis is observed in multiple cardiac conditions including hypertension and aortic stenosis. Excessive fibrosis is associated with adverse clinical outcomes, but longitudinal human data regarding changes in left ventricular remodelling and fibrosis over time are sparse because of the slow progression, thereby making longitudinal studies challenging. The purpose of this study was to establish and characterize a mouse model to study the development and regression of left ventricular hypertrophy and myocardial fibrosis in response to increased blood pressure and to understand how these processes reverse remodel following normalisation of blood pressure.n = 31) subjected to angiotensin II-induced hypertension for 6 weeks and investigated reverse remodelling following normalisation of afterload beyond 6 weeks (n = 9). Left ventricular (LV) volumes, mass, and function as well as myocardial fibrosis were measured using cine CMR and the extracellular volume fraction (ECV) s.We performed a longitudinal study with serial cardiovascular magnetic resonance (CMR) imaging every 2 weeks in mice (p < 0.001) resulted in higher indices of LV hypertrophy  and myocardial fibrosis  whilst LV ejection fraction fell . We found a strong correlation between ECV and histological myocardial fibrosis .Increased blood pressure , LV mass , ECV (0.30 ± 0.02 vs 0.27 ± 0.02) and LVEF  improved but remained impaired compared to baseline . There was a strong inverse correlation between LVEF and %ECV during both systemic hypertension  and the increases in ECV observed in the first two weeks of increased blood pressure predicted the reduction in LVEF after 6 weeks .Following cessation of angiotensin II and normalisation of blood pressure (69 ± 5 vs baseline 65 ± 12 mmHg; We have established and characterized angiotensin II infusion and repeated CMR imaging as a model of LV hypertrophy and reverse remodelling in response to systemic hypertension. Changes in myocardial fibrosis and alterations in cardiac function are only partially reversible following relief of hypertension. Pressure overload heart disease with concomitant myocardial fibrosis is observed in multiple common cardiac conditions including hypertension and aortic stenosis –8. WhileRodent models of pressure overload cardiomyopathy have been developed and potentially allow monitoring of disease progression, from the onset of pressure overload out to the advanced stages of heart failure –16. ThesThe purpose of this study was to develop and characterize a mouse model of reversible hypertension induced cardiomyopathy and to use state-of-the-art in vivo imaging to interrogate LV hypertrophy, myocardial fibrosis, and cardiac function both before and after afterload reversal. Ultimately, our aim was to create a model that might help develop novel non-invasive biomarkers of LV decompensation in response to pressure overload and provide insight in to the time-course of clinically relevant conditions.n = 9) of the animals receiving a 6-week infusion were assessed for an additional 28 days after discontinuation of the infusion to allow investigation of reverse remodelling. Baseline measurements were taken at the start of the study, and before any intervention so that each animal could serve as its own control and intra-subject analysis could be performed. A control cohort of animals  received a placebo infusion of saline (0.9% NaCl) (n = 9) and was included to study and correct for any age- and procedure-related effects not attributable to angiotensin II. Throughout the experiments, animals were on a regular chow diet, housed 5 mice per cage in a 12 h:12 h light/dark cycle in animal facilities at the University of Edinburgh.Thirty-one 14 ± 2 weeks, male C57BL/6 J mice  were subjected to a continuous angiotensin II infusion at 480 ± 34 ng/kg/min for up to 6 weeks  were used . MinipumAll animals underwent serial cardiovascular magnetic resonance (CMR) imaging to assess LV structure and function as well as myocardial fibrosis. CMR was performed initially at baseline, before the onset of hypertension (so that progression of adverse remodelling could be compared to baseline), and then every 2 weeks during angiotensin II infusion. In the reverse remodelling subgroup, a final CMR scan was performed 4 weeks after the angiotensin II infusion had been discontinued. At the end of the final imaging session, animals were sacrificed by exsanguination under deep anaesthesia with the heart stored for further histological analysis.2/0.5 L/min air for maintenance). Prior to imaging, an Anicath 26G cannula  was placed intraperitoneally for administration of the gadolinium-based contrast agent . Animals were placed in a CMR cradle with electrocardiogram (ECG) leads placed subcutaneously. The animals were positioned supine with hearts in the centre of the coil, and in the centre of the CMR scanner. A pressure transducer was placed under the torso for constant monitoring of respiration , and a rectal probe was inserted to monitor and maintain body temperature at 37 ± 0.5 °C via a feedback-controlled warm air system . Throughout the imaging session we adjusted the warm air system to maintain target body temperature and as a result a stable heart rate at 530–600 beats/min and a respiratory rate of 45–75 breaths/min.All CMR scans were performed on a 7 T preclinical horizontal-bore CMR system  equipped with a 33-mm inner diameter quadrature radiofrequency coil for mice . Animals were anaesthetised using isoflurane . We acquired eight phase-encoding echos per segment and 8 signal averages were used to compensate for respiratory motion. After acquisition of a baseline T1 map, gadobenate dimeglimine was injected via the intraperitoneal cannula, and a second T1-mapping dataset was acquired 20 min post-injection. During the time between the T1-mapping acquisitions, cine images were acquired for structural and functional assessment. The short axis, vertical and horizontal long axis cardiac images were acquired using an ECG triggered and respiratory-gated gradient echo sequence  with gradient and radiofrequency spoiling. Eighteen phases were acquired with a field of view of 30 × 30 mm, a 128 × 128 matrix, and 2 signal averages were used. For the LV short axis, nine consecutive 1-mm-thick slices were acquired, which encompassed the entire heart from base to apex. Late gadolinium enhancement (LGE) imaging was performed between 12 and 18 min after contrast administration with a short-axis cardiac-triggered/respiratory-gated T1-weighted gradient echo inversion-recovery scan with the following imaging parameters: TR: 1000 ms (depending on respiration rate), TE: 1.45 ms, field of view: 30 × 30 mm, number of signal averages: 4, inversion time: 560 ms, flip angle: 90°, nine 1-mm thick slices covering the entire left ventricle.Scout images were taken to confirm correct positioning and to orientate 1.0-mm short axis slices covering the heart. T1 mapping for calculation of regional myocardial T1 relaxation times was accomplished using a gradient-echo, cardiac-gated modified Look-Locker inversion recovery sequence (MoLLI) during which 30 images of a single mid-ventricular slice were acquired at unique inversion times  with the recovery time after each slice-selective inversion pulse of about 4.5 s, as described previously , 25. ImaData were analysed using cvi42 software . The short axis cine LV images were used for the assessment of LV volumes, mass and ejection fraction. The epicardial and endocardial contours were carefully identified and planimetered in end-systole and end-diastole for LV volume quantification. The LV mass was calculated from the total myocardial volume (excluding trabeculations and papillary muscles) multiplied by the density of the myocardium (1.05 g/mL). Maximal LV wall thickness was evaluated in all 17 LV segments from cine images of the LV in end-diastole . For LV Histological validation was performed for each CMR technique used to measure myocardial fibrosis. After the final imaging session, animals were euthanized by exsanguination under isoflurane anaesthesia. The heart was removed and transferred into 10% neutral buffered formalin  for fixation for at least 20 h. After fixation, hearts were processed and embedded in paraffin in a short axis orientation so that the cut sections would all show the ventricle lumen. Slides were stained in a 0.1% sirius red solution in saturated picric acid . All picrosirius red stained slides images were acquired on the AxioScan Z1  and analysed using Image-Pro Premiere 9.1  using a tissue specific threshold. One midventricular slice was analysed for each heart to enable correlation with T1 mapping data. The area of fibrosis was expressed as a percentage of the total myocardial area in that section .t-test, paired Student t-test, ANOVA for continuous variables, Wilcoxon rank-sum test for ordinal variables and the χ2 test or Fisher’s exact test for categorical data. The relationship between 2 continuous variables was assessed using the Pearson’s correlation coefficient. A 2-sided p < 0.05 was considered statistically significant.Continuous variables were tested for distribution with the Shapiro-Wilk test. Data are presented as mean ± SD, median [interquartile range] or percentages where appropriate. Differences between groups were assessed with the use of a 2-sided Student p < 0.001) and remained stable for the remainder of the infusion phase . Wall thickness and LV mass were elevated after 2 weeks and increased further up to the 4-week time point  after which both plateaued  was elevated after 2 weeks of angiotensin II infusion compared to baseline . There was a strong correlation between the histological assessment of myocardial fibrosis (% myocardium comprised of fibrosis) and the ECV% as measured by CMR , ECV demonstrated progressive increases. This increase in ECV demonstrated a similar pattern of change as the blood pressure with an initial increase  followed by a plateau phase after 4 weeks (p > 0.40). Consistent with this, LVEF also demonstrated an ongoing gradual reduction with time spent on the angiotensin II infusion   4 weeks following its discontinuation compared