In this study, the effects of graphene oxide (GO) on the microstructure of cement mortars were studied using scanning electron microscopy (SEM), thermogravimetric (TG), and X-ray diffraction (XRD) techniques. Cement mortar samples with different proportions of GO  were prepared. The test results showed that GO affected the crystallization of cement hydration products, C–S–H  and CH . The morphology of hydration products changed with the increase of GO content. Furthermore, the results of XRD analyses showed that the diffraction peak intensity and the crystal grain size of CH (001), (100), (101), and (102) for GO samples increased considerably compared with the control sample. Based on the results, it can be understood that GO can modify the crystal surface of CH, leading to the formation of larger crystals. Graphene oxide (GO) is one of the graphene derivatives, which basically consists of a several layers of wrinkled two-dimensional carbon sheet with various oxygen-containing functional groups such as hydroxyl, carboxyl, and epoxy groups on its surface and/or between the inter-sheet layers . GO is uIn addition to ordinary cement material, several works have also been carried out to study the performances and microstructure of GO reinforced geopolymer and other special cementitious materials. Zhong et al.  had prepHowever, the influence mechanism of GO on cement hydration products is still uncertain and yet to reveal. This paper mainly studied the effects of GO on morphology and microstructure of cement hydration products. The influence mechanism of GO on cement hydration was revealed using the following test methods: X-ray diffraction (XRD), thermogravimetric (TG), and scanning electron microscopy (SEM) observations. The cement used for this experiment was PII (Portland Type II) 52.5 N ordinary Portland cement supplied by Jiangnan Onoda Cement Co., Ltd. . The chemical compositions of Portland cement are shown in −1 (–OH), 1731 cm−1 (–COOH), and 1384 and 1094 cm−1 (–O–), respectively [The Fourier-transform infrared spectroscopic (FT-IR) spectra  of GO is shown in ectively . These oCement paste samples with different contents of GO  were prepared. Water-to-cement ratio of all samples was 0.40. First, the GO solution was diluted into the deionized water. Then, the mixture was added with polycarboxylate superplasticizer and gently stirred with a glass rod. The superplasticizer used was not only to maintain the workability of cement paste samples, but also acted as a dispersing agent, and the dosage of superplasticizer agent was 0.18 wt %. In the practice, the difference of workability between different samples is small. After that, the mixture solution was agitated using an ultrasonic method  to achieve homogeneous dispersion of GO in the solution. After 30 min of agitation, the mixture was stirred at a low-speed for 30 s, and cement was subsequently added into the mixture and stirred in a similar manner for another 2 min. When siliceous sand was added, the blend was mixed at a high-speed rotation for 2 min. After mixing, the GO cement samples were immediately poured into a 40 mm × 40 mm × 160 mm mold. The final specimens were striped after 24 h and cured in water at 20 ± 1 °C, until specified ages of testing. Samples were packed in small bottles with anhydrous ethanol for microscopic tests. Microstructural properties of hydrated cubes were evaluated after 28 days of curing. A sample consisted of plain cement mortar without and with 0.8 wt % GO were prepared following the same procedure above.X-ray diffraction (XRD) was used to analyze the hydration products of cement pastes. XRD patterns were recorded at a scanning rate of 2°/min from 2θ = 5° to 2θ = 80° with Cu Kα radiation (λ = 1.5418 Å) on a Bruker D max/RB diffractometer . Scanning electron microscope  was used to analyze the morphology of cement paste. Differential thermal analysis  was employed to measure the calcium hydroxide content of GO cement samples at different ages (3 and 28 days) through semi-quantitative analysis. In this test, the heating rate was 20 °C/min, and nitrogen was used as a DSC  standard purge gas due to its better heat conductivity. The material of the pans was corundum.The effects of GO contents  on flexural and compressive strength of cement paste at different ages are shown in CH crystals are the second most important hydration products after C–S–H gel  as theirD is the size of grains in the direction perpendicular to the crystal plane; λ is the X-ray wavelength; θ is the diffraction angle; β is the diffraction peak half width; K is a constant equal to 0.89.It is commonly known that CH crystals clearly present a hexagonal plate shape in hardened cement paste . If the GO significantly improved the mechanical properties of cement mortar, with a greater effect on the early age strengths. In general, the flexural and compressive strengths of cement paste increased significantly with the increase of GO content. When 0.08% GO was added, the 28-day flexural strength improvement was the greatest (27.1%), whereas the compressive strength increased by 16.4%. The morphology of the hydration products changed with the increase of GO content. The microstructural change was mainly attributed to the large specific surface area of GO accompanied with a high amount of oxygen functional groups, which served as nucleation sites in the formation of hydration products during the cement hydration process. The XRD results indicated that GO could promote the formation of CH crystals. The diffraction intensity and crystal size of CH in their different planes observed in GO cement samples were greater compared with the control sample. So, it can be concluded that GO could lead to the formation of larger CH crystal sizes and promote higher CH crystallizations in the cement paste. Properties of GO modified cement, such as fracture, porosity, and durability have not been fully investigated, but it would be worthwhile to carry them out in the near future.


Type 1 diabetes (T1DM) may lead to changes in left ventricular (LV) function and cardiomyopathy in the absence of coronary artery disease or hypertension, possibly due to alterations in sympathetic innervation and myocardial oxidative metabolism and efficiency. The primary aim of this study is to evaluate the association between CMR imaging variables  and diastolic function) and the presence of T1DM at baseline and 3-years follow-up. The secondary aim is to assess the difference of CMR imaging variables in T1DM between males and females.45 T1DM patients , and 9 matched healthy controls (HC)  were studied with CMR. All T1DM are followed for 3 years, underwent a follow-up CMR exam at 3 years, while adhering to the current standard of care, and CMR at follow-up were available for 27 of the T1DM  for T1DM). The CMR exam consisted of cine images , myocardial grid-tagged images, and transmitral velocity-encoded flow images for measuring left ventricular mass ratio (LVMR=LV mass/LV end-diastolic volume) and ejection fraction (EF), strain and apical-to-basal torsion, and mitral early-to-atrial filling ratio (E/A), respectively. Student's t-test was conducted between patients at baseline and follow-up, between female and male patients, and between patients and HC (p < 0.05 was considered significant).There were no differences between T1DM and HC at baseline in any of the measured variables Figures . In the The results demonstrated that at baseline, T1DM showed no significant differences compared to HC. At 3-years follow-up, LV mass , apical-to-basal torsion, and diastolic function (represented by E/A) normalize toward the measurement ranges in HC, and are accompanied by decreased basal LV strain. In conclusion, CMR is a valuable technique for evaluating global and regional cardiac function in T1DM patients and for following measurements' changes over time. Larger studies with longer follow-up time are needed to better understand the nature of ventricular remodeling in T1DM.


