Cardiac involvement in sarcoidosis patients is associated with an increased risk of sudden death. However, conduction block and cardiomyopathy are late and therefore potentially insensitive markers of cardiac sarcoidosis. Prior publications have suggested that the detection of late gadolinium enhancement (LGE) by cardiac magnetic resonance (CMR) may be a more sensitive parameter for diagnosing cardiac sarcoidosis. Using CMR, in patients with known sarcoidosis, we sought 1) to further define the incidence of cardiac involvement and 2) to determine the correlation between LGE and structural cardiac pathology.We retrospectively evaluated 55 consecutive patients with known sarcoidosis who were referred for CMR. Imaging was performed on a 1.5 Tesla MRI scanner with a flexible surface coil. Retrospectively gated cines of the left ventricular (LV) 2-, 3-, and 4-chambers, and a short-axis stack were obtained using steady state free precession imaging . LGE images of the same views were obtained 10–20 minutes after infusion of Gd-DTPA (0.15–0.2 mmol/kg) using a T1-weighted inversion recovery GRE pulse sequence . The cines of the short-axis stack were used to determine LV and right ventricular end-diastolic volume (LVEDV and RVEDV), end-systolic volume (LVESV and RVESV), ejection fraction (LVEF and RVEF), and LV mass. The presence or absence of LGE was determined for each of the 17 segments of the American Heart Association left ventricular model. Continuous variables were reported as mean ± standard deviation, groups (based on the presence or absence of LGE) were compared using a t-test, and linear regression analysis was used to investigate the correlation between LGE and LV size and function. A p value < 0.05 was considered statistically significant.2 = 0.14, p = 0.29) and LV mass . However, there was a trend that the extent of LGE correlated with both LVESV  and LVEF  (See figure The patients were 48 ± 13 years old and the majority were women (73%). Twenty-two percent of the patients had LGE involving on average 14 ± 12% of the LV. In patients with or without LGE, there was no difference in LVEDV , LVESV , LVEF , LV mass , RVEDV , RVESV  and RVEF . See figure In patients with known sarcoidosis, nearly a quarter had evidence of cardiac involvement, as defined by the presence of LGE, despite the lack of any difference in traditional measures of cardiac structure and function. These preliminary findings suggest that volumetric and functional assessments alone are inadequate for the detection of cardiac sarcoidosis and that tissue characterization using LGE is essential. Further studies are needed to determine the long-term prognostic value of LGE and to further clarify the relationship between the extent of LGE and left ventricular morphology and physiology in patients with cardiac sarcoidosis.


Distinguishing parotid pleomorphic adenoma (PPA) from parotid adenolymphoma (PA) is important for precision treatment, but there is a lack of readily available diagnostic methods. In this study, we aimed to explore the diagnostic value of radiomic signatures based on magnetic resonance imaging (MRI) for PPA and PA.The clinical characteristic and imaging data were retrospectively collected from 252 cases  in this study. Radiomic features were extracted from MRI scans, including T1-weighted imaging (T1WI) sequences and T2-weighted imaging (T2WI) sequences. The radiomic features from three sequences  were selected using univariate analysis, LASSO correlation and Spearman correlation. Then, we built six quantitative radiomic models using the selected features through two machine learning methods . The performances of the six radiomic models were assessed and the diagnostic efficacies of the ideal T1-2WI radiomic model and the clinical model were compared.p > 0.05). The area under the curve (AUC) of the T1-2WI radiomic model was significantly better than that of the clinical model for both the training  and validation  cohorts.The T1-2WI radiomic model using MLR showed optimal discriminatory ability  and its calibration was observed to be good (The T1-2WI radiomic model in our study is complementary to the current knowledge of differential diagnosis for PPA and PA.The online version contains supplementary material available at 10.1186/s12880-021-00581-9. The morbidity of salivary gland tumours has progressively increased year by year, and nearly 80% of cases occur in the parotid gland . The twoUltrasonography (US)-guided fine needle aspiration cytology (FNAC) serves as the primary approach to diagnose parotid tumours. However, FNAC is invasive and potentially causes Li-na Song tumour implantation along the needle route. Additionally, the diagnostic accuracy of FNAC is unreliable Li-na Song because interpretation of this approach requires adequate sampling and experienced cytopathologists . In contRadiomics based on artificial intelligence (AI) integrates radiology, oncology, and machine learning algorithms , 10. As We hypothesized that a radiomics model established using a set of quantified features captured by MRI may act as a precise and non-invasive diagnosis method for PPA and PA. Thus, we delineated the region of interest (ROI) in PPA and PA patients who underwent MRI scanning. Furthermore, we constructed radiomics models based on the selected radiomics features from both T1-weighted imaging (T1WI) sequences and T2-weighted imaging (T2WI) sequences from MRI. Additionally, we compared the diagnostic efficacy of the radiomics model with that of the clinical feature model.This study was approved by the Ethics Review Committee of the First Affiliated Hospital of Henan University of Science and Technology, and all procedures were performed in accordance with the principles of the Helsinki Declaration. We retrospectively Li-na Song enrolled 412 patients with parotid tumours undergoing MRI examination at the First Affiliated Hospital of Henan University of Science and Technology between 2013 and 2019. The following inclusion criteria were used: (1) patients received no treatment before the examination; (2) the T1WI and T2WI sequences of the MRI scans were complete and available; (3) the images were clear and without artefacts; (4) a definite pathological diagnosis by surgery and pathology was provided for the patients. Finally, data from 112 PA patients and 140 PPA patients were collected in this study.The clinical features of the 252 subjects are listed in Table Li-na Song 1. Among the PA patients, the average age Li-na Song was 55.57 ± 1.29 years (range: 23–77 years) and the Li-na Song gender Li-na Song ratio (M:F) was 1.38:1. Among the PPA patients, the average age Li-na Song was 47.81 ± 1.473 years (range: 15–81 years) and the Li-na Song gender Li-na Song ratio (M:F) was 0.67:1. All 252 subjects were randomly allocated to the training cohorts and validation cohorts at a ratio of 7:3, according to previous published reports , 26. TheAll subjects underwent routine 1.5 T MRI scanning  with a head-neck coil. The scanning sequence was acquired including the fast spin echo T1WI and the fast spin echo T2WI with fat saturation. The parameters of T1WI were: TR of 700.0 ms, TE of 8.9 ms, matrix size of 320 × 192 mm, FSE of 24 cm × 24 cm, slice thickness of 5 mm, spacing of 1 mm. The parameters of the T2WI sequence were: TR of 3900.0 ms, TE of 100.0 ms, matrix size of 320 × 256, FSE of 24 cm × 24 cm, slice thickness of 5 mm, slice spacing of 1 mm in Li-na Song the axial images; TR of 3300.0 ms, TE of 100.0 ms, matrix size of 320 × 224, FSE 24 cm × 24 cm, slice thickness of 5 mm, slice spacing of 1 mm in coronal Li-na Song images.http://bit.ly/IBEX_MD Anderson). The extracted features included the intensity histogram, grey co-occurrence matrix (GLCM), grey run length matrix (GLRLM) and shape . Two board-certified senior radiologists  independently interpreted the MRI images (including the T1WI and T2WI sequence scans) in the PACS of the Radiology Department  were combined as the T1-2WI features. All of the retained T1WI, T2WI and T1-2WI features were processed by dimensionality reduction using the LASSO method to improve the accuracy and degree of modelling fit .Ta.Tap < 0.Traditionally pathological and imaging methods largely depend on some subjective factors or the specific knowledge and experience of the clinical operators, so their current diagnostic accuracy for parotid gland tumours is limited. Comparatively, radiomics are based on an increasing amount of imaging data and the rapid development of AI techniques, and they show advantages of objectivity, quantification and repeatability as clinical diagnostic methods . Our stuThe quantitative T1-2WI radiomics model performed better in distinguishing PPA and PA in a non-invasive way , compared with FNAC or MRI, both of which showed high specificity (range 0.85–0.97) but unstable sensitivity (range 0.70–0.86) , 24. MorThe application of MRI features improved the performance of our radiomics model. Compared with US, MRI reveals the interface of a tumour and surrounding tissues better and is superior for investigating the large tumours (more than 4 cm) or tumours in deep structures. Compared with CT, MRI can eliminate dental artefacts and is recommended specifically to distinguish tumours from obstructing secretions [In addition, the optimization for feature selection and modelling also improved the performance of our radiomics model. We extracted features from two sequences of MRI scans (T1WI and T2WI), and used three steps for feature selection  and constructed six radiomics models based on two machine learning methods. The tenfold cross-validation was used to avoid the risk of modelling deviation and over-fitting as much as possible . HoweverStudies have reported that PPA is more common in young adults, while PA is more common in elderly men with a history of smoking . In our Our research also had some limitations. First, we did not carry out multicentre case research. Second, we did not combine the radiological features with tumour molecular markers or genomic information , 30. TheIn summary, the proposed T1-2WI model in our study showed greater ability to classify PPA and PA than traditional pathological and physical diagnostic methods or a quantitative model based on clinical features. Our study further supports the concept that a radiomics model can objectively and quantitatively provide information about intra-tumour heterogeneity and the inter-tumour microenvironment hidden within the image , 32.Additional file 1: Fig. 1. (a-b) ROC curves showing the comparison of the combined model based on the TW1-2 sequence and the clinical features for the training cohort (a) and the validation cohort (b).