to baseline values of 0.24 ± 0.03 (p = 0.06). Importantly, the LVEF again demonstrated a similar pattern to ECV, showing a trend towards recovery  yet remaining lower at 4 weeks than at baseline .Four weeks after the end of the angiotensin II infusion, reversal of the pressure overload state was observed with mean arterial blood pressure values returning to baseline  and the reduced LVEF after 6 weeks  continues for too long then irreversible fibrosis will develop in the LV, leading to long term impairment of systolic function. Further studies should investigate whether reversing pressure overload earlier might potentially lead to complete recovery in LV function and whether the optimal timing can be identified using imaging or other biomarkers. This strategy could ultimately then be applied to patients with aortic stenosis, thereby optimizing the timing of aortic valve replacement.We acknowledge that our study has limitations. While our model recreates the myocardial response to increased afterload observed in patients with hypertension and aortic stenosis, it is not a pure model for either. Moreover, angiotensin II might have triggered diffuse fibrosis irrespective of the elevated blood pressure . For T1-Using state-of-the-art in vivo CMR imaging, we have developed a mouse model of LV hypertrophy and reverse albeit incomplete remodelling in response to systemic hypertension which allows tracking of changes in LV remodelling, myocardial fibrosis and systolic function. In this study, we have demonstrated that myocardial fibrosis appears to be the primary determinant of LV dysfunction both before and after reversal of pressure overload.Additional file 1.


Acute bouts of ultra-endurance exercise may be deleterious for cardiac structure and function as demonstrated by a reduction in diastolic and systolic function concomitant, and elevations in humoral markers of cardiac myocyte damage above acute myocardial infarction cut-off levels – most notably reflected by an elevation in troponin levels. A possible mechanism of biomarker release may be secondary to acute myocardial inflammation. CMR is established as the imaging modality of choice to visualize myocardial inflammation and fibrosis using STIR (short tau inversion recovery) imaging and early/delayed enhancement imaging following intravenous contrast administration. The relationship between ultraendurance exercise, biomarker elevation and CMR imaging for inflammation and fibrosis has not been studied before.We proposed that acute ultra endurance exercise in moderately trained athletes leading to elevation of cardiac troponin is associated with CMR detectable myocardial inflammationWe performed CMR in 18 male athletes of moderate to high fitness levels 24 hrs pre and 6 hours post a marathon run. Each scan was performed by the same operator on a 1.5 T Siemens Avanto scanner using a 4 channel body array coil. Myocardial structure and function was assessed using breathhold SSFP cine imaging in long and short axis views. The presence of myocardial inflammation and oedema was assessed using STIR imaging and a 3–4 minute spin echo sequence immediately post 0.1 mmol intravenous gadolinium-DTPA  given using an automated injector, to assess relative gadolinium enhancement. Inversion recovery segmented-FLASH imaging with TI adjusted to null normal myocardium to highlight regions of fibrosis was used to image delayed enhancement. Each subject had bloods drawn for TnI, NT-proBNP, and CRP at baseline, immediately post and 6 hours after the run. Each CMR scan was analyzed by a blinded observer for wall thickness per segment, volumes and function, myocardial oedema using customized software . Delayed enhancement images were analysed using Medis software  using a full width half maximum technique.All 18 subjects completed the study protocol and none complained of any cardiovascular symptoms. Biventricular volumes, stroke volume, ejection fraction, and mass were unchanged pre and 6 hrs post marathon. The majority of subjects were found to have a rise in BTproBNP levels immediately and 6 hours after the race as well as elevations in TnI above the level of cut off for myocardial infarction (P = 0.001). There were no focal regions of visual signal increase on the STIR images in any of the 18 subjects. Global myocardial oedema was predefined using a cut off ratio of 1.9 comparing SI of myocardium to skeletal muscle on STIR imaging, and a relative 45% increase in the SI myocardium/skeletal muscle immediately post intravenous gadolinium on relative gadolinium enhancement imaging (rGE). No subject reached these cut off values. None had any visual myocardial fibrosis on late enhancement imaging or using automated software .Serum markers of myocardial cell damage post ultra endurance exercise are not associated with CMR detectable levels of myocardial oedema, inflammation or scarring. These findings suggest lower degrees of myocardial damage than that normally sustained in patients with acute myocardial infarction or myocarditis, inspite of similar levels of troponin elevation.