The Evaluating Xience and left ventricular function in PCI on occlusiOns afteR STEMI (EXPLORE) trial did not show a significant benefit of percutaneous coronary intervention (PCI) of the concurrent chronic total occlusion (CTO) in ST-segment elevation myocardial infarction (STEMI) patients on global left ventricular (LV) systolic function. However a possible treatment effect will be most pronounced in the CTO territory. Therefore, we aimed to study the effect of CTO PCI compared to no-CTO PCI on the recovery of regional LV function, particularly in the CTO territory.Using cardiovascular magnetic resonance (CMR) we studied 180 of the 302 EXPLORE patients with serial CMR (baseline and 4 months follow-up). Segmental wall thickening (SWT) was quantified on cine images by an independent core laboratory. Dysfunctional segments were defined as SWT < 45%. Dysfunctional segments were further analyzed by viability  ≤50%.). All outcomes were stratified for randomization treatment.p = 0.03). This recovery was most pronounced in the dysfunctional but viable segments(TEI < 50%) . Furthermore in the CTO territory, recovery of SWT was significantly better in the dysfunctional segments in patients with Rentrop grade 2–3 collaterals compared to grade 0–1 collaterals to the CTO .In the dysfunctional segments in the CTO territory recovery of SWT was better after CTO PCI compared to no-CTO PCI (ΔSWT 17 ± 27% vs 11 ± 23%, CTO PCI compared with no-CTO PCI is associated with a greater recovery of regional systolic function in the CTO territory, especially in the dysfunctional but viable segments. Further research is needed to evaluate the use of CMR in selecting post-STEMI patients for CTO PCI and the effect of regional LV function recovery on clinical outcome.NTR1108, Date registered NTR: 30-okt-2007.Trialregister.nl  In STEM-up (FU) . An in-d-up (FU) . In elec-up (FU) , 7. Howen = 302) between 2007 and 2015 were randomly assigned in a 1:1 ratio to CTO PCI within 7 days after primary PCI (n = 148) or to a conservative strategy (no-CTO PCI) for at least 4 months (n = 154). Patients were eligible if during successful primary PCI a concurrent CTO was found in a non-infarct related artery (IRA). Important exclusion criteria were >48 h hemodynamically instability and conditions impeding CMR imaging such as renal failure, atrial fibrillation and indication for pacemaker or implantable cardioverter-defibrillator (ICD) within 4 months after randomization. The primary endpoints of the trial were LVEF and LVEDV at 4 months follow-up measured on CMR. At 4 months follow-up there was no significant difference on LV function between patients randomized to CTO PCI and patients randomized to no-CTO PCI . Also, no significant differences in the secondary endpoints of left ventricular systolic volume, left ventricular mass and infarct size were observed. CTO was defined as a 100% luminal narrowing without antegrade flow or with antegrade or retrograde filling through collaterals. The coronary vessel in which the CTO was located should have a reference diameter of at least 2.5 mm. For patients with multiple CTOs, the main CTO was defined as the CTO supplying the largest amount of myocardium. All coronary angiographies were evaluated by an independent angiography corelab to assess location and characteristics of culprit lesion, CTO lesions and quality of the collaterals. Collateral quality assessment was done at the baseline angiogram (primary PCI). Presence and extent of retrograde collateral flow was determined using the Rentrop classification score [The design and main results of the EXPLORE trial were described in detail previously . BrieflyCI n = 14 or to a CMR was performed on a 1.5-Tesla scanner using a dedicated phased array cardiac receiver coil. For LV function imaging, during repeated breath holds, ECG-gated balanced steady-state free-precession cine images were obtained in short-axis orientation covering the left ventricle from base to apex. For infarct analysis of the myocardium, at least 10 min after administration of a gadolinium-based contrast agent, late gadolinium-enhanced (LGE) images were acquired using an inversion recovery gradient-echo pulse sequence with slice locations identical to the cine images.A 16-segment model, excluding the apex, was used to analyze the segmental function in each patient. Endo- and epicardial borders were manually outlined on all short-axis cine slides on the end-diastolic and end-systolic images, which has been shown to have a high reproducibility and reliability , 10. SWTp-value <0.05 was considered to indicate statistical significance.Data are presented as mean ± standard deviation for continuous variables. Discrete variables were summarized as frequencies and percentages. Baseline characteristics were compared using the independent-samples T-test, or Fisher’s exact probability test in case of binary endpoints. Changes in LVEF, LVEDV and infarct size within each group were tested with paired student t-test. We evaluated the recovery of regional segmental outcome (percentage of SWT) in relation to the presence of dysfunctional segments at baseline and the presence of viability (TEI <50%) at baseline. All outcomes were stratified for randomization treatment. Because within 1 patient the regional function in the different segments is strongly related and not an independent outcome, multilevel analysis was used (linear regression) . In the From the 302 patients randomized in the EXPLORE Trial, 180 patients completed serial CMR (baseline and 4 months FU) and were included in the present analysis , for LVEDV it was 5.5 ± 32.2 ml versus 3.0 ± 25.7 ml (p = 0.57). There was no significant difference in functional recovery between CTO PCI and no-CTO PCI, also the decrease in infarct size was not different between the 2 groups  were available for analysis of function (percentage SWT at 4 month FU compared to baseline). Although a significant recovery of SWT was seen over time, there was no difference between the treatment arms . In the segments that were dysfunctional at baseline (n = 1511) no significant recovery of SWT was seen in the CTO PCI group compared to no-CTO PCI . In dysfunctional segments with TEI < 50% (n = 1127) there was also no significant difference on the recovery of SWT after CTO PCI compared to no-CTO PCI . In dysfunctional segments with TEI > 50% (n = 82) there was no significant difference in recovery of SWT between CTO PCI and no-CTO PCI . Table A total of 2576 segments (p = 0.03). In dysfunctional segments with TEI <50% in the CTO territory CTO PCI resulted in a significantly better recovery of SWT compared to no-CTO PCI . In dysfunctional segments with TEI > 50% in the CTO territory there was no significant difference in recovery after CTO PCI compared to no-CTO PCI . Figure There were 845 segments in the CTO territory available for analysis Table . In CTO not lead to a better improvement of SWT. In dysfunctional segments in the IRA territory the recovery was comparable between the treatment groups  .In the CTO territory the recovery of SWT of segments was compared in patients with Rentrop grade 2–3 versus grade 0–1 collaterals to the CTO territory. Baseline SWT of all the segments in the CTO territory was not different between the patients with Rentrop grade 2–3 collaterals (43 ± 32%) and the patients with grade 0–1 collaterals to the CTO (41 ± 36%) (difference in baseline SWT: p = NS). In dysfunctional segments in the CTO territory recovery of SWT was better in the patients with Rentrop grade 2–3 collaterals compared to grade 0–1 collaterals  . KirschbIn both treatment groups there was an increase of SWT at 4 months, probably due to recovery of the stunned myocardium, caused by acute interruption of blood flow. Recovery of stunned myocardium will lead to  recovery of LV function, typically over hours to days . In a chFurthermore, the effect of CTO PCI on regional LV function might be associated with other positive effects of CTO PCI such as prevention of arrhythmias. Presence of a CTO affects the electrophysiological properties of the myocardium and restoration of antegrade blood flow to the ischemic and dysfunctional CTO territory might enhance electrical stability. In ICD patients with a CTO, compared to patients without a CTO, more ICD therapy was delivered . This inIn our study segments in the CTO territory showed better recovery of SWT in case of Rentrop grade 2–3 collaterals compared to grade 0–1 collaterals. In single CTO patients without a prior MI, patients with Rentrop grade 3 collaterals showed less resting regional wall abnormalities with minimal resting perfusion abnormalities on myocardial perfusion SPECT. However, most patients did have stress induced perfusion defects. These findings suggest that chronic stunning rather than true hibernation is the primary cause of regional wall abnormalities . This stThere are several limitations applicable to this study. Our sample size might be too small to detect differences, especially in the various subgroups. Unfortunately, baseline CMR was not performed in all patients included in the EXPLORE trial, though the baseline characteristics are comparable between patients with and those without serial CMR. Overall the patients included in the study had a moderately reduced LVEF, therefore the results might not be applicable to all patients, especially the patients with a severely reduced LVEF or patients presenting with cardiogenic shock. However SWT analysis was a predefined secondary endpoint of the EXPLORE trial.In dysfunctional segments in the CTO territory, CTO PCI compared with no-CTO PCI was associated with a marked improvement of regional function. Furthermore, in dysfunctional segments with TEI < 50% in the CTO territory CTO PCI compared to no-CTO PCI resulted in a better recovery of SWT, while in dysfunctional segments with TEI > 50% there was no treatment effect on regional function. Furthermore patients with grade 2–3 collaterals compared to grade 0–1 collaterals to the CTO showed a significantly better SWT recovery in the dysfunctional segments. Further studies are needed to investigate the effect of this regional improvement on clinical outcome and how to use CMR in selecting patients for CTO PCI after STEMI.