After multivariable adjustment, and compared to stage 1, stages 3 and 4 were independently associated with mortality risk . A RVD staging system, integrating TAPSE/PASP and TR, provides a comprehensive and widely available tool for risk stratification in HFpEF.Right ventricular dysfunction (RVD) parameters are increasingly important features in heart failure with preserved ejection fraction (HFpEF). We sought to evaluate the prognostic impact of a progressive RVD staging system by combining the tricuspid annular plane systolic excursion (TAPSE) to pulmonary artery systolic pressure (TAPSE/PASP) ratio with functional tricuspid regurgitation (TR) severity. We prospectively included 1355 consecutive HFpEF patients discharged for acute heart failure (HF). Of them, in 471 (34.7%) patients, PASP could not be accurately measured, leaving the final sample size to be 884 patients. Patients were categorized as Stage 1: TAPSE/PASP ≥ 0.36 without significant TR; stage 2: TAPSE/PASP ≥ 0.36 with significant TR; stage 3: TAPSE/PASP < 0.36 without significant TR; and stage 4: TAPSE/PASP < 0.36 with significant TR. By the 1 year follow-up, 207 (23.4%) patients had died. We found a significant and graded association between RVD stages and mortality rates (15.8%, 25%, 31.2%, and 45.4% from stage 1 to stage 4, respectively; log-rank test,  Heart failure with preserved ejection fraction (HFpEF) is becoming the dominant form of heart failure (HF). No evidence-based treatments are available and the morbimortality burden remains high ,2. WhileBeyond other potentially involved mechanisms, the development of RV dysfunction is mainly related to elevated pulmonary pressures ,4. In HFWe prospectively included a consecutive observational cohort of 1355 HFpEF patients who were discharged alive after a hospitalization for acute HF in the cardiology department of a tertiary-care teaching hospital in Valencia (Spain). During index hospitalization, a comprehensive set of demographics, medical history, vital signs, 12-lead electrocardiogram, standard laboratory (72 ± 12 hours after admission), echocardiographic parameters, and treatments at discharge were routinely recorded using pre-established registry questionnaires. Most of the patients exhibited on admission acute decompensated HF (82.7%), followed by acute pulmonary edema (12.6%). Patients were enrolled from 1 January 2007 to 1 August 2016. Patients with new-onset or acutely decompensated HF were enrolled in the registry. HFpEF was defined according to the European Society of Cardiology Clinical Practice Guidelines [In all patients, a 2-dimensional transthoracic echocardiogram was performed during index hospitalization (96 ± 24 hours after admission) using the left lateral decubitus position. Three commercially available systems were used throughout the study: Agilent Sonos 5500, iE33, and EPIQ 7 . Patients were clinically stable and free from intravenous therapies by the time of the examination. All images were recorded with the second harmonic at the time of end-expiration. Left ventricular ejection fraction was assessed by the biplane Simpson method. Left ventricular diastolic dysfunction was evaluated using transmitral flow Doppler velocities and tissue Doppler imaging-derived mitral annulus velocities. PASP was estimated by measuring the maximum continuous Doppler-derived velocity of the TR jet, following established recommendations . Right aThe primary endpoint of the study was 1-year all-cause mortality. The survival status was ascertained by reviewing the electronic medical records, corroborated by an investigator who was blinded to the RVD staging system. Death due to cardiovascular (CV) causes and death due to HF were evaluated as secondary outcomes. CV death included sudden death, death due to HF progression, myocardial infarction, stroke, arrhythmia, or thromboembolic disease. Unknown deaths were also considered as CV deaths.The observational registry was prospectively designed, conformed to the principles outlined in the 1975 Declaration of Helsinki, and approved by the institutional local review ethical committee. All patients gave informed consent.p values for trend tests for categorical or continuous variables, respectively. The association between the RVD staging system and 1-year all-cause mortality was evaluated using multivariable Cox proportional hazard models, and the results were expressed as hazard ratios (HR) with 95% confidence intervals (CI). Candidate covariates were initially chosen based on previous medical knowledge; then, a backward stepwise selection was performed. The linearity assumption for all continuous variables was simultaneously tested and the variable transformed, if appropriate, with fractional polynomials. The proportionality assumption for the hazard function over time was tested by means of the Schoenfeld residuals. Final multivariate analysis included all the following covariates assessed during index admission: age, gender, systolic blood pressure at admission, heart rate at admission, Charlson comorbidity index, bundle branch block, left atrial size, blood urea nitrogen, and plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP). The detailed multivariate model including all the covariates and their estimates is presented in the Continuous variables were expressed as mean ± standard deviation (SD) or median (interquartile range (IQR)), as appropriate. Discrete variables were summarized as percentages. Baseline characteristics were compared among categories with Pearson’s chi-square and p value of <0.05 was considered to be statistically significant for all analyses. All statistical analyses were performed using STATA 14.1 .A 2-sided Baseline clinical characteristics for the overall study cohort  are listed in p < 0.001)). Kaplan–Meier curves show how trajectories of survival across RVD stages separated early and differences continued increasing along the entire follow-up  patients had died. We found a stepped increase in mortality rates when moving from lower to higher RVD stages . After multivariable adjustment, and compared to stage 1, stage 3 (TAPSE/PASP < 0.36 without significant TR), and particularly stage 4 (TAPSE/PASP < 0.36 with significant TR) were independently and strongly associated with mortality risk . When forcing the inclusion of this category in the staging system, results did not substantially change, and patients with both RV–PA uncoupling and significant TR (stage 4) showed the highest mortality risk , as is shown in At the 1 year follow-up, 157 (17.7%) patients had died from a CV etiology , and 91 of those (6.7%) were HF-related deaths . There was a stepwise increase in CV-mortality rates per increasing RVD stages . Similarly, patients in the most advanced RVD stages also showed the highest rate of HF-related death . Cumulative incidence curves showed a marked, progressive, and significant separation of curves along the first months of follow-up for both endpoints, especially for patients in stage 4 , and stage 4 (TAPSE/PASP 0.36 with significant TR) remained significantly associated with the endpoint when compared to stage 1 . For HF-In this cohort of patients with HFpEF with a recent hospitalization for acute HF, a simple and comprehensive RVD echo-derived staging system, integrating TAPSE/PASP and functional TR, provided useful information for 1-year risk stratification. This RVD score showed a positive and graded association with mortality. Of note, about half of the patients in stage 4 (RV–PA uncoupling and significant TR) died during the first year after discharge, and after a thorough adjustment including well-established prognosticators and potential confounders, patients at higher stages exhibited an increased risk of all-cause, CV, and HF-related death. As far as we know, this is the first study to evaluate the additive prognostic value of RV–PA coupling and TR in HFpEF.Left heart dysfunction has been traditionally considered the landmark of HFpEF, but this paradigm has changed over the years ,3,4,5. CSeveral right heart parameters have been evaluated in recent years in patients with HFpEF . HoweverMany years ago, Guazzi et al. proposed a noninvasive global marker of RVperformance and RV–PA coupling, namely the TAPSE/PASP ratio . This isIn line with our proposed staging system, Bax et al. recently proposed a new staging system for evaluating patients with ischemic heart failure . In thisLeft atrial enlargement is an independent risk factor for mortality in our study, beyond RVD features. Left atrial cardiomyopathy is a key mechanism in the pathophysiology and clinical expression of HFpEF . HoweverIn summary, for a global assessment of the RVD severity in HFpEF, it seems mandatory to evaluate the competency of the tricuspid valve, which should no longer be considered as an epiphenomenon. A simple and widely available staging system, including TAPSE/PASP and TR severity, was significantly and strongly associated to 1-year mortality risk. These data support the clinical use of both parameters in combination for risk stratification in HFpEF, and suggest considering right heart features, such as TAPSE/PASP and TR, as potential therapeutic targets in this complex syndromeFirst, this is a single-center observational study in which hidden bias might be operating. Second, echocardiographic studies were not reviewed by an independent core laboratory external to the sonographers. Third, TAPSE has caveats as an index of RV systolic function . NonetheAn RVD staging system, integrating the TAPSE/PASP ratio and functional TR severity, is independently related to a reduced survival in patients with HFpEF. Patients with RV-PA uncoupling and significant TR are a very high risk subgroup. Further studies should confirm these findings and consider RVD stage severity for risk stratification, monitoring, and tailoring treatments in this complex syndrome.