In recent decades, investigators have strived to describe and quantify the orientation of the cardiac myocytes in an attempt to classify their arrangement in healthy and diseased hearts. There are, however, striking differences between the investigations from both a technical and methodological standpoint, thus limiting their comparability and impeding the drawing of appropriate physiological conclusions from the structural assessments. This review aims to elucidate these differences, and to propose guidance to establish methodological consensus in the field. The review outlines the theory behind myocyte orientation analysis, and importantly has identified pronounced differences in the definitions of otherwise widely accepted concepts of myocytic orientation. Based on the findings, recommendations are made for the future design of studies in the field of myocardial morphology. It is emphasised that projection of myocyte orientations, before quantification of their angulation, introduces considerable bias, and that angles should be assessed relative to the epicardial curvature. The transmural orientation of the cardiomyocytes should also not be neglected, as it is an important determinant of cardiac function. Finally, there is considerable disagreement in the literature as to how the orientation of myocardial aggregates should be assessed, but to do so in a mathematically meaningful way, the normal vector of the aggregate plane should be utilised.  Myocardial architecture and cardiac function are closely linked ,4,5,6,7.Since the beginning of the 1990s, diffusion tensor magnetic resonance imaging has been extensively used in the experimental setting to characterise myocardial architecture in both autopsied  and beat1), secondary (e2), and tertiary (e3). A complete mathematical description of a tensor is beyond the scope of this paper, but the interested reader is advised to consult specific literature dedicated to this matter [In general, a tensor is described using its three orthogonal axes. These are called eigenvectors, which are designated as being primary , then provides the global geometric coordinate system for defining the position of the heart (ax), a second local coordinate system should be introduced, which can be positioned relative to the individual region of interest in the heart (l), circumferential (ec), and radial (er). The circumferential vector is orthogonal to the left ventricular long axis, and tangential to the epicardium. The longitudinal vector is orthogonal to the circumferential vector, and again tangential to the epicardium. The radial vector is orthogonal to both the longitudinal and circumferential vectors. It is also normal to the epicardium, or more accurately normal to the epicardial tangential plane [l and ec), while the circumferential and radial vectors (ec and er) define the local horizontal plane (C). The radial and the longitudinal vectors (er and el) define the local sagittal plane (B). In order to describe the orientation of the chains of cardiomyocytes, it is agreed that unique points of reference are needed. There is general agreement in the published literature that, in the first instance, the global orientation of the heart itself should be described using the left ventricular long axis. This is usually achieved by placing a line between the apex and the fibrous continuity between the leaflets of the aortic and mitral valves ,45,46,47he heart A. In somhe heart , as thishe heart B. On thial plane  . When viewed from the east, however, the tower is obviously leaning (B). The straight appearance of the tower in panel A is an artefact brought upon by the projection of the tower into the camera lens. It would be inappropriate to use two-dimensional photography in an attempt to quantify the inclination of the tower. All projected angles in the setting of myocardial morphology are subject to projection artefact. ©2018 Google, Data SIO, NOAA, U.S. Navy, NGA, GEBCO, Landsat/Copernicus.This review points towards several controversies in the field of myocardial architecture. Data obtained by high-resolution imaging can be analysed, displayed, and mathematically modified in myriads of ways. We can learn much that is novel from studies of myocardial micro-architecture, but currently there is little consensus in the literature as to how myocyte orientation is defined and quantified. For as long as disagreements prevail, we will remain unable to compare studies and draw valid anatomical, physiological, and clinical conclusions. Based on this review we suggest the following points be considered in future studies of myocardial architecture. Firstly, as myocardial thickening occurs perpendicular to the epicardium, its curvature should be taken into account when assessing myocyte orientations. Second, there is no need to project myocyte orientations prior to quantification. In fact, projection introduces considerable bias. Third, the transmural component of myocyte orientation should be assessed, as it is a major determinant of cardiac function. Fourth and last, the normal vector of the myocardial aggregates should be used when quantifying aggregate orientation.