Pulmonary embolism is associated with significant mortality and impaired long-term functional outcomes. Timely identification and treatment is crucial for successful management. Unfortunately, prompt diagnosis can be challenging in patients without overt signs of cardiovascular compromise. Point-of-care cardiac ultrasound (POCCUS) can be used to identify signs of acute pulmonary embolism, risk stratify patients for adverse outcomes and assess response to therapy. This report describes a patient with submassive pulmonary embolism and evidence of acute right ventricular strain on POCCUS successfully treated with thrombolytic therapy. The dynamic changes observed on point-of-care ultrasound are presented. Pulmonary embolism (PE) is a common and significant condition affecting one to two out of every 1,000 patients presenting to the emergency department (ED).3Unfortunately, prompt and accurate bedside diagnosis can be challenging. Only 5% of acute PE patients may present with observable signs of shock.While a variety of diagnostic modalities for identifying RV dysfunction exist, comprehensive transthoracic echocardiography (TTE) is the standard. Signs of RV strain, including RV dilation and hypokinesis, may be readily identified on TTE in up to 30% of normotensive patients.A 33-year-old female with a history of mild intermittent asthma was sent from a mental and behavioral healthcare facility for evaluation of acute dyspnea. Her dyspnea began three hours prior to arrival and was associated with chest tightness, which she described as similar to previous asthma exacerbations. In addition, her medical history included hypertension, generalized anxiety disorder, bipolar disorder, and polysubstance abuse. She denied hemoptysis, lower extremity swelling, history of prior deep vein thrombosis or PE, estrogen use, current or prior malignancy, recent surgery or trauma.Triage vital signs were temperature 36.5°C, blood pressure 106/58 mmHg, heart rate 120 beats per minute, respiratory rate 32 breaths per minute, and oxygen saturation 92% on room air. She appeared anxious and unable to sit still on the gurney. Her lungs were clear to auscultation with symmetric air movement bilaterally without wheezing. Her exam was otherwise normal. Her electrocardiogram (ECG) demonstrated sinus tachycardia with right bundle branch block (RBBB) . PortablOn initial impression, the diagnosis of pulmonary embolism was considered. The patient was risk stratified with a Wells Criteria for Pulmonary Embolism score of one and a half, for tachycardia, and a Pulmonary Embolism Rule-out Criteria (PERC) score of two, for tachycardia and hypoxemia.Laboratory results were significant for elevated D-dimer of 2524 ng/mL , B-type natriuretic peptide (BNP) 7295 pg/mL, troponin I 0.117 ng/mL, and lactic acid 5.4 mmol/L. POCCUS demonstrated signs of RV strain with a dilated RV on the parasternal long axis (PLAX)  and septWhat do we already know about this clinical entity?Point-of-care cardiac ultrasound (POCCUS) is a skill that emergency physicians can perform rapidly at the bedside to assess for right ventricular (RV) strain in submassive pulmonary embolism (PE) to identify patients at risk of hemodynamic decompensation.What makes this presentation of disease reportable?We present POCCUS images obtained before and after successful thrombolysis of PE. Resolution of RV dysfunction was observed.What is the major learning point?Resolution of RV dysfunction was visualized only one hour after thrombolytic infusion was initiated. POCCUS applications for evaluating RV strain are reviewed.How might this improve emergency medicine practice?Protocols using POCCUS to guide systemic thrombolytic therapy with a goal of preventing cardiovascular collapse may pose a safe option for managing patients with submassive PE.Treatment with therapeutic heparin was initiated. Despite this, the patient remained dyspneic, uncomfortable and anxious with no improvement in vital signs. The risks and benefits of thrombolytic therapy, compared to observation, were discussed in depth with the patient. She elected for thrombolytic therapy and was treated with alteplase 100 mg infused over two hours. Repeat POCCUS performed one hour after thrombolytic administration demonstrated significant improvement of RV strain , and repThis case highlights important concepts in the management of acute PE, particularly the utility of EP-performed POCCUS for identifying RV dysfunction and treatment response. Real-time differentiation of normotensive patients with acute PE at risk for deterioration is often difficult. Patients may maintain normal vital signs until the moment of deterioration, elevation in troponin or BNP due to myocardial necrosis may be delayed for hours, and comprehensive TTE may not be available. EP-performed POCCUS is an important risk stratification tool in acute non-massive pulmonary embolism and has been established as highly accurate for identifying the presence of RV dysfunction.6The simplest POCCUS method to identify RV strain is through a visual estimation of the RV to left ventricular (LV) diameter ratio . A norma14The diagnosis of RV strain can be further established by the presence of flattening of the interventricular septum or bowing of the septum into the LV. The PSAX view can aid in identifying these abnormalities. The “D” sign refers to a flattening of the interventricular septum in the PSAX view resulting in a “D”-shaped ventricle, compared to the normal “O” shape, indicating elevated RV pressures  right. P15In the setting of increased pulmonary artery pressures, the RV free wall will also become hypokinetic, as it is too weak to contract against the sudden increase in filling pressures. The RV apex may continue to beat hyperdynamically in an attempt to maintain adequate cardiac output. This is best seen on an A4C view at the apex of the RV, where the hyperdynamic apex meets the hypokinetic and dilated RV free wall. This RV hypokinesis with apical sparing is referred to as “McConnell’s sign” and is 94% specific for acute PE.10Tricuspid annular plane systolic excursion (TAPSE) measurement is another useful application for identifying RV strain in acute PE. TAPSE is measured as the displacement of the tricuspid annulus from end-diastole to end-systole. TAPSE measurement is obtained with the A4C view using motion mode (M-mode). The M-mode cursor is placed from the apex of the heart through the lateral tricuspid annulus allowing for visualization and measurement of annulus movement over time. Displacement of the annulus of <16mm is consistent with RV strain. Kopecna et al. demonstrated TAPSE measurement to be the least user-dependent and most reproducible echocardiographic finding of RV dysfunction in normotensive patients with PE.17The presence of right heart thrombus in the setting of PE is associated with worsened outcomes and may be identified with POCCUS. In an analysis of 1,113 patients with acute PE, the presence of RV thrombus on baseline echocardiography was associated with nearly twice the mortality rate at 14 days (21% vs. 11%) and three months (29% vs. 16%) as compared to those without.19The acute echocardiographic abnormalities associated with PE resolve over time with treatment and recovery.POCCUS is a skill that EPs can perform rapidly at the bedside to assess for RV strain in submassive PE. POCCUS applications for evaluating RV strain include identification of RV dilation and hypokinesis, impaired septal wall motion, McConnell’s sign, and TAPSE measurement. This case also highlights the utility of POCCUS in identifying resolution of RV dysfunction after the administration of systemic thrombolytic therapy. Protocols incorporating POCCUS to initiate and guide therapy with a goal of preventing cardiovascular collapse in high-risk patients may pose a safe option.