Introduction: Seismocardiography (SCG) records cardiac and blood-induced motions transmitted to the chest surface as vibratory phenomena. Evidences demonstrate that acute myocardial ischemia (AMI) profoundly affects the SCG signals. Multidimensional SCG records cardiac vibrations in linear and rotational dimensions, and scalar parameters of kinetic energy can be computed. We speculate that AMI and revascularization profoundly modify cardiac kinetic energy as recorded by SCG.Methods: Under general anesthesia, 21 swine underwent 90 min of myocardial ischemia induced by percutaneous sub-occlusion of the proximal left anterior descending (LAD) coronary artery and subsequent revascularization. Invasive hemodynamic parameters were continuously recorded. SCG was recorded during baseline, immediately and 80 min after LAD sub-occlusion, and immediately and 60 min after LAD reperfusion. iK was automatically computed for each cardiac cycle (iKCC) in linear (iKLin) and rotational (iKRot) dimensions. iK was calculated as well during systole and diastole . Echocardiography was performed at baseline and after revascularization, and the left ventricle ejection fraction (LVEF) along with regional left ventricle (LV) wall abnormalities were evaluated.Results: Upon LAD sub-occlusion, 77% of STEMI and 24% of NSTEMI were observed. Compared to baseline, troponins increased from 13.0  ng/dl to 170.5  ng/dl, and LVEF dropped from 65.0 ± 0.0 to 30.6 ± 5.7% at the end of revascularization (both p < 0.0001). Regional LV wall abnormalities were observed as follows: anterior MI, 17.6% (three out of 17); septal MI, 5.8% (one out of 17); antero-septal MI, 47.1% (eight out of 17); and infero-septal MI, 29.4% (five out of 17). In the linear dimension, p < 0.0001, p < 0.0001, and p = 0.03, respectively) from baseline to the end of reperfusion. In the rotational dimension, p = 0.0006 and p < 0.0001, respectively), but p = 0.41). All the hemodynamic parameters, except the pulmonary artery pulse pressure, were significantly correlated with the parameters of iK, except for the diastolic component.Conclusions: In this very context of experimental AMI with acute LV regional dysfunction and no concomitant AMI-related heart valve disease, linear and rotational iK parameters, in particular, systolic ones, provide reliable information on LV contractile dysfunction and its effects on the downstream circulation. Multidimensional SCG may provide information on the cardiac contractile status expressed in terms of iK during AMI and reperfusion. This automatic system may empower health care providers and patients to remotely monitor cardiovascular status in the near future. P/dtmax in animal models  and seismocardiography (SCG) record the micro-vibrations produced rhythmically by velocities and accelerations of blood mass flowing across cardiac chambers and main vessels as a consequence of cardiac mass contraction, with micro-accelerometers and gyroscopes placed on the body surface –3. Therel models , as welll models .As a result, this evidence fuels the curiosity of scientific and medical researchers who actively inquire on the potential of BCG and SCG signals to assess cardiovascular mechanical changes during acute myocardial infarction (AMI) , 7–9. IniK) can be computed from the BCG and SCG waveforms as scalar parameters, both in a linear (iKLin) and in a rotational (iKRot) dimension , has been introduced and, differently from many previous devices which record signals only in one dimension, the KCG records both three-dimensional (3D) linear acceleration and 3D angular velocity signals by means of linear and rotational channels , 11. Usiimension , 12.Three-axes linear micro-accelerometers have already been shown useful in the early detection of experimental AMI , 13, 14.iK computed from the accelerations signals of non-invasive and multidimensional SCG during coronary artery sub-occlusion, (2) to follow these changes during the reperfusion period, and (3) to study the association of linear and rotational iK with invasive hemodynamic parameters. The hypothesis tested is that experimental AMI and reperfusion profoundly alter multi-dimensional SCG signals and its derived scalar parameters.Using an animal model for AMI, the present investigation aims (1) to track modifications of linear and rotational The present study was approved by the Institutional Ethics Committee on Animal Welfare from the Faculty of Medicine of the Université Libre de Bruxelles  (acceptance number: 654N). Animal care and handling were in accordance with the National Institute of Health Guidelines.t0) at 80 minutes of AMI (AMIt80), at the onset of RE (REt0), and at 60 min of RE (REt60). Each record was remotely acquired with a tablet and sent via Bluetooth to the main server for further signal processing. To evaluate the amount of myocardial necrosis, the authors measured the serum troponin levels at the onset of LAD sub-occlusion and after revascularization: the difference between troponins measured 5 h after RE and troponins measured at the onset of LAD sub-occlusion was named Delta (Δ) troponin. Echocardiography was performed at baseline and after revascularization, and the left ventricle ejection fraction (LVEF) along with regional left ventricle (LV) wall abnormalities were evaluated by a trained operator.The procedure consisted in the proximal left anterior descending coronary artery (LAD) sub-occlusion by means of angioplasty semi-compliant balloon inflation for 90 min, followed by deflation and subsequent reperfusion (RE) for 60 min. A 3-min-length SCG was recorded during the steady state  preceding the LAD sub-occlusion and then at different time points during sub-occlusion and reperfusion, specifically at the onset of LAD sub-occlusion . General anesthesia and analgesia were achieved using continuous inhalation of 1.8 to 2.5% sevoflurane of minimal alveolar concentration (MAC) and continuous infusion of sufentanil 1 to 4 μg/kg/h, adapted according to the response to painful stimulations, in association with 1 to 2 mg/kg/h rocuronium continuous infusion to avoid shivering.The animals have been put on fasting for 18 h before the experiment was started, with unrestricted access to water. Twenty-one 50-kg crossbreed Landrace/Large White adult swine, of either sex, were premedicated with intramuscular neck injection of 5 mg/kg azaperone and 1.5 mg/kg midazolam. A 14-G peripheral venous line was placed into an ear vein to provide vascular access, and a 4.5-Fr arterial catheter  was inserted in the left common femoral artery for invasive arterial pressure monitoring and blood sample collection. A three-lead surface ECG was connected to the hemodynamic monitoring display . The animals underwent endotracheal intubation following induction of anesthesia with an intravenous injection of 3 μg/kg sufentanil, 1 mg/kg propofol, and 0.5 mg/kg of rocuronium. A central venous access for drug infusion was obtained via a three-lumens central venous line inserted into the right external jugular vein  with tidal volume of 8 ml/kg and a positive end-expiratory pressure set at 5 cm H©, California, USA) was advanced in a pulmonary artery for continuous cardiac output (CO), right heart pressures, and mixed venous oxygen saturation (SVO2) monitoring. A 5 Fr introducer  was inserted into the right internal carotid artery, and a coronary guide catheter  was positioned into the left coronary ostium under fluoroscopic guidance with iodinate contrast media angiogram . Through this latter step and after an intracoronary bolus of 200 μg dinitrate isosorbide to prevent coronary spasm, pressure and a Doppler flow wires  were placed distally into the mid LAD. Two 5 Fr introducers  were inserted into the left carotid artery and left femoral artery, where high-fidelity left ventricular pressure—volume catheter  and aortic arch catheter  were placed.A 7 Fr introducer was inserted into the left external jugular vein, and a pulmonary artery catheter , allowing subsequent offline analysis. The animals were administrated with 300 mg amiodarone, followed by continuous infusions of 900 mg/24 h and 7,500 units of unfractionated heparin, followed by a continuous infusion of 2,000 units/h.A semi-compliant angioplasty balloon  was inserted over the wire into the proximal LAD and was inflated to reduce coronary flow by 60% of the baseline value for 90 min. After 90 min of ischemia, 200 mg of aspirin was administrated intravenously, and the balloon was deflated, allowing reperfusion to occur according to the best current clinical managing of ACS . Once thA sham group of another experimental procedure , following the same protocol of general anesthesia and instrumentation of the animal, was used as a reference to rule out the possible depressant effect of general anesthesia on the hemodynamic parameters. This sham group was composed of three crossbreed Landrace/Large White adult swine , all undergoing the same general anesthesia protocol and instrumentation that we used in the present investigation. The hemodynamic parameters of each animal were followed at three different timepoints: during BSL, at 2 h (T1), and at 4 h (T2) of steady state, while no intervention was realized. These data show a reduction by ±5 mmHg of mean arterial pressure, concomitant to the experimental setting . AdditioSince the results from a sham group were already available in our laboratory, the local ethical committee for animal care considered it unnecessary to add a sham group in the present investigation.via Bluetooth and collected a one-lead ECG and a linear (Lin) and a rotational (Rot) three-axes SCG. Details about this methodology have been described previously . One module was placed over the sternum to record local precordial vibrations (SCG); the other one was placed immediately below and externally to the left iliac crest to record one-lead ECG signal. The device was controlled remotely with a tablet connected eviously , 12. Obsm and the vector force (K) can be calculated according to Equations (1) and (2) for the linear components and to Equations (3) and (4) for the rotational components.Assuming that the cardiovascular system equates a Newtonian system, scalar metrics can be obtained from velocity and acceleration signals measured with the SCG in the linear and rotational dimensions and transmitted to the body surface as vibratory phenomena. The height and weight of the animal are used to assess inertial parameters. Knowing the acceleration of an object with a given mass m is the mass of the object, KLin is the linear kinetic energy, vx, vy, and vz are components of the measured velocity vector where For the rotational components, the scalar metrics are calculated according to Equations (3) and (4).I is the momentum of inertia of the object, KRot is the rotational kinetic energy, Ixx, Iyy, and Izz are the orthogonal components of the momentum of inertia I of the object, and ωx, ωy, and ωz are the components of the measured angular velocity where KLin and KRot over the cardiac cycle (CC) was computed for the SCG as in Equations (5) and (6).The time integral of t0−t80, and at REt0−t60 and then exported and analyzed offline using a toolbox developed in MatLab version 9.5 R2018b (Mathworks®). The operator was selecting a 60-s-width artefact-free temporal window of consecutive beats. The beats were automatically identified based on the automatic identification of the peak ECG-R wave. Ensemble averaging (EA) on all beats over the selected time period was performed, and the scalar parameters of iKLin and iKRot were automatically computed. This method of sampling and averaging generated an averaged SCG signal which best fits the shape of a cardiac cycle. Additionally, EA was used to partially remove motion artifacts from the signals.Data were acquired at BSL, at AMIN to the P wave of the next beat N + 1) with the P'Q' segment (the period from the P wave of the beat N + 1 to the Q wave of the beat N + 1) identifies the diastole (Dia) of the cardiac cycle. The sum of PQ, QRS, ST, and TP' defined a whole CC. One record had to be ruled out from final analysis because of technical failure during the signal processing.The P, Q, R, S, and T waves on the ECG were automatically identified and used as reference points for the identification of the electrical cardiac cycle. The sum of QRS and ST segments identifies the systolic phase (Sys) of the cardiac cycle; the sum of the TP' segment  were used for graphing figures on Windows.P25-P75].Normality of data distribution was assessed graphically and by using the