N = 4) and (b) sham surgery . Tagged and steady‐state free precision cardiac MRI was performed on each mouse at 1, 4, and 7 weeks after surgery. At/week7, the mice were euthanized following right/left heart catheterization with RV/LV tissue harvested for histology and gene expression (using RT‐PCR) studies. Compared to Sham mice, the PAB group revealed a significantly decreased LV and RV ejection fraction, and LV maximum torsion and torsion rate, within the first week after banding. In the PAB group, there was also a slight but significant increase in LV perivascular fibrosis, which suggests elevated myocardial stress. LV fibrosis was also accompanied with changes in gene expression in the hypertensive group, which was correlated with LV contractile mechanics. In fact, principal component (PC) analysis of LV gene expression effectively separated Sham and PAB mice along PC2. Changes in LV contractile mechanics were also significantly correlated with unfavorable changes in RV contractile mechanics, but a direct causal relationship was not established. In conclusion, a purely biomechanical insult of RV pressure overload resulted in biomechanical and transcriptional changes in both the RV and LV. Given that the RV relies on the LV for contractile energy assistance, considering the LV could provide prognostic and therapeutic targets for treating RV failure in PH.Pulmonary hypertension (PH) results in right ventricular (RV) pressure overload and eventual failure. Current research efforts have focused on the RV while overlooking the left ventricle (LV), which is responsible for mechanically assisting the RV during contraction. The objective of this study is to evaluate the biomechanical and gene expression changes occurring in the LV due to RV pressure overload in a mouse model. Nine male mice were divided into two groups: (a) pulmonary arterial banding  failure is a common endpoint in pulmonary hypertension. While most clinical and research efforts are focused on the RV, our research shows that the left ventricle undergoes bio‐mechanical and gene‐expression changes in response to RV pressure overload. To this end, the overall objective of this work is to characterize LV biomechanical and biochemical changes that occur in response to biomechanically induced RV pressure overload.22.1Guide for Care and Use of Laboratory Animals) and approved by the local Administrative Panel on Laboratory Animal Care .All animal related experiments were carried out according to the guidelines outlined by the National Research Council , and stained by Masson's trichrome stain as described in  at 3 time points: 1‐week after PAB; 3‐weeks after PAB; and 7‐weeks after PAB just before terminal catheterization. LV torsion rate was measured from tagged MR images using a post‐processing protocol described previously in , and (4) stroke work (W). EF was measured by semi‐automatic segmentation of the ventricular cavity at end‐systole and end‐diastole by MRI. Finally, W ‐a measure of the stroke work required to displace the blood volume of a single heart beat ‐ was measured as the area bounded by the pressure‐volume loop  maximum LV torsion during systole; (2) LV torsion rate; (3) LV and RV ejection fraction  used to generate that plot. The authors declare that a mouse was never excluded from a specific analysis to adjust results, but only due to data availability.t‐test. All other pairwise comparisons were made using the nonparametric two‐sided Wilcox rank sum test. For datasets with a lot of zeros , the proportions of non‐zeros within the two groups was assessed using the Chai‐square test (p < .05 considered significant).All statistical analysis, waveform signal processing, and calculation presented in this manuscript was coded using Matlab (Mathwors). Means within a longitudinal test were compared using a paired 2), with occasional logarithmic transformation to correct for skewed distributions.The relationship between variables (e.g. gene expression vs. ventricular torsion rate) was evaluated using coefficient of determination . The waveform was reconstructed using Fourier Series with 3 harmonics.P) and volume waveforms were synchronized at end‐diastole. While all MRI images begin at end‐diastole, in the pressure waveform, this point was identified as the second peak of ∂2P/∂t2.To construct pressure‐volume curves, the pressure (33.1p2‐tailed < .05). However, all 4 PAB mice revealed some nonzero level of fibrosis in the LV as well. In contrast, only 1 out of the 5 Sham mice had 0.23% fibrosis in the LV, which is below 1 standard deviation of the fibrosis amount in the PAB sample . Qualitatively analyzing example histology with