Myocardial active relaxation and restoring forces are known determinants of left ventricular (LV) diastolic function. We hypothesize the existence of an additional mechanism involved in LV filling, namely, a hydraulic force contributing to the longitudinal motion of the atrioventricular (AV) plane. A prerequisite for the presence of a net hydraulic force during diastole is that the atrial short-axis area (ASA) is smaller than the ventricular short-axis area (VSA). We aimed (a) to illustrate this mechanism in an analogous physical model, (b) to measure the ASA and VSA throughout the cardiac cycle in healthy volunteers using cardiovascular magnetic resonance imaging, and (c) to calculate the magnitude of the hydraulic force. The physical model illustrated that the anatomical difference between ASA and VSA provides the basis for generating a hydraulic force during diastole. In volunteers, VSA was greater than ASA during 75–100% of diastole. The hydraulic force was estimated to be 10–60% of the peak driving force of LV filling (1–3 N vs 5–10 N). Hydraulic forces are a consequence of left heart anatomy and aid LV diastolic filling. These findings suggest that the relationship between ASA and VSA, and the associated hydraulic force, should be considered when characterizing diastolic function and dysfunction. The mechanisms involved in left ventricular (LV) diastolic filling and their relative importance remain an area of active investigation123456719At the end of LV systole, calcium ions are pumped back into the sarcoplasmatic reticulum, allowing for actin and myosin filament cross-bridges to uncouple and slide back to their initial position. This process is referred to as “active relaxation” since it requires energy in the form of adenosine triphosphate. Active relaxation is not instantaneous, and thus takes time to occur. Consequently, residual contractile forces are present early on during isovolumic relaxation upon the onset of diastole before all active relaxation has had a chance to occur, and this incomplete relaxation initially impedes LV myocardial fibers lengtheningrestoring force9elastic recoil14passive tensionrestoring force); (ii) during myocardial relaxation this potential energy is converted to kinetic energy, by movement of the myocardium back to its resting length (elastic recoil); (iii) when the myocardium is elongated beyond its resting length, a force is generated to bring it back to equilibrium or oppose further lengthening (passive tension). The passive tension is also related to what is referred to as passive myocardial stiffness. Granzier and Irvin3Simultaneously with active relaxation, restoring forces act during LV diastole. These forces are generated by the myocardium and are attributed to the giant intracellular protein titinTo date, there is no method that can quantify and differentiate between active myocardial relaxation and the different elastic forces1313in vivo measurement and comparison of the LA and LV short-axis areas have not been reported.We hypothesize the existence of an additional mechanism involved in LV filling, namely, a hydraulic force contributing to the atrioventricular (AV) plane motion in the apex-to-base direction. Hydraulic forces are based on Pascal’s principle, and have previously been hypothesized to contribute to diastolic filling2223Therefore, we hypothesize that if the atrial short-axis area (ASA) is smaller than the ventricular short-axis area (VSA), it thus provides the anatomical basis for the presence of a hydraulic force during diastolic filling. The aims of this study were to (a) illustrate the effects of hydraulic forces in an analogous physical model of the LA and LV, (b) measure and compare the ASA and VSA in healthy volunteers, and (c) calculate the magnitude of the hydraulic force.Methods - Theoretical Background Related to Hydraulic Forces. The physical model illustrates the effect of hydraulic forces displacing a hollow piston  is shown in Endo is smaller than ASA (p = 0.02) whereas VSAEpi is larger than ASA (p = 0.02).The relationship between ASA, VSAEndo and ASA at mid diastasis was 7.7 ± 1.4 cm2 yielding a hydraulic force of 1.0 ± 0.2 N. The difference between VSAEpi and ASA at mid diastasis was 25.4 ± 2.3 cm2 yielding a hydraulic force of 3.4 ± 0.3 N. By comparison, the peak driving force of LV filling was estimated to be between 5–10 N , and thus the hydraulic force (1–3 N) represents between 10–60% of the peak driving force.The difference between VSAThe main finding of this study is that the ASA is smaller than the VSA for the vast majority of the duration of diastole. This difference in short-axis area between the atrial and ventricular sides of the AV plane is the anatomical basis for the generation of a hydraulic force in the apex-to-base direction during diastole. The hydraulic force aids LV lengthening during diastole and facilitates AV plane displacement toward its end-diastolic position. The effect of the hydraulic force works in parallel with the restoring forces generated by ventricular contraction, which are released during diastole. The main difference between the two mechanisms is that restoring forces are mainly generated on a molecular level within the myocardium, whereas hydraulic forces are generated on the macroscopic level and are a consequence of the diastolic blood chamber pressure acting upon the anatomic surfaces of the heart. The estimation and comparison of the hydraulic force with the previously estimated peak driving force show that they are of the same order of magnitude. The effect of the hydraulic force is illustrated in a physical model , and theEpi, hydraulic forces act during the entire duration of diastole. If considering VSAEndo, they act during 75% of the duration of diastole, starting immediately after the rapid filling phase. The hydraulic force is highest at the end of diastole when ASA and VSA differ the most. The elastic recoil and the hydraulic force complement each other since the hydraulic force is maximal at the end of diastole when the elastic recoil has diminished. Stored elastic energy and hydraulic forces both contribute to LV diastolic filling. The theoretical background previously used to measure and calculate recoil forces is based on measurement of the inflow to the LV across the mitral valveThe size of the LA and the LV vary during the cardiac cycle. Since the hydraulic force is proportional to the time-varying difference between ASA and VSA (assuming negligible pressure differences between the LA and the LV), changes in ASA and VSA during LV filling influence the magnitude of the hydraulic force. If considering VSAAs long as there is a difference in short-axis area between the LA and the LV, there will be a force pushing the AV plane towards the base of the heart despite equal pressure in the LA and LV. This requires that in order to achieve a momentarily static equilibrium position of the AV plane during diastasis8Many industrial systems exploit Pascal’s principle to generate a large force through a large area by applying a smaller force to a smaller area. Examples of such devices are the hydraulic press, hydraulic lifts, and hydraulic brakes. The particular shape of the heart could be the result of an evolutionary adaptation that enabled the generation of such forces. Based on observations regarding the geometry of the heart, others have constructed and described a mechanical pump with two chambers (representing the LA and LV) and two valves , and for which filling is based on hydraulic forces generated by a difference in area between the upper and the lower chamberSeveral studies have highlighted the importance of changes in the size of cardiac chambers in heart failure2728Our study underscores the importance of maintaining a normal difference in short-axis area between the LA and the LV in order to generate adequately strong hydraulic forces to contribute to normal diastolic filling. Notably, the balance between ASA and VSA contributes to the forces involved in LV filling, but also the forces involved in LA contraction. Further studies on the consequences of pathological disruption or surgical intervention on this balance are justifiedper se is not relevant to the LV hydraulic forces as long as the aortic valve is closed, thus separating the effects of the different pressures in the LV and aortic root. The hydraulic forces acting on the surface of the closed aortic valve from the lumen of