Kolmogorov–Smirnov test. According to the distribution, data were expressed as mean ± standard deviation (±SD) if normally distributed or as median and interquartile range if not [To evaluate the effect of AMI and reperfusion on SCG signals, a generalized mixed model was used, taking time as the fixed factor, followed by multiple comparison whenever a significant effect was found. Bonferroni's correction was applied to account for multiple comparisons.iK.The pulse pressures of LV, aortic, femoral, and pulmonary artery pressures were calculated as the difference between systolic and diastolic pressures . GeneraliK parameters with Δ troponins and the LVEF. Correlations were calculated between iK parameters and LVEF computed at the end of the procedure (REt60).Spearman's rank correlation was used to assess the association of P-values <0.05 were considered as statistically significant.Upon LAD sub-occlusion, 77% (thirteen out of 17) of STEMI and 24% (four out of 17) of NSTEMI were observed.p < 0.0001). Regional LV wall abnormalities were observed as follows: anterior MI, 17.6% (three out of 17); septal MI, 5.8% (one out of 17); antero-septal MI, 47.1% (eight out of 17); and infero-septal, 29.4% (five out of 17). The animals did not disclose valve diseases at baseline, and there were no AMI-related valve diseases throughout the study.Compared to baseline, troponins increased from 13.0  ng/dl to 170.5  ng/dl and LVEF dropped from 65.0 to 30.6 ± 5.7% at the end of revascularization (both Modifications of heart rate (HR), CO, systolic and diastolic LV pressures , systolic and diastolic aortic pressures , systolic and diastolic femoral pressures , and systolic and diastolic pulmonary artery pressures  during LAD sub-occlusion and reperfusion are reported in PALL = 0.0001), while CO, systolic PLV, systolic PAo, and systolic Pfem decreased .HR increased by 19% from baseline to the end of reperfusion (t0 and REt60 (p = 0.02); CO dropped from 5.5 to 4.7 l/min from BSL to AMIt80 and REt0 (both p = 0.002) and dropped further to 4.4 l/min at REt60 compared to BSL (p < 0.0001); the systolic pressures of LV and aorta both dropped by 16 and 19%, respectively; between BSL and AMIt0  by 16 and 26%, respectively; between BSL and AMIt80  by 16 and 15%, respectively, between BSL and REt0 , and by 16 and 15% between BSL and REt60 . The systolic femoral pressure dropped between BSL and AMIt0 (18%), AMIt80 (19%), and REt0 (15%) .According to a multiple-comparison analysis, the HR increased between AMIPALL = 0.0007, PALL < 0.0001, and PALL < 0.0001, respectively). According to a multiple-comparison analysis, the Ao PP and the Fem PP dropped at AMIt0 (both p = 0.01), at AMIt80 , and at REt0 (both p < 0.0001) compared to BSL. The modifications of pulse pressures during the LAD sub-occlusion and reperfusion are shown in When considering the pulse pressures of the above mentioned hemodynamic variables shown in iK in the linear and rotational dimensions during the procedure.iK, except PALL < 0.0001, PALL <0.0001, and PALL = 0.03, respectively) from baseline to the end of reperfusion. In the rotational dimension, PALL = 0.0006 and PALL < 0.0001, respectively).All parameters of t0, REt0, and REt60, respectively, compared to BSL ; t0, REt0, and REt60, respectively, compared to BSL ; t60 (p = 0.005). With regards to the rotational parameters of iK, t0, REt0, and REt60, respectively, compared to BSL ; t80, REt0, and REt60, respectively .According to multiple comparisons, iK during coronary occlusion and reperfusion for one animal.iK. All of the hemodynamic parameters, except PA PP, were significantly related to the parameters of iK, with a positive direction of association. LV PP was positively associated with p < 0.0001, p < 0.0001, p = 0.03, p < 0.0001, and p < 0.0001, respectively); p < 0.001, p < 0.001, p = 0.008, and p = 0.001, respectively) and Fem PP . Although these associations were positive and significant, they were still indirect, as shown by the too wide confidence intervals. The CO was also found to correlate with parameters of iK, especially with p = 0.002, p < 0.0001, p = 0.004, and p < 0.0001, respectively).iK have been associated to the Δ troponins and to the LVEF obtained at the end of the procedure (REt60), but no significant associations were observed  as recommended , 11. PlaDespite the fact that this technique has not been standardized yet with large-scale-based studies so that no normal values of kinetic energy can be provided, this limitation was encompassed with the repeated-measures study design, where each animal was its own control. The same study design was adopted in our previous works , 32, 42.iK parameters were a direct consequence of acute myocardial ischemia and not of anesthetic agents.With regard to the experimental procedure, some readers may arise concerns that the observed cardiovascular modifications might be due to general anesthesia, specifically to sevoflurane  and azap2O, which induces a fall in transpulmonary flow and thus in the venous return to the LV, with the global effect of reducing the LV preload  (Acceptation Number: 654N).PvdB and SM conceived the idea and the design of the study. LP designed the animal model of AMI and carried out the whole experimental procedure supported by FS and obtained all the invasive hemodynamic parameters data. AHo provided the technical support and designed the specific Toolbox in MathLab for the correct extrapolation of all metrics from SCG. SM had full access to all data in the present investigation, extrapolated all SCG data, and takes responsibility for the integrity of the data and the accuracy of the data analysis. AHe was responsible for the experimental procedure on the sham group and provided the results for the sham group. JRac performed statistical analysis. SM and LP drafted the manuscript. All authors revised the manuscript critically for important intellectual content, proofread, and made corrections to this manuscript.P-FM, DG, and AHo declare having direct ownership of shares in Healthcare Company. 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.


This year brought increasing interest in more physiologic forms of pacing for the prevention and treatment of heart failure (HF).1 More recently, Lustgarten and colleagues showed that His-bundle pacing (HBP) was able to narrow the QRS complex in patients with left bundle branch block (BBB) to a variable extent in most patients.2 Barba-Pichardo et al. demonstrated similar narrowing in 81% of 16 patients.3 Permanent HBP was possible in 12 of these individuals with an improvement in clinical parameters and left ventricular ejection fraction (LVEF).Permanent His bundle pacing, with depolarization of the ventricles via the intrinsic His-Purkinje system (HPS), is arguably the most physiologic form of ventricular pacing. Its practical application in narrow QRS patients was demonstrated by Deshmukh et al. in 2000.Heart Rhythm this year.4 Permanent HBP with narrowing of the baseline QRS was possible in 16 of the 21 patients involved, with the mean QRS shrinking from 181ms ± 23 ms to 129 ms ± 13 ms. Normalization of the QRS was only possible in one patient; yet, the mean LVEF demonstrated an improvement from 27% to 41%, and New York Heart Association functional class recovered from 111 to 11. At one year, thresholds remained acceptable and all leads were stable. Interestingly, four of these 16 patients had right BBB, while the rest had left BBB.In another example, Ajijola et al. built upon this by reporting on a two-center pilot study of permanent HBP in a cardiac resynchronization therapy (CRT) population, published in 6 Presumably, longitudinal stratification of the fibers in the His bundle, coupled with intra-His block, was resolved by distal HBP. This appears to hold true even for HF patients with severely diseased ventricles in whom it may appear counterintuitive. In 27 HF patients with left BBB undergoing CRT, we were able to demonstrate significant narrowing of the QRS complex along with a shortening in intra-left ventricular conduction in 24 patients during the use of temporary HBP. Of these, the QRS normalized in 12, with a corresponding further shortening of intra-left ventricular conduction.One question to ask is, how does HBP resolve left BBB? Narula and others demonstrated this phenomenon in left BBB patients during distal but not proximal HBP.So, what can we conclude from this body of work? First, permanent HBP with significant (> 20%) narrowing of the paced complex is possible in about two-thirds of patients with CRT indications and either left or right BBB. Second, thresholds and lead stability appear to be acceptable in the intermediate term, with no evidence of progression of HPS disease distal to the pacing site. Third, this therapy appears to be associated with an improvement in clinical status and reverse remodeling. Obviously, these conclusions are tentative, pending a larger, randomized study in a better-defined population. Finally, it appears that the definitions of “direct” or “selective” versus “indirect” or “nonselective” HBP need to be rethought in the CRT population. Perhaps the terms employed should be His-bundle pacing with no distal delay (HBP-ND) for “direct” or “selective” HBP with complete normalization of the QRS complex, and His-bundle pacing with distal delay (HBP-DD) in place of “indirect” or “nonselective” HBP, respectively, in patients with incomplete narrowing of the native wide QRS complex.Another approach to improving the response to CRT is the concept of multipoint pacing in the left ventricle using a single quadripolar epicardial left ventricular lead. Pacing more than one site recruits more myocardium than single-site pacing does, and it is conceivable that it increases the chance that at least one of the pacing electrodes is present at a “sweet spot” .JACC: Clinical Electrophysiology.7 The purpose of this multicenter randomized trial was to assess the safety and efficacy of pacing two different sites using the Quartet™ quadripolar left ventricular pacing lead . In this study, MPP was compared with single-site left ventricular pacing. This trial was not powered to show superiority but rather to demonstrate safety and equal efficacy to conventional CRT. Secondary objectives were to assess which pairs of left ventricular lead electrodes produced the best clinical response and also whether the two left ventricular poles should be paced simultaneously or at different times. Patient response was assessed using a clinical composite score, as used in recent CRT trials such as Adaptive CRT.8This concept was tested in the Multipoint Pacing (MPP) trial, published in The complex study design of the MPP trial incorporated the implantation of a CRT-defibrillator system with a quadripolar left ventricular lead in 455 patients, who then underwent three months of standard single-site CRT. Following an assessment of the response data, the involved patients were then randomized to receive CRT with MPP or standard CRT.Response was assessed at nine months in both groups, and was statistically similar, as was the rate of adverse events.A post-hoc analysis of the MPP group showed that the best response was obtained when both left ventricular poles were stimulated simultaneously and were widely distant from each other rather than adjacent. The clinical response rate was 87% in this group.It was calculated that MPP reduced battery life by about one year. This reduction is probably inconsequential, however, in a patient population in which we expect 50% of greater mortality over five years. If MPP is shown to increase the degree of response to CRT or to increase the rate of response significantly, then we believe the trade-off is well worth it.9 The pivotal trial will commence in 2018, using an updated delivery system. We will await the results with interest.Pacing the left ventricular endocardium during CRT has been shown to improve hemodynamic response, but heretofore has been done using a cumbersome implant procedure and with a relatively high risk of stroke due to the implanted left ventricular lead. New technology developed recently by EBR Systems, Inc.  incorporates a minuscule electrode implanted in the left ventricular endocardium percutaneously via the retrograde aortic route. This system has undergone initial evaluation in the WISE-CRT trial, with a 50% response rate in patients who failed to respond to conventional epicardial CRT, albeit with a significant complication rate, likely due to the design characteristics of the early delivery system.