collagen staining in a single Sham  and β‐MHC  in PAB animals, relative to Sham. Performing PCA  on all 5 measured genes  clustered PAB and Sham animals within the plane of the first two principal components  and torsion rate (p2‐tailed < .05) at 1‐week after surgery, relative to controls, without significant changes in either metric for the duration of the experiment. Unlike in the RV, LV stroke work was reduced by half after PAB . In fact, as opposed to Sham animals where LV work is 9 times greater than RV work, the stroke work is roughly equal in the two ventricles after PAB. Furthermore, the weight of the LV and septum, relative to the total body weight of the animal, is also significantly decreased after PAB . This plot combines all temporal measurements of PAB and Sham animals. Therefore, since the study protocol performed MRI measurements in 4 PAB animals and 5 Sham animals, at 3 time points, there are a total of 12 red dots  and 15 black dots . Similar associations were found between maximum LV torsion rate and RV ejection fraction .Figure 3.4We measured LV tissue expression of 4 miRNA candidates  that were chosen based on previous data and a literature review, ATP2A2 gene to evaluate calcium dynamics, and two mRNAs coding for contractile proteins . Gene expression in the LV was compared between PAB and Sham mice, and ‐within the PAB cohort‐ correlated with LV contractile mechanics (maximum LV torsion and LV torsion rate).−ΔΔCt = 2.41 ± 0.88 in Sham vs. 4.51 ± 0.56 in PAB, p2‐tailed < .05) . Also, the ATP2A2 gene – measured in 3 PAB and 4 Sham mice‐ was significantly downregulated in the LV of PAB mice (p2‐tailed < .05), relative to the sham cohort  was used for dimensionality reduction  of all biochemical analysis performed for the LV with the same available sample size. This included miR‐130, miR‐93, let‐7b, α‐MHC, and β‐MHC. Figure R2 = 1.00, p2‐tailed < .05) and let‐7b  in the PAB cohort /d(time) occurs simultaneously in normal sinus rhythm . This is consistent with multiple studies that showed cardiac growth and remodeling in the RV occurs within the first week of the initial insult  mRNA expression because they were known to be miss‐regulated in the RV after PAB ‐encoding mRNA, which controls multiple aspects of cardiac muscle contractility and energy management through CaDownregulation of SERCA2a in both the RV and pulmonary circulation is a well‐documented phenotype of PAH, and forced over‐expression decreases vascular proliferation, RV hypertrophy, and RV fibrosis to normal levels . However, all relationships presented revealed statistical significance.The expression of genes explored within the LV was limited. Financial constraints prevented us from performing microarray analysis, but the current results offer justification for additional gene expression studies in the LV.The results presented in this study are limited to correlation, without addressing causality. Future studies will be prospectively designed to draw causal inference Pearl,  between 5The clinical and translational significance of this study is the observation that purely biomechanical insults within the RV induced significant changes in LV mechanics, gene expression, and contractile protein expression. We found that LV ejection fraction, stroke work, and torsion rate were all significantly decreased at 7‐weeks after induced RV pressure overload by pulmonary arterial banding. Furthermore, we found changes within the LV in gene expression, calcium handling, and contractile protein expression, which were highly correlated to a decrease in maximum LV torsion and torsion rate.These changes within the LV are currently overlooked in patients with RV pressure overload, but they could serve as important prognostic markers of RV function and outcome. Furthermore, given that the RV heavily relies on mechanical energy transfer from the LV, these findings could be used as a therapeutic target for mitigating or even reversing RV functional decline in PH.This work was supported by the National Institutes of Health: NIH K25 HL133481 and the Jayden DeLuca Foundation. MB was supported by a Max Kade Foundation postdoctoral fellowship. ES received support by NHLBI R01 HL128734, Department of Defense PR161256, Wall Center for Pulmonary Vascular Disease Stanford. DI has received research support from Actelion Pharmaceuticals Ltd, Eli Lilly & Co, and United Therapeutics; the University of Colorado contracts with Actelion Pharmaceuticals Ltd, Bayer HealthCare, Eli Lilly & Co, and United Therapeutics for DD Ivy to be a consultant. DD Ivy receives grant funding from the National Institutes of Health and the Food and Drug Administration.