the LV are independent of the pressure inside the aorta. The aortic root can be viewed as a pressurized bottle closed with a cap, where the cap is the aortic valve. If one tries to move the bottle, the pressure in the bottle does not make the bottle more or less difficult to move, as long as the bottle is closed. The aortic root follows the movement of AV plane towards the base, but the hydraulic force in the LV does not depend on the pressure in the aortic root, as long as the aortic valve remains closed. The relationship between the atrium and the ventricle with regards to hydraulic forces differs from the relationship between the ventricle and the aorta. Since the mitral valve is open during diastole, the atrium and ventricle are, hydraulically speaking, a single chamber. The blood pressure acts everywhere in the two contiguous chambers enabling the movement of the AV plane. Furthermore, the aorta is not unattached to other structures, and thus the aortic structure as such, including the stretch of the walls of the aorta and the great vessels, has been speculated to play a role in diastolic fillingThe contributions of the aortic root and aortic valve to the hydraulic forces of LV diastolic filling deserve to be addressed. Firstly, the aortic root is a structure that is integrated into the basal septal part of the LV. As such, the anatomical presence of the root entails that it is a part of the short-axis area of the LV, the VSA. The blood pressure during diastole inside the aortic root The number of subjects participating in this study (n = 10) was limited. However, the magnitude of mean differences in VSA and ASA, and level of statistical significance  show thaThe LA has an irregular shape and therefore it can be challenging to identify and measure the largest atrial short-axis in cardiovascular magnetic resonance (CMR) images. Additionally, the atrial wall is thinner than the ventricular wall (approximately 2 mm vs 10 mm) and its thickness is typically not conspicuously visualized in CMR images due to limitations in spatial resolution. However, given its limited thickness, the atrial wall has a negligible impact on the accuracy of measuring the ASA and subsequently estimating the hydraulic forces. In order to minimize the error in the ASA measurement, we included the atrial appendage when visible and delineated the atrial contour in multiple slices. The single largest area from the atrial slices was then selected as the ASA to be compared with VSA.When computing the hydraulic force, we do not take into account the transmitral and intraventricular pressure gradient present during early rapid filling34epi, we have assumed that the LV intraluminal blood pressure acts upon the entire cross-section of the LV and neglected the complex myocardial structure. This assumption is difficult to validate with clinical or experimental methods since the myocardium consists of both fluids  and solids (tissue fibers). Measurements of fluid pressure require invasive techniques. The estimation of the fiber stress distribution within the myocardium is also challenging, and this complexity is related to a number of factors. First, when active relaxation takes place the myocardium continuously changes its mechanical properties. Second, the myocardium is anisotropic and inhomogeneous37Endo, and it is likely that the addition of the intramyocardial hydraulic forces render the total effective VSA to be somewhere between VSAEndo and VSAEpi.We have measured the VSA both as the endocardial and epicardial border of the LV myocardium. The rationale for using the endocardial border is that the blood is in direct contact with this myocardial border. The rationale for using the epicardial border is that both the interstitial pressure within the myocardium23Epi is reduced during systole , while the apical region is not fixed, but has been shown to exhibit negligible longitudinal movement during the cardiac cycle2240Visual inspection of CMR images gives the impression that ASA is smaller than VSA. Short-axis area is defined as the cross-section obtained by cutting the LA or LV with a plane parallel to the AV plane . Since fAL and FVL in The effect of hydraulic force on a curved surface is composed of two orthogonally directed force components (vectors), namely, the longitudinal component acting in the base-apex direction, and the radial component acting orthogonally to the longitudinal component . For theThe exact anatomy of the AV plane is complex and includes the mitral valve orifice which is often described as having the shape of a saddle. Notably, the exact three-dimensional geometry of the AV plane is less relevant when it comes to understanding the hydraulic forces acting upon the AV plane in the apex-base direction. From the perspective of the physics of these apex-to-base directed forces, the geometry of relevance is reduced to the largest short-axis areas, orthogonal to the apex-base direction, which exist on either sides of the AV plane. The resultant force component along the apex-to-base direction can by definition only act on the effective area orthogonal to the direction of the force, regardless of the three-dimensional geometry of the anatomy. The AV plane’s largest area on the ventricular side corresponds to the VSA and the largest area on the atrial side to the ASA.Based on the aforementioned considerations, if we consider the AV plane as a piston with a central lumen and two different areas , one repIt should be noted that pressure is a non-directional magnitude, a scalar, whereas force is a vector acting in a given direction. When referring to hydraulic force in this article, we are referring to the apex-to-base directed component of the resultant force generated by the pressure in the LV and LA on the myocardium.In order to illustrate the effect of hydraulic forces displacing a movable piston with different areas, we built a physical model of the LA and LV, which is shown in Data were obtained from 10 healthy volunteers  which have previously been studied for other purposesEndo) and including (VSAEpi) the LV myocardium. The VSA segmentation was performed in multiple short-axis slices in the vicinity of the AV plane and the largest endocardial and epicardial area at each time point was selected as VSAEndo and VSAEpi, respectively.CMR images were analyzed using the freely available software Segment To understand the relative contribution of hydraulic forces in relation to the peak driving force of LV filling, we sought to estimate the magnitude of the peak driving force and the hydraulic force. The peak driving force per unit mass during diastolic filling has been previously estimated in a population of young healthy subjects and is equal to approximately 25 mN/gIn mechanics and physiology, inertial load is mass accelerated by a force. In the heart, the diastolic inertial load is the total mass of myocardium and blood set in motion as a result of myocardial relaxation that unmasks the stored elastic strain powering left ventricular recoil during diastole. Quantification of inertial load is challenging. Conceptually, inertial load includes the left ventricular myocardium as well as the blood accelerated from a resting position during early rapid filling, but also includes motion of the roots of the great vessels with closed valves.In order to estimate an approximate range of the inertial load, we used the LV mass of young healthy subjects, which on average has been shown to be approximately 125 gEndo − ASA) and (VSAEpi − ASA) at mid diastasis, respectively.A hydraulic force is calculated as Force = (Pressure) × (Difference in Area). Mean LV diastolic pressure was estimated from normal individuals to be 10 mmHg or equivalently 1333 PaEndo and VSAEpi for each individual at a specific time point were compared with the corresponding ASA. All data are expressed as mean ± SEM. The difference between VSA and ASA was tested using the Wilcoxon signed rank test. The statistical analysis was performed using MATLAB  and a difference with a p-value < 0.05 was considered statistically significant.Values obtained for VSAHow to cite this article: Maksuti, E. et al. Hydraulic forces contribute to left ventricular diastolic filling. Sci. Rep.7, 43505; doi: 10.1038/srep43505 (2017).Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