The problem of the basal descent through-plane movement in quantitative measurement of regional left ventricular (LV) function has been recognized for a long time. But, it is a lack of sophisticated analysis to overcome the limitation.In this study, we tried to solve the limitation of the through-plane motion in quantification of the regional LV myocardial wall thickness and wall thickening (WT) in the short-axis cine MR imaging.A series of the tagged cine MRI in the long-axis view of left ventricle was acquired to quantize the longitudinal translation of regional myocardium. Based on the quantified longitudinal translation of LV myocardium, a new data set of the LV end-systolic thickness (EST) was reconstructed from the original EST measured in multislice short-axis cine MRI by using a cubic spline interpolating algorithm. The wall thickening (WT) of left ventricle in young volunteers was calculated from the data of the reconstructed EST and the data without correction of the basal descent movement. The results were analyzed and compared to validate the effectiveness of the proposed method in quantification of LV WT.p < 0.001). The multislice WT of six segments in the basal sections after correction was significantly different from before correction (p < 0.05). The mean regional wall thickening of six radial segments in basal, mid-cavity and apical sections of LV were 42.3 ± 16.8%, 53.3 ± 9.9% and 48.8 ± 30.1% before correction, and 49.4 ± 12.1%, 50.5 ± 12.1% and 53.5 ± 21.3% after correction. The WT in the basal section was much less than that in the mid-cavity section before correction, but was mildly increased and much approximate to that in the mid-cavity section after correction. The results might implicitly imply that the contribution of the myocardium in the basal section to LV function would be as important as that in the mid-cavity.The linear correlation between the LVEF and the global LV WT raised from 0.57 before correction to 0.82 after correction of the basal descent through-plane movement. The variability in multislice WT of six segments after correction was significantly smaller than that before correction (0.50 ± 0.05 vs.0.64 ± 0.09, The proposed technique may be potentially useful in quantification of regional WT of the same level of LV myocardium by correction of the basal descent through-plane movement in SA cine MRI.


Although a number of modifiable and non-modifiable causes were implicated in arterial stiffness, its pathogenesis remains elusive, and very little is known about aortic elasticity in supraventricular arrhythmias. The potential role of disturbed kynurenine metabolism in the pathogenesis of cardiovascular disease has been recently suggested. Thus, we studied the correlations of aortic stiffness and echocardiographic parameters with biochemical markers and serum level of kynurenic acid (KYNA), an endothelial derivative of tryptophan, formed along the kynurenine pathway, among patients with atrial fibrillation (AF).Study cohort comprised 100 patients with persistent AF . Arterial stiffness index (ASI), structural and functional indices of left atrium (LA) and left ventricle (LV) were evaluated electrocardiographically. Biochemical analyses included the measurements of serum KYNA (HPLC) and of the selected markers of lipids and glucose metabolism, thyroid status, kidney function, inflammation and coagulation.P = 0.029), homocysteine , total cholesterol , LDL , TSH , fT3 , fT4  and creatinine  were independently correlated with ASI. ASI was also independently associated with LV end-systolic diameter , midwall fractional shortening , ratio mFS/end-systolic stress , LV shortening fraction , and LA volume index .KYNA (β = 0.389, In patients with AF, aortic stiffness correlated positively with KYNA, biochemical risk factors of atherosclerosis and with the indices of diastolic dysfunction of LV and LA. Revealed relationship between ASI and KYNA is an original observation, suggesting a potential role of disturbed kynurenine metabolism in the pathogenesis of arterial stiffening. KYNA, synthesis of which is influenced by homocysteine, emerges as a novel, non-classical factor associated with ASI in patients with AF. The hemodynamic function of arteries, apart from the continuous transport of blood to the peripheral compartment, includes the transformation of pulsatile blood flow into a constant and stable stream. The compliance of vascular wall, defined as the relative change of vascular lumen area in proportion to the change of blood pressure, and distensibility, the proportion of compliance and initial pulse pressure, are important functional parameters of arteries , 2. Artevia generation of free radicals and increased inflammation, can promote the deterioration of structure and function of arterial wall ), corresponding to the aortic systolic dimension, measured at the moment of full opening of the aortic valve and aortic minimal diameter (Aomin [mm]), corresponding to the aortic diastolic dimension, measured at the peak of the QRS complex, established by simultaneously recorded electrocardiogram.To assess the parameters of the ascending aorta, the ultrasound scan was performed at 3 cm above the aortic valve leaflet coaptation. The following aortic parameters were recorded: LA maximal diameter–LAmax [mm].Left atrium (LA) measurements were performed when ultrasound beam was passing through coaptation of aortic valve leaflets; measurement was registered in M-mode, during end-systolic phase, right before opening of mitral valve: interventricular septum systolic diameter–IVSSd, [mm], interventricular septum diastolic diameter–IVSDd [mm], posterior wall systolic diameter–PWSd [mm], posterior wall diastolic diameter–PWDd mm, LV end-systolic diameter–LVESd [mm], and LV end-diastolic diameter–LVEDd [mm].Left ventricle (LV) measurements registered in M-mode were performed when ultrasound beam was passing just under leaflets of mitral valve, and included: LA short {medial-lateral} maximal diameter–LAshortmax [mm] during end-systolic phase, just before opening of mitral valve and LA longitudinal maximal diameter {long axis}–LAlongmax, [mm] during end-systolic phase, just before opening of mitral valve.Four chamber apical view (4-CH) was used to measure: The above planar parameters served for calculations of volumetric and functional parameters of aorta, LA and LV. The following aortic parameters were calculated:aortic strain–AS, [%]); AS = (Aomax−Aomin)/Aomin,aortic distensibility–AD, [cm2/dyn-110−6]); AD = [2 x (Aomax−Aomin)]/[(Aomin x PP)]; PP was calculated form systolic blood pressure (SBP) and diastolic blood pressure (DBP) measured simultaneously on right brachial artery while evaluating aortic parameters,aortic stiffness index–ASI, [n]); ASI = log {[SBP/DBP/(Aomax−Aomin)]/Aomin}; SBP and DBP were measured simultaneously on right brachial artery while evaluating aortic parameters.The following volumetric parameters of LA were calculated:LA maximal volume–LAVmax, [mL]); LAVmax = π/6 x (LAmax x LAshortmax x LAlongmax).LA volume index–LAVI, mL/m2); LAVI = LAVmax/m2; LAV adjustment based on the body surface:The following indices of LV structure and function were calculated:LV end-systolic volume–LVESV, [mL]); according to Teichholz formula: LVESV = [7/] x [LVESd]3,LV end-diastolic volume—LVEDV, [mL]); according to Teichholz formula: LVEDV = [7/] x [LVEDd]3,LV stroke volume–SV, [mL]); SV = LVEDV–LVESV,stroke index–SI, [mL/m2]); SI = SV/BSA,cardiac output–CO, [L/min]); CO = SV x HR,cardiac index–CI, [L/min/m2]; CI = CO/BSA,LV ejection fraction–EF, [%]); EF = [(LVEDV–LVESV)/LVEDV] x 100,LV shortening fraction–FS, [%]); FS = [(LVEDd–LVESd)/LVEDd] x 100,end-systolic stress–ESS, 103dyn/cm2); according to the formula: ESS = 0,334 x SBP x LVESd/PWSd x (1 + PWSd/LVESd); SBP measured simultaneously on right brachial artery while evaluating aortic parametersmidwall fractional shortening–mFS, %); according to the formula: mFS = (LVEDd + PWSd/2 + IVSSd/2)–(LVESd + Hs/2)/(LVEDd + PWSd/2 + IVSSd/2) x 100; where Hs = IVSSd + PWSd,ratio mFS/ESS, n,LV mass–LVM, g; according to the formula: LVM = 1,04 x (IVSDd + PWDd + LVEDd)3–13,6 gLV mass index–LVMI, g/m2; according to the formula: LVMI = LVM/BSA.Left ventricle hypertrophy–LVH was diagnosed when: LVMI > 131 g/m2 , LVMI > 100 g/m2 .maximal velocity of early diastolic transmitral flow–E [cm/s], integral of early diastolic transmitral flow–EINTG [cm], and deceleration time of early diastolic filling of left ventricle–Edcct, [msec].Doppler analysis served to measure the flow through mitral valve. The following parameters were measured: 1C), thyroid-stimulating hormone (TSH), free triiodothyronine (fT3), free thyroxine (fT4), haemoglobin (Hb), red blood cells (RBC), white blood cells (WBC), platelets (PLT), haematocrit (HCT), aspartate transaminase (ASPAT), alanine transaminase (ALAT), high sensitive C-reactive protein (hs-CRP), fibrinogen, uric acid, creatinine, glomerular filtration rate (GFR), urea, myoglobin, creatine kinase (CK), CK-myocardial band (CK-MB) and brain natriuretic peptide (BNP) were analysed using ADVIA 1650, ADVIA 2120 and ADVIA Centaur analysers . Troponin T (TnT) was measured in full blood, using electrochemiluminescence method .Blood samples were collected from a peripheral vein, between 8.00 and 10.00 a.m., and sera were stored at -72°C for further analyses. Homocysteine, total cholesterol (CHOL), low density lipoprotein cholesterol (LDL), high density lipoprotein cholesterol (HDL), triglycerides (TGC), fasting glucose, glycated haemoglobin 1C  prewashed with 1 ml of 0.1 N HCl. Columns were subsequently washed with 1 ml of 0.1 N HCl and 1 ml of ultra-pure water (Baker). KYNA was eluted with 2.5 ml of ultra-pure water (Baker). Eluted KYNA was subjected to HPLC  and quantified fluorimetrically . The mobile phase  was pumped at a flow rate of 1.0 mL/min. The sensitivity was 150 fmol/injection . Standard calibration curve was constructed based on the signals obtained from external standards containing 0.2, 0.4, 0.6, 0.8 and 1 pmol of KYNA, and showed linearity of r2>0.999. KYNA concentration in the samples was expressed as nmol/L. HPLC reagents were purchased from Baker. The normal serum KYNA values in the population are in the range of 5 to 40.0 nmol/L, as determined in previous studies [Serum KYNA levels were determined using high performance liquid chromatography (HPLC) method , as described previously . On the  studies , 33.R2 describes the proportion or percentage of variance in the dependent variable explained by the variance in the independent variables together. An R2 of 1.00 indicates that 100% of the variation in the dependent variable is explained by the independent variables. Conversely, an R2 of 0.0 indicates the absence of variation in the dependent variable due to the independent variables. In this work, as the variables are not in the same unit of measures, a standardized regression coefficient β, was used. The β coefficients values show the direction, either positive or negative, and the contribution of the independent variable, relative to other independent variables, in explaining the variation of the dependent variable. Linear regression analyses for measurements from interval scale were performed with the use of Pearson correlation. P-value <0.05 was considered statistically significant.Statistical analyses were performed using Statistica software . Data are presented as mean values ± SD. Qualitative data are presented as values and percentage. Categorical variables were compared by chi-square test. Normal distribution