ACR) have increased risk of heart failure. We hypothesized this was because of cardiac tissue changes rather than silent coronary artery disease.Patients with type 2 diabetes mellitus and elevated urinary albumin:creatinine ratio  and in ACR+ve than ACR−ve diabetes mellitus patients . ACR+ve patients also had lower E′ measured by echocardiography  and elevated high‐sensitivity cardiac troponin T 18% versus 4% ≥14 ng/L (P=0.05). Rate of silent myocardial ischemia or infarction were not influenced by ACR status. Renin–angiotensin–aldosterone blockade was associated with increased left ventricular ejection fraction  and decreased extracellular volume fraction  but no changes in diastolic function or high‐sensitivity cardiac troponin T levels.In a case‐controlled observational study 130 subjects including 50 Asymptomatic diabetes mellitus patients with persistent microalbuminuria have markers of diffuse cardiac fibrosis including elevated extracellular volume fraction, high‐sensitivity cardiac troponin T, and diastolic dysfunction, which may in part be reversible by renin–angiotensin–aldosterone blockade. Increased risk in these patients may be mediated by subclinical changes in tissue structure and function.URL: http://www.clinicaltrials.gov. Unique identifier: NCT01970319. Asymptomatic diabetes mellitus patients with persistent microalbuminuria have markers of diffuse cardiac fibrosis including elevated cardiac extracellular volume fraction, high‐sensitivity cardiac troponin T, and diastolic dysfunction, which may in part be reversible by renin–angiotensin–aldosterone blockade.These findings suggest that increased risk in this patient group is mediated by subclinical changes in tissue structure and function rather than occult coronary artery disease. Future randomized studies are needed to establish whether extracellular volume fraction, high‐sensitivity cardiac troponin T, or diastolic dysfunction themselves or the associated adverse prognosis can be altered by intervention.Type 2 diabetes mellitus is well established as an independent risk factor for the development of heart failure and does not appear to show a relationship with conventional risk factors including age, sex, existing coronary artery disease (CAD), and hypertension.Patients with type 2 diabetes mellitus and albuminuria have higher risk of heart failure,Multiparametric cardiovascular imaging has been used to detect subclinical changes in cardiac structure and function in type 2 diabetes mellitus including increased left ventricular (LV) mass, concentric remodeling of the left ventricle,In addition, several cardiovascular imaging methods have been used to show that type 2 diabetes mellitus is associated with increased rates of CAD,Given that the exact pathogenic mechanisms for heart failure in diabetes mellitus remain unclear, we aimed, through a combination of an observational and interventional study, to establish the pattern of subclinical cardiac disease in patients with diabetes mellitus and persistent microalbuminuria and determine whether the risk of heart failure is mediated by occult CAD or changes in cardiac structure and tissue characteristics. The interventional part of the work investigated whether detected abnormalities are reversible after blockade of the RAAS.2), uncontrolled hypertension, and treatment with insulin or ACE inhibitor/angiotensin receptor blocker. Ten‐year likelihood of developing CAD and related mortality were calculated using the Framingham risk score.The study was approved by the National Research Ethics Service (13/YH/0098) and all participants gave informed consent. A total of 100 patients with type 2 diabetes mellitus were recruited from 30 primary care health centers in the local area from August 2013 to March 2015. Fifty consecutive patients with persistent microalbuminuria (ACR+ve), urinary ACR >2.5 mg/mol in males and >3.5 mg/mol in females, were recruited after their annual diabetes mellitus check before commencement on an ACE inhibitor in line with national guidelines.In accordance with current guidelines, all patients with persistent microalbuminuria were started on an ACE inhibitor by their primary care team following the baseline investigations′, A′, and S′ were measured using inbuilt software blinded to clinical details according to international guidelines.All patients underwent echocardiography  focused on Doppler measurements of mitral inflow and tissue Doppler imaging of the lateral and medial mitral annulus for the assessment of diastolic function. E/A ratio, E® technology. Data were acquired during breath‐holding at end expiration. T1 maps were acquired in a midventricular slice. Native T1 mapping used a breath‐held Modified Look‐Locker Inversion recovery (MOLLI) acquisition (ECG triggered 5(3s)3, spatial resolution 1.98×1.98×10 mm3 [reconstructed to 1.25×1.25 mm2]), single‐shot, SENSE factor 2, prepulse delay 350 ms, trigger delay set for end‐diastole (adaptive), flip angle 35°, acquisition duration per image 170 to 185 ms (dependent on field of view).Patients and controls underwent CMR using an identical protocol on a dedicated cardiovascular 3 Tesla Philips Achieva system equipped with a 32‐channel coil and MultiTransmit®, Bayer Pharma, Berlin, Germany).Next, myocardial perfusion CMR was planned in the same 3 short‐axis slices using a spoiled turbo gradient‐echo sequence. This was performed while intravenous adenosine was administered at 140 μg/kg per minute for 3 minutes and repeated >10 minutes later at rest. Gadobutrol (0.075 mmol/kg) was administered for each stress and rest perfusion imaging (GadovistCine images covering the entire heart in the LV short axis (slice thickness 10 mm); left atrium in short axis (slice thickness 5 mm) and in orthogonal long axis planes was acquired. Late gadolinium enhancement (LGE) in matching LV short‐ and long‐axis planes was carried out more than 6 minutes after rest perfusion imaging as described previously.Postcontrast T1 mapping was carried out exactly 15 minutes following last contrast injection using the identical pulse sequence and planning as the native T1 map (above).CMR data were assessed quantitatively using commercially available software . Epicardial and endocardial borders were traced offline on the LV cine stack at end‐diastole and end‐systole to calculate end‐diastolic, end‐systolic LV volumes, stroke volume, ejection fraction (EF), and LV mass. Left atrial volume was calculated by tracing the left atrial endocardial border at end‐systole when the left atrium was largest.Pre‐ and postcontrast myocardial T1 values with a 3‐parameter exponential fit with Look‐Locker correction were measured from the midventricular short‐axis slice in the septum. ECV was calculated from native and postcontrast T1 times of myocardium and blood pool and hematocrit as previously reported excluding any areas of scar seen on LGE imaging.Twenty milliliters of blood was drawn from each subject at the time of each CMR. Full blood count, urea and electrolytes, and hemoglobin A1c were measured at that time. Serum was stored at −70°C and tested for hs‐cTnT , NT‐proBNP ; Cobas 8000  and aldosterone ; local laboratory‐validated radioimmunoassay. Patients with hs‐cTnT ≥14 ng/L and NT‐proBNP ≥125 ng/L were defined as having elevated levels of these biomarkers that have been independently associated with adverse outcomes in type 2 diabetes mellitus.® Statistics 20.0 . Continuous variables were expressed as mean±SD. Categorical variables were expressed as N (%) and compared using Fisher exact test. Shapiro–Wilk test was used to test normality and depending on the result ANOVA and and Kruskal–Wallis test were used to compare means of ACR+ve, ACR−ve, and controls. Paired t test or Wilcoxon test were used to compare parameters before and after treatment. P<0.05 was considered statistically significant.Statistical analysis was performed using IBM SPSSBased on reported difference in ECV between those with and without diabetes mellitus,A total of 464 patients with diabetes mellitus were approached, of whom 128 patients agreed to participate with 50 ACR+ve and 50 ACR−ve completing the full protocol . Native T1 and ECV were also higher in ACR+ve than ACR−ve patients  . Two of 50 ACR+ve and 2/50 ACR−ve patients had clinically significant inducible ischemia on adenosine stress perfusion imaging. None of the controls had inducible ischemia.T1 mapping could be analyzed in all scans. At baseline, native T1 and ECV were higher in patients with diabetes mellitus than in controls  but there was no significant difference in E/A ratio, average E/E′, or S′.There were no significant differences in LV EDV, ESV, mass, EF, or left atrial volume between ACR+ve, ACR−ve, or control Table . AverageP=0.05). No difference was seen in the proportion of patients with elevated NT‐proBNP or serum aldosterone levels. Patients with elevated hs‐cTnT had significantly elevated native T1 and ECV . In patients with elevated NT‐proBNP, ECV was higher  but the difference in native T1 did not reach significance .There was a trend to more ACR+ve than ACR−ve patients having elevated hs‐cTnT levels  but the change in 24‐hour blood pressure was not statistically significant  but not native T1 . There was also a significant decrease in LV EDV  and an associated increase in LV EF  but there was no significant change in LV mass or left atrial volume. E/A ratio, E′, E/E′, or S′ measured by echocardiography were not altered by treatment with RAAS inhibition. On repeat biomarker assessment the proportion of patients with elevated hs‐cTnT or NT‐proBNP was not altered by RAAS inhibition.After 1‐year treatment with RAAS inhibition 14/30 (47%) had a decrease in ACR to the extent they would no longer be considered ACR+ve. RAAS inhibition was associated with a decrease in ECV . This rate at baseline was already comparable with the 15.5% Framingham predicted risk of developing coronary disease over the subsequent 10 years. This result is also in keeping with previous studies of patients with type 2 diabetes mellitus, although it should be noted that patients in these studies were not necessarily asymptomatic.Conversely, the rate of inducible ischemia detected on adenosine stress CMR was only 4%, which is lower than comparable studies using single‐photon emission computed tomography.′, suggesting more advanced diastolic dysfunction. Previous studies have suggested that more severe diastolic dysfunction in diabetes mellitus predicts those who are likely to go on to develop clinically important heart failure.Diastolic dysfunction was a common finding in our study population , in keeping with previous studies.Treatment with RAAS inhibition was associated with a modest improvement in systolic function, although there were no significant changes in diastolic function measured by echocardiography. This is in keeping with the observation that RAAS inhibition is a much better treatment for heart failure with reduced EF than with preserved EF and diastolic dysfunction.Interestingly, RAAS inhibition was not associated with a decrease in LV mass. It is well recognized that there is a strong correlation between blood pressure and LV mass.Microalbuminuria has been used for some time as a screening biomarker to identify patients with diabetes mellitus with increased cardiovascular risk,Patients with type 2 diabetes mellitus have elevated levels of both hs‐cTnT and NT‐proBNP, which appear to be predictive of adverse cardiovascular events including heart failure.This study was a nonblinded observational study, and the results need to be confirmed in a larger blinded randomized cohort. Furthermore, the study was not powered to investigate the prevalence of silent CAD or heart failure end points but did include multiple surrogate imaging end points. We have not carried out coronary angiography because this invasive procedure would not be ethically appropriate in asymptomatic low‐risk patients. However, stress perfusion imaging excluded significant silent ischemia in these patients and therefore CAD is unlikely to be responsible for our findings. For the same reasons, we did not carry out myocardial biopsy to confirm increased extracellular matrix histologically. However, ECV measured by CMR has been validated against histology in other disease processesAsymptomatic patients with type 2 diabetes mellitus and persistent microalbuminuria have several markers suggestive of diffuse cardiac fibrosis including elevated ECV, hs‐cTnT, and diastolic dysfunction. The prevalence of silent myocardial ischemia or infarction was not influenced by ACR status. Treatment with an ACE inhibitor was associated with improvement in LV EF and ECV regression. These findings suggest that increased risk in this patient group is mediated by subclinical changes in tissue structure and function rather than occult CAD, which may have implications for the management of these patients.Guarantors of integrity of entire study Swoboda, Plein; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; approval of final version of submitted manuscript, all authors; literature research, Swoboda, Plein; statistical analysis, Swoboda, and manuscript editing, all authors.Swoboda (FS/12/88/29901) and Plein (FS/1062/28409) are funded by British Heart Foundation fellowships. This study was supported by the National Institute for Health Research Leeds Clinical Research Facility. The views expressed are those of the author(s) and not necessarily those of the NHS, NIHR, or the Department of Health.Witte and Kearney have received research funding from Medtronic UK. Other authors have no disclosures.


The aim of this study was to examine the associations of isolated minor nonspecific ST-T abnormalities (NSSTTA) on 12-lead electrocardiogram (ECG) with left ventricular (LV) diastolic function and LV geometry on echocardiography. A cross-sectional study comprised of 74,976 Koreans who underwent ECG and echocardiography as part of a comprehensive health examination between March 2011 and December 2014. ECG was coded using Minnesota Code criteria. The frequencies of NSSTTA, impaired LV relaxation, and echocardiographic LVH were 1,139 (1.5%), 21,118 (28.2%), and 1,687 (2.3%) patients, respectively. The presence of NSSTTA was positively associated with the prevalence of impaired LV relaxation and LVH on echocardiography. In a multivariable-adjusted model, the odds ratio (95% CIs) comparing patients with NSSTTA to control patients was 1.55 (1.33–1.80) for impaired LV relaxation and 3.15 (2.51–3.96) for echocardiographic LVH. The association between NSSTTA and impaired LV relaxation was stronger in the intermediate to high cardiovascular disease-risk group than in the low-risk group according to Framingham Risk Score stratification (P for interaction = 0.02). NSSTTA were associated with increased prevalence of impaired LV relaxation and LVH, suggesting NSSTTA as an early indicator of subclinical cardiac dysfunction and geometric abnormalities. Decreased early mitral annulus velocity, a measure of impaired left ventricular (LV) relaxation, was associated with fatal and nonfatal cardiovascular events, including overt heart failure3. LV hypertrophy (LVH) is a strong predictor of non-fatal and fatal cardiovascular events4. Therefore, it is important to identify impaired LV relaxation and LVH in asymptomatic individuals for establishing preventive strategies before adverse cardiovascular events occur.Heart failure is a progressive disease associated with aging, and up to half of heart failure cases are attributed to diastolic dysfunction7. However, the precise mechanism underlying the poor cardiovascular prognosis of NSSTTA has not been fully elucidated, and the echocardiographic characteristics of NSSTTA have not been explored yet.Electrocardiogram (ECG) is an inexpensive and convenient tool to assess the geometric and functional status of the heart and is widely used in clinical practice. Furthermore, ECG can reveal past heart events and predict future cardiovascular disease (CVD). Isolated minor nonspecific ST-T wave abnormalities (NSSTTA), one of the most common ECG abnormalities, are considered a benign finding in asymptomatic individuals, but several studies have found that NSSTTA are associated with increased risk of cardiovascular events or deathTherefore, the goal of this study was to examine the associations between NSSTTA and echocardiographic findings, including geometric changes and LV functional status, in a large sample of Korean men and women who participated in a health check-up program.9. Over 80% of the participants were employees of various companies or local government organizations and their spouses, and the health screening exams were paid for by employers under the Korean Industrial Safety and Health Law. The remaining participants voluntarily purchased self-paid screening exams at the health screening center. This study consisted of 74,976 men and women who underwent echocardiography as part of a comprehensive health