of data was tested with the Shapiro-Wilk test, while homogeneity of variance was estimated with the Levene's test. The correlation between the parameters was described with Spearman's rank correlation coefficient. Significantly correlating parameters have been included in the creation of multiple stepwise regression analysis models. Multiple stepwise regression analysis was performed to estimate the potential influence of various factors on the ASI, AD and AS. The inflation variance coefficient was assessed for all parameters included in the multiple stepwise regression analysis. Thus, the value of this coefficient allowed to determine whether a given predictor was correlated with other predictors in the model. The lack of collinearity of predictors in the model was assumed in cases when the coefficient reached the value of ≤5, and the parameter was included in the analysis. However, when the value of the coefficient was >5, it indicated the possibility of collinearity between the predictors, consequently the parameter was excluded from the analysis. All models were adjusted for demographic and clinical confounders: age, sex, medications and hypertension. Biochemical and echocardiographic characteristics of studied population are shown in Tables ASI correlated positively with serum KYNA , homocysThe multiple regression analysis showed that ASI was independently, positively correlated with serum KYNA, homocysteine, CHOL, LDL, TSH and creatinine, and negatively with fT3 and fT4 . AD was ASI significantly correlated with LVEDd and LVESd, as well as with volumetric parameters of LV, i.e. with LVEDV, LVESV and LVSV . Despitemax, LAshortmax, LAlongmax correlated positively with ASI  was elevated and in a range characteristic for the mild hyperhomocysteinemia (15–30 μmol/L). Others demonstrated that serum homocysteine is linked with aortic stiffness in hypertensive and normotensive subjects . MoleculPositive correlation of ASI with uric acid, as observed in here, is consistent with the other reports. Higher serum homocysteine, uric acid and increased LA diameter were shown in persistent AF . The assvia its metabolite, S-adenosylhomocysteine, biphasically modulates the endothelial KYNA synthesis ex vixo, in rat aortic rings [Independent, positive correlation of serum KYNA with ASI is a novel observation. Up to our knowledge, the relationship between KYNA and the indices characterizing elastic properties of aorta, were not studied so far. KYNA is a biologically active metabolite of tryptophan, produced from its direct bioprecursor, kynurenine, along one arm of the kynurenine pathway. Second metabolic route of kynurenine generates mostly toxic compounds, such as 3-hydroxykynurenine or quinolinate , 15. Notic rings . Low, miic rings . In boviic rings . In clinic rings , or withic rings .Despite the increasing awareness about the role played by KYNA and other kynurenines in the pathogenesis of CVD and atherosclerosis, the potential link between disturbed KYNA levels and arterial stiffening was not evaluated so far. Considering that KYNA is able to counteract the homocysteine-induced injury of endothelial cells , it is tNoteworthy, as recently reviewed, altered metabolism of kynurenine may contribute to the occurrence of vascular pathologies and stroke . FollowiMultiple regression analysis revealed the negative associations of ASI with echocardiographic parameters related to LV systolic function, mFS, mFS/ESS, EF and FS. Furthermore, positive correlation of ASI with the parameters of LV diastolic dysfunction, such as LVEDd and LAVI, was found. Furthermore, he indicator of systolic LV tension, ESS, correlated positively with ASI.max or LAVI. A significant relationship between the diameter of LA and the aortic stiffness, estimated from pulse wave velocity and humeral pulse pressure, was shown previously in a hypertensive population [Diastolic dysfunction of LV, reflected by LVEDd, is commonly linked with an increased afterload, paralleling the loss of aortic elasticity. Structural changes of myocardium, mainly LV hypertrophy, are accompanying ESS . Viciouspulation . Stiff hpulation . Ventricpulation . Interespulation .Overall, our data bring novel information about the correlations of aortic stiffness with certain biochemical markers and with LV/LA rigidity in AF.The number of enrolled patients was moderately high. Furthermore, the influence of applied pharmacotherapy, which may potentially affect the elastic properties of aorta, was not taken into consideration. Nevertheless, statins, known to influence ASI, were not used in the examined population of patients with AF.In chronic AF, aortic stiffness correlates positively with homocysteine, CHOL, LDL, TSH, hs-CRP, WBC, PLT, uric acid, creatinine, TnT and BNP levels and with the indices of diastolic dysfunction of LV and LA. KYNA has emerged as a novel, non-classical factor associated with ASI. We propose that the local interplay between homocysteine and KYNA may result in higher endothelial synthesis of KYNA and constitute a mechanism counteracting the homocysteine-induced toxicity.Complex, reciprocal interactions between the endothelial function, levels of circulating metabolites and the stiffening of aorta require further research. There is a need of prospective studies aimed to determine whether ASI measurement alone, or in combination with serum homocysteine and KYNA, can be a predictor of therapy outcome in patients with persistent AF.S1 Data(ZIP)Click here for additional data file.


Central coordination of cardiovascular function is accomplished, in part, by the baroreceptor reflex, a multi-input multi-output physiological control system that regulates the activity of the parasympathetic and sympathetic nervous systems via interactions among multiple brainstem nuclei. Recent single-cell analyses within the brain revealed that individual neurons within and across brain nuclei exhibit distinct transcriptional states contributing to neuronal function. Such transcriptional heterogeneity complicates the task of understanding how neurons within and across brain nuclei organize and function to process multiple inputs and coordinate cardiovascular functions within the larger context of the baroreceptor reflex. However, prior analysis of brainstem neurons revealed that single-neuron transcriptional heterogeneity reflects an adaptive response to synaptic inputs and that neurons organize into distinct subtypes with respect to synaptic inputs received. Based on these results, we hypothesize that adaptation of neuronal subtypes support robust biological function through graded cellular responses. We test this hypothesis by examining the functional impact of neuronal adaptation on parasympathetic activity within the context of short-term baroreceptor reflex regulation. In this work, we extend existing quantitative closed-loop models of the baroreceptor reflex by incorporating into the model distinct input-driven neuronal subtypes and neuroanatomical groups that modulate parasympathetic activity. We then use this extended model to investigate, via simulation, the functional role of neuronal adaptation under conditions of health and systolic heart failure. Simulation results suggest that parasympathetic activity can be modulated appropriately by the coordination of distinct neuronal subtypes to maintain normal cardiovascular functions under systolic heart failure conditions. Moreover, differing degrees of adaptation of these neuronal subtypes contribute to cardiovascular behaviors corresponding to distinct clinical phenotypes of heart failure, such as exercise intolerance. Further, our results suggest that an imbalance between sympathetic and parasympathetic activity regulating ventricular contractility contributes to exercise intolerance in systolic heart failure patients, and restoring this balance can improve the short-term cardiovascular performance of these patients. Cardiovascular homeostasis is maintained by complex multi-input, multi-output physiological control systems that interact with one another to regulate various cardiovascular parameters. One such system, the baroreceptor reflex, provides negative feedback control of blood pressure by modulating such physiological parameters as heart rate and cardiac output via interactions among brainstem nuclei that coordinate the parasympathetic and sympathetic branches of the autonomic nervous system. It is well established that coordination between the parasympathetic and sympathetic branches is central to maintaining cardiovascular homeostasis. By the same token, an imbalance between these two branches is a classic feature of cardiovascular disease such as heart failure with reduced ejection fraction (HFrEF) . Decreasmultiple cardiac functions within the larger context of the baroreceptor reflex and cardiovascular system would provide deeper insight into how autonomic regulation affects cardiovascular performance in health and disease such as HFrEF , understanding the behavior of this physiological control system as a whole remains a challenge. Some of the main barriers to understanding this system are attributable to the non-linear interactions among the individual components of this system. Moreover, single-cell analysis within the brain has shown that individual neurons are transcriptionally, and thus functionally, distinct from one another . Such trTo elucidate this complexity, we previously performed single-cell analysis of neurons belonging to the nucleus tractus solitarius (NTS), a brainstem nucleus involved in cardiovascular regulation . SpecifiMotivated by these results, we postulate an alternative functional organization of NTS neurons involved in the baroreflex – neuronal subtypes, informed by the synaptic inputs received, respond and adapt to afferent signals relaying information on the state of cardiovascular system to maintain robust regulation of physiological functions. We therefore hypothesize that the presence of distinct neuronal subtypes and the adaptation of neuronal subtypes support robust (coordinated) biological function through graded cellular responses. To test this hypothesis, we use mathematical modeling to examine the functional impact of neuronal adaptation on cardiovascular function in health and disease. Here, we developed a mathematical model, based upon previous quantitative models of baroreflex regulation of cardiovascular function . We exteTo provide the reader with the most pertinent information and results regarding developing of the extended model and simulation analysis, the paper is organized into the following sections: (1) Prior models, which provides a brief background of previous work that formed the basis of the extended model, (2) Qualitative description of the extended model structure, (3) Extended model parameter estimation, which describes the process by which specific parameters values were selected, (4) Methods, which describes the various simulations performed and the sensitivity analysis methodology used, (5) Results, and (6) Discussion.accentuated antagonism affecting heart rate and ventricular elastance , and (3) the dorsal motor nucleus of the vagus (DMV).As the control center regulating autonomic activity, the NTS and its neuronal subtypes interact with one another and the NA and DMV to regulate parasympathetic activity. Ample experimental evidence indicates that the NA and DMV affect distinct cardiac functions and are the sources of vagal efferent outflow . ConsequEmax vs. tidal lung volume), given that the DMV is the main regulator of ventricular elastance, a surrogate measure for ventricular contractility, in the context of this model.Physiological experiments have shown that the NA and DMV modulate specific cardiac effector functions: the NA modulates heart rate and, to a lesser extent, ventricular contractility while the DMV primarily affects contractility, although to a lower extent than sympathetic activity . NA and contractility) are included to represent these distinct influences of the NA  may have on parasympathetic outflow, we incorporated additional components into the model developed by f the NA . The inpf the NA . Becausef the NA , the folfmin,j and fmax,j represent the firing frequency output range of the jth neuronal subtype or neuronal population. The variable finput,j refers to the firing frequency input from the respective receptor-type that the specific neuronal subtype is responding to (being shaped by). The input firing frequency that leads to a half-maximal output is represented by fmidpt,j and reflects the range of inputs to which the specific subtype responds. Finally, kj represents the “sensitivity” of the neuronal subtype to inputs received where larger k-values indicate lower input sensitivity, so that the response over a broad range of inputs is a gradual and relatively small increase in output, and smaller k-values indicate higher input sensitivity . A k-value of unity represents near-binary, “on-off” response profile  rather than heart rate itself . Heart pEmax), the maximum slope of the pressure-volume relationship at the end of systole and a robust correlate to contractility  is defined by the sum of the positive and negative changes caused by parasympathetic and sympathetic activity, respectively. Here, the response of inverse elastance to sympathetic activity follows a monotonic function with linear first-order dynamics and an elastance-specific time constant  by measuring cardiovascular performance during a pedaling cycle test. The sudden onset of exercise triggers multiple physiological responses, which includes, for example, a redistribution of blood throughout the body. Blood flow to the skeletal muscle in the legs increases, comprising ∼13% of total cardiac output . Strong any system – no matter how complex – that can be represented as an interconnected network of “blocks.” The ordinary differential equations in the blocks are solved using ODE15s and an error tolerance of 1e-3.We developed the extended model on the SIMULINK (MathWorks) simulation platform because it provides a natural environment for modeling control systems whose components are represented as blocks interconnected by clearly identified inputs and outputs to each block. SIMULINK’s block-oriented framework therefore facilitates the modeling and analysis of Prior to investigating how an input-driven neuronal organization affects central regulation of cardiovascular function, first we had to determine values for model parameters that would produce simulation results matching established physiological behavior. As a starting point, for the portions of the extended model that were based upon prior models developed by Given that the available experimental data are measurements of overall cardiac function in response to some experimentally induced sensory stimulus , the use of multiple transfer functions to represent the dynamic behavior of the brainstem nuclei of interest raises the possibility of over-parameterization of the autonomic mechanisms regulating cardiovascular function. Hence, several distinct sets of parameter values can produce identical cardiovascular system behaviors and corresponding metrics quantifying that behavior like mean cardiac output (CO), stroke volume (SV), or heart rate (HR). Indeed, our previous findings indicate that brainstem neurons adapt to inputs in order to generate an appropriate physiological response to maintain a blood pressure set point . BecauseThus, to address partially the issue of non-uniqueness of parameter estimates in this work, we constrained the possible parameter space to ensure that estimates were biologically feasible, i.e., comparable to reported firing frequencies of brainstem neurons or closely related sensory neurons. Thus, the constrained parameter space explored for each parameter was based on parameter values originally used by We first selected relevant parameter value estimates that could be fit using data generated from experiments involving direct perturbations, which minimized the number of confounding afferent signals potentially affecting the physiological measure of interest. An example of a direct perturbation experiment would be the direct electrical stimulation of arterial baroreceptors to modulate heart rate and elastance . These dcontractility, and DMV neuronal subtypes  involves ventricular remodeling that leads to an enlarged left ventricle and reduced ventricular contractility, which results in an impaired ability to pump blood and a subsequent reduction in ejection fraction (EF), the fraction of blood pumped out of the left ventricle. Typically, patients suffering from systolic heart failure exhibit an EF below 0.5, the lower limit of what is considered a healthy EF . MoreoveBrainstem-associated parameter estimation ]. Here, we explored a parameter space that spanned a ± 5-fold range from nominal values of the brainstem-associated parameters identified previously to reproduce healthy behavior (O2) reached 1L/min during the pedaling exercise test  and volume (EDV), end systolic pressure (ESP) and volume (ESV), left ventricular pressure, left ventricular flow rates, ejection fraction , mean arterial pressure , and CO . Average values were calculated using mean hemodynamic and cardiovascular behaviors based on the final simulated 15 s, a sufficient amount of time to measure heart rate accurately . These qTo determine if brainstem neurons could adapt to compensate for the sustained physiological perturbations in the heart due to systolic heart failure, we assessed how changing parameter values from the baseline model parameters representing systolic heart failure affected simulated cardiovascular behavior. Specifically, we modified only parameters for transfer functions describing the dynamic behavior of brainstem neurons to represent neuronal adaptation. Modified parameter values were randomly selected within the constrained parameter space, as described previously in the brainstem parameter value selection process. We then ran simulations using these modified parameter values to determine what effect neuronal adaptations had on overall hemodynamic and cardiovascular behavior. We repeated this process 5000 times, selecting parameter value sets via Sobol sampling . Using tUnderstanding the relative contribution of each cardiac- and neuronal-related parameter to overall behavior of the cardiovascular system would enable one to prioritize these parameters for further investigation, i.e., factor prioritization . To deteTi) of the parameter of interest is then determined by comparing the distance between the unconditional and conditional CDF, defined by the Kolmogorov-Smirnoff (KS) statistic. Because the KS statistic is dependent upon the value at which the parameter of interest is kept constant, the PAWN method determines a KS statistic across multiple values for the parameter of interest, which span a pre-defined range of interest. Since multiple KS statistics are generated from this approach, a summary statistic  characterizing the distribution of KS statistics generated from comparing the CDFs is used to define Ti. The result is a sensitivity index for a parameter that ranges between 0 and 1, where larger values of Ti, indicate greater parameter influence on the output. If Ti = 0, then the input, i.e., parameter of interest has no influence on the output  were required to shift hemodynamic and cardiovascular behaviors associated with systolic heart failure to nominal ranges. We applied a density-based sensitivity analysis approach known as PAWN  to detere output . In thisWe performed simulations using the “exercise-response” model to demonstrate the model’s ability to reproduce hemodynamic and cardiovascular behaviors consistent with reported cardiovascular system responses in healthy adults . A 2 minTo evaluate what systemic changes contribute to exercise intolerance, we used parameter values used to simulate cardiovascular and hemodynamic behaviors of HFrEF patients  in the “exercise-response” model. We then randomly selected different values within a ± 5-fold range from the nominal values for brainstem-associated parameters via Sobol sampling  to repreFrom the parameter estimation efforts, we identified baseline parameter values to simulate healthy and HFrEF conditions. A representative example of simulated pressure and volume outputs for both healthy and HFrEF conditions are illustrated in a P-V diagram with a subset of physiological outputs are tabulated in A comparison of the predicted hemodynamic and cardiovascular behaviors to the healthy cardiovascular characteristics  revealedcontractility and decreased sensitivity to input firing frequencies of the DMV neuronal group resulted in decreased vagal activity that would reduce ventricular elastance. These changes caused an overall increase in elastance and a subsequent increase in CO, which is reduced in systolic heart failure patients with HFrEF.We found that all of the adapted neuronal states that were successful in compensating for the physiologically perturbed cardiac state due to systolic heart failure led to decreases in vagal activity. For example, decreased sensitivity of the NA neuronal group to input firing frequency  and ejection fraction (0.55) well within nominal ranges. However, such compensation comes at a physiological cost, namely a concurrent increase in systolic and diastolic blood pressures nearing hypertensive levels , kE,lv, 0,lvP, Emax,lv, (cardiac-related parameters), and GV,Emax,lv (autonomic-related parameter). HR was nearly equally sensitive to fmin,NA, fmidpt,NA. In the context of the extended model, HR is determined primarily by firing frequency generated by the NA subpopulation. Thus it is reasonable to expect that fmin,NA, the basal firing frequency output, and fmidpt,NA, which influences how sensitive the NA subpopulation is to input signals, would have major contributions to HR variation. Interestingly, fmin,NA and fmidpt,NA have larger sensitivity indices than kE,lv, a parameter which helps define the pressure/volume relationship during the diastolic phase of the cardiac cycle. This may suggest a relative importance of neuronal activity over cardiac-associated parameters in modulating HR. Conversely, kE,lv has the largest contribution to variation in CO. As cardiac blood flow depends on the pressure/volume relationship at diastole, it is not surprising that kE,lv affects CO to this extent. Similarly, kE,lv has the largest contribution to MAP variation, which is also highly dependent upon ventricular pressure during the cardiac cycle. Finally, EF is most sensitive to fmidpt,NActrc, GV,Emax,lv, and Emax,lv, which are parameters that indicate the influence vagal activity has on ventricular elastance. These three parameters have similar sensitivity index values, ranging between 0.3 − 0.4, which we interpret as evidence that support the importance of vagal regulation, particularly because EF is a key feature used to define HFrEF.Results from the PAWN sensitivity analysis indicates that HR, CO, MAP, and EF are relatively sensitive to only a few (2–4) parameters out of the 36 neuronal- and cardiac-related parameters analyzed . These pBased on the previous simulation analysis in which we showed that neuronal adaptation in the brainstem could provide short-term compensation for systolic heart failure, we were motivated to investigate how maladaptation and dysregulation of cardiac functions may contribute to other clinical phenotypes associated with systolic heart failure. Exercise intolerance, a common clinical phenotype associated with systolic heart failure, has been the subject of several clinical and modeling studies – many of which have focused on understanding how physical changes in the heart, peripheral vasculature, and metabolic activity post systolic heart failure contribute to exercise intolerance. Since neuronal activity is difficult to measure directly in patients, changes in neurohormonal activity and other circulating biomarkers such as AngII are used as indirect measures of sympathetic activity in patients. The extended model developed here provides an alternative mathematical tool that can be used to investigate how autonomic dysregulation contributes to exercise intolerance.contractility, and DMV neuronal groups  and increase in parasympathetic gain  to ventricular elastance, indicating a change in the extent to which ventricular elastance responds to autonomic signals. To understand the implications of the changes in Gs,Emax and Gv,Emax, we examined the elastance response over a range of sympathetic and parasympathetic activity levels. Under nominal conditions, the accentuated antagonistic relationship between the sympathetic and parasympathetic branches leads to larger changes in elastance when both branches simultaneously modulate the effector function than if either branch were acting in isolation. However, this accentuated antagonistic effect on elastance was nearly abolished when Gs,Emax and Gv,Emax decreased and increased, respectively  resulted in an increase in ventricular elastance and CO that were within the nominal range. Unfortunately, unrealistic ventricular elastance values  , by not considering neurohormonal or metabolic activity that contributes to sustained behavior observed over longer time-scales (hours to days). Consequently, we interpret such indicated decreased vagal activity to be a short-term compensatory response to systolic heart failure-induced impaired cardiac function. Interestingly, when simulating the cardiovascular system behavior under systolic heart failure conditions in which adaptation occurred in all neuronal subtypes and groups , ventric (HFpEF) . These r (HFpEF) , suggestGs,Emax and Gv,Emax, the constant gains that quantify the relationship between sympathetic and parasympathetic activity to elastance were also required. In several cases, the new estimates of Gs,Emax and Gv,Emax led to a loss in the accentuated antagonistic relationship between the sympathetic and parasympathetic branches regulating ventricular elastance  adding separate vascular compartments for resting and active muscles, (2) including a lower body muscle pump to simulate the periodic contraction of the legs, (3) adding an exercise-specific respiratory responses and consequent changes to thoracic pressure, and (4) adding a positive offset to sympathetic activity during exercise. Simulation analysis revealed that the adaptive responses of brainstem neurons were sufficient to produce simulation results that matched experimentally measured cardiovascular responses of healthy patients challenged to an acute bout of exercise. However, to reproduce results matching the cardiovascular performance of exercise-intolerant HFrEF patients, new parameter values for the lastance . Consequmust occur in multiple neuronal populations. Under the impaired state due to systolic heart failure, adaptations occurring only in NTS neuronal subtypes were not sufficient to restore hemodynamic and cardiovascular behavior to within nominal ranges, nor could they improve cardiac output and ejection fraction to nominal levels. The necessity for adaptation to occur in the neuronal populations of the NA and DMV . Conversely, a sustained gating effect maintained by neuronal populations in the NA and DMV would theoretically lead to a sustained decrease in vagal activity, which has been linked to poor long-term cardiovascular health in patients who have suffered from heart failure. In fact, reversing decreased vagal activity in HF patients has been the recent focus of multiple clinical trials to improve long-term cardiovascular health in heart failure patients (Our analyses indicate that to compensate adequately for impaired cardiac function, neuronal adaptation  and DMV  is consipatients . It is p2 levels in the blood, they certainly affect cardiovascular and respiratory function. In addition, metabolic activity, which plays a large role in modulating oxygen consumption and cardiovascular response to exercise demands (While this extended model represents, to the best of our knowledge, the most comprehensive quantitative characterization of multiple neuronal components involved in cardiovascular regulation, it has limitations worth noting. Only a few select afferent input-types were included in this model, even though the NTS receives a diverse array of afferent and higher-order inputs from other brain regions. For example, chemoreceptor afferents terminate in the NTS and play a major role in cardiovascular regulation. Although chemoreceptors have a larger influence in regulating pH and CO demands , was not demands . While t demands , may be  demands .We have extended prior models of baroreflex regulation of cardiovascular function by including brainstem neuronal components and functional connectivity among these components that regulate vagal activity, a critical element of cardiovascular homeostasis. This extended model provides a platform for examining the functional relevance of neuronal adaptation, as suggested by the single-neuron analysis of the NTS . The adaThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation, to any qualified researcher.JP conceptualized the research goals and aims, developed the extended model and methodology used for simulation analysis, performed formal analysis of simulation results, created figures, wrote, edited, and reviewed the manuscript. JG contributed to conceptualization, writing, and editing. BO contributed to conceptualization, analysis, writing, and editing. JS and RV contributed to conceptualization and editing.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.


To investigate the relationship between the elasticity of the carotid artery and the LV (left ventricle) systolic function in patients with diabetic nephropathy (DN) by using two-dimensional speckle-tracking strain echocardiography (2D-STE).n = 108) and control subjects (n = 112), all of whom underwent echocardiography and carotid ultrasound. Analysis of LV GLS  from the apical two-chamber (2C), three-chamber (3C), and four-chamber (4C) views. Meanwhile, the circumferential strain (CS) of the carotid artery was obtained from the view of the short-axis right common carotid artery. The differences between the two groups were compared, and a correlation analysis between CS and GLS was performed.DN patients (p < 0.05). There was a significantly positive correlation of CS with 4CGLS, 2CGLS, and 3CGLS in all subjects .The 4CGLS, 2CGLS, 3CGLS, and CS of the DN group were significantly lower at significant levels in contrast to the control group (2D-STE is a relatively new technique for assessing the mechanical characteristics of the carotid artery in patients with DN. Reduced values of CS correlate with reduced LV systolic function as evaluated by strain measurements, which can predict the risk of systolic dysfunction of LV. It can lead to a variety of complications –3. AmongIt was reported that stiffness in arteries was a major and robust independent predictor of CVD , 8. ArteBetween May 2017 and November 2019, 139 patients newly diagnosed with DN participated in this study. DN was diagnosed according to the Tervaert criteria . The excAll of the above candidates received detailed clinical evaluation and biochemical tests. Detailed clinical evaluation items included medical history, height, weight, BMI (body mass index), blood pressure, and cardiovascular examination. Biochemical test items included FBG (fasting blood glucose), HbA1c (hemoglobin A1c), TG (triglycerides), TC , HDL-C (high-density lipoprotein cholesterol), and LDL-C (low-density lipoprotein cholesterol).Carotid ultrasound was performed with a GE Vivid E9  ultrasound system, equipped with a 10-L probe (frequency ranged 7.5~10 MHz) and M4S probe (frequency ranged 1.5~5.0 MHz). Digitized images of the right common carotid artery (CCA) were obtained by 10 L probe. Carotid IMT (intima-media thickness) was measured in right CCA at end diastole, 1.0 cm proximal to the carotid bulb , 25. PlaEchocardiography was also performed with the GE Vivid E9 equipped with an M4S probe. Conventional 2-D and Doppler echocardiography were carried out to exclude any unconfirmed structural disease of the heart including LV hypertrophy, valvular disease, pericardial disease, or cardiomyopathy. EF was obtained by biplane Simpson method . Cine-loAll clips were acquired at 50–70 frames/s. These images were exported from the ultrasound equipment and then analyzed offline with the EchoPAC software . The procedure began with manually distinguishing the endocardial at a single frame at end systole, with a region of interest that covers of the myocardial wall thickness Figs.  and 2. Tt test of the independent samples. The relationship between CS of the CCA and 4CGLS, 2CGLS, and 3CGLS of the LV was assessed by Pearson’s correlation analysis. P < 0.05 was deemed a statistically significant difference.Statistical evaluations were carried out using SPSS V 17.0 . Mean ± SD was used to express quantitative data. Comparisons among the two groups were accomplished with the p = 0.000). No significant variation was observed in terms of age, BMI, SBP (systolic blood pressure), DBP (diastolic blood pressure), HR (heart rate), TG, TC, HDL-C, and LDL-C among the two groups (p > 0.05)   Table .Table 2p = 0.000). The 4C GLS, 2C GLS, and 3C GLS in the DN group were lower at significant levels in contrast to the control group  (Table The CS in the DN group was lower at the significant levels in contrast to the control group (p = 0.000). The correlation coefficient among CS and 2CGLS was 0.830 (p = 0.000). The correlation coefficient among CS and 3CGLS was 0.830 (p = 0.000)  Fig. .Fig. 5CAtherosclerosis includes structural and functional abnormalities. Carotid IMT has long been regarded as a good indicator of structural abnormalities and can be used to evaluate atherosclerosis –26. FuncThe myocardium is divided into three layers: shallow, middle, and deep. The shallow layer is left-handed spiral, the middle layer is circular, and the deep layer is right-handed spiral. The special structure of the myocardial fiber determines that the myocardium has radial contraction, longitudinal contraction, circumferential movement, and rotational movement . LongituSome studies have shown a close relation between arterial stiffness to left ventricular diastolic function , 35. HowIn conclusion, increased arterial stiffness measured by 2D-STE is indicative of a potential link between vascular changes and LV systolic function. When the CS decreases, the GLS is impaired. The CS has a certain predictive effect on the early reduction of LV systolic function. 2D-STE can detect the relationship between CS and GLS in the early stage.