examination between March 2011 and December 2014.The Kangbuk Samsung Health Study is a cohort of Korean men and women who underwent comprehensive annual or biennial examinations at Kangbuk Samsung Hospital Total Healthcare Centers in Seoul and Suwon, South KoreaWe excluded 11,741 participants for the following reasons: missing data on either ECG, levels of serum glucose, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), or triglycerides, body mass index (BMI), or systolic blood pressure (BP) (n = 393); a history of malignancy (n = 2176); a history of CVD (n = 1085); decreased LV systolic function (ejection fraction <50%), hypertrophic, dilated and ischemic cardiomyopathy, mitral/aortic stenosis of mild grade or greater, moderate or higher grade of mitral/aortic regurgitation, or post-operative cardiac surgery including valve replacement (n = 3213); or the presence of major ECG abnormalities according to the Minnesota Code (n = 4874). Because some participants met more than one exclusion criteria, 74,976 participants were included in this study. This study was approved by the Institutional Review Board of Kangbuk Samsung Hospital, and the requirement for informed consent was waived because we used de-identified retrospective data that had been routinely collected during the health screening process. We confrm that all methods were performed in accordance with the relevant guidelines and regulations.8. Smoking status categories included never, former, and current. Alcohol consumption was categorized into none, moderate (≤20 g/day), and high (>20 g/day). The physical activity was assessed using the validated Korean version of the International Physical Activity Questionnaire Short Form10. Health-enhancing physically active (HEPA) was defined as physical activity that meets either of two criteria: (i) vigorous intensity activity on three or more days per week accumulating ≥1500 MET min/week; or (ii) seven days of any combination of walking, moderate intensity, or vigorous intensity activities achieving at least 3000 MET min/week10.Information on demographic characteristics, smoking status, alcohol consumption, education level, and medical history were collected by standardized, self-administered questionnaires as previously described2). Obesity was defined as BMI ≥ 25 m/kg2 according to the proposed criteria for obesity in Asian populations. BP was measured using an automated oscillometric device  while subjects were in a sitting position with the arm supported at heart level. Three readings were recorded for each individual, and the average BP of the second and third readings was used for analysis to reduce errors in measurement. Hypertension was defined as a systolic BP ≥ 140 mmHg, a diastolic BP ≥ 90 mmHg, or current use of antihypertensive medication.Height and weight were measured by trained nurses and BMI was calculated as height (m) divided by weight (kg) squared (m/kg8. Insulin resistance was assessed with the homeostatic model assessment – insulin resistance (HOMA-IR) equation: fasting blood insulin (uU/mL) × fasting blood glucose (mmol/L)/22.5. Diabetes was defined as a fasting serum glucose ≥126 mg/dL, hemoglobin A1c ≥ 6.5%, or current use of insulin or anti-diabetic medications.Measurements for serum biochemical parameters, including levels of glucose, insulin, high sensitivity C-reactive protein (hsCRP), total cholesterol, triglycerides, LDL-C, and HDL-C, are described in detail elsewhere11. Criteria for major ECG abnormalities were any of the following5: Q-QS wave abnormalities, major ST-T wave abnormalities, LVH, atrial fibrillation, atrial flutter, Wolff-Parkinson-White syndrome, complete bundle-branch block, and intraventricular block. NSSTTA were classified according to Minnesota Codes 4-3, 4-4, 5-3, and 5-4.Standard 12-lead ECG were obtained at a 25 mm/s paper speed and at 1 mV/cm amplification with an ECG recorder . ECG was performed in all subjects the same day as the echocardiographic examination and was interpreted by two experienced cardiologists who were blinded to the echocardiographic results and codified with the Minnesota Code3 − LVESD3] + 0.6 g12. The LV mass index (LVMI) was calculated as LV mass/height2.7, and LVH was defined as LVMI ≥ 45 g/m2.7 for women and ≥49 g/m2.7 for men13. The anteroposterior dimension of the left atrium (LA) was also measured.Conventional echocardiography was performed with ultrasound scanners  by registered diagnostic cardiac sonographers. Linear measurements of LV posterior wall thickness (PWT), intraventricular septum thickness (IVST), and diameter of the LV cavity at the end of diastole and systole were obtained in M-mode in the parasternal long axis view. The LV ejection fraction was calculated from LV end-diastolic diameter (LVEDD) and end-systolic diameter (LVESD) using the Teichholz method. The LV mass was calculated with measurements obtained in M-mode using the following equation: LV mass = 0.8 × [1.04 × (LVEDD + IVST + PWT)15.To assess diastolic function, the pulse-wave Doppler transmitral LV inflow velocity in the apical 4-chamber view was sampled. The early diastolic mitral inflow peak velocity (E), late diastolic peak velocity (A) during atrial contraction, and deceleration time of the E velocity (DT) were measured. The early (E′) and late (A′) velocities from tissue Doppler imaging of the septal mitral annulus were also measured. Impaired LV relaxation was defined as E′ < 8 cm/sDescriptive statistics were used to summarize the characteristics of participants by the presence of NSSTTA. Age- and sex-adjusted mean values and 95% CIs of echocardiographic findings were also examined according to the presence of NSSTTA.To determine the association of NSSTTA with impaired LV relaxation and LVH, we used a logistic regression model to estimate odds ratios with 95% confidence intervals (CIs). We used three models with progressively increased adjustment for confounding variables. Data were initially adjusted for age and sex and then were further adjusted for study center (Seoul or Suwon), year of screening exam, smoking history , alcohol intake , physical activity, educational level , and BMI. Finally, model 2 was further adjusted for family history of heart disease; history of diabetes and history of hypertension; levels of glucose, LDL-cholesterol, HDL-cholesterol, and triglycerides; and systolic BP.2), HOMA-IR (<2.5 vs. ≥2.5), hsCRP (<1.0 vs. ≥1.0), diabetes (no vs. yes), hypertension (no vs. yes), and Framingham Risk Score (<10% vs. ≥10%). Interactions between subgroups were tested using likelihood ratio tests comparing models with and without multiplicative interaction terms. All P-values were two-tailed, and P-values < 0.05 were considered statistically significant. We used STATA version 14.0  for data analysis.We performed stratified analyses in pre-specified subgroups defined by sex , age (<50 vs. ≥50 years), smoking (never or ex-smoker vs. current smoker), alcohol intake (<20 vs. ≥20 g/day), HEPA (no vs. yes), BMI , HOMA-IR (<2.5 vs. ≥2.5), hsCRP (<1.0 vs. ≥1.0), diabetes (no vs. yes), and hypertension (no vs. yes)  Table ; otherwis) Table . The assIn this large study of young and middle-aged men and women, we identified two major findings. First, we found an association between the presence of NSSTTA on ECG and impaired LV relaxation and LVH on echocardiography. These associations persisted even after adjustment for potential confounders, including cardiovascular risk factors. Second, the association between NSSTTA and impaired LV relaxation was stronger in the intermediate to high CVD-risk group than in the low-risk group according to Framingham Risk Score stratification.20. The P-wave dispersion, QRS-voltage-duration products, QT interval, T-wave inversion, and T-peak to T-end interval are ECG findings or measurements observed at various points in the cardiac cycle that have been found to be related to diastolic dysfunction20. Several of these studies, and ours, present data that supports that the main mechanism explaining the relationship between LV diastolic dysfunction and ECG abnormalities is related to abnormal repolarization of electrical activity18. The difference between the ECG findings in our study from those of previous studies is that NSSTTA are commonly assessed in clinical settings, whereas previous study parameters are not easily applicable in clinical practice18.Previous studies have examined the associations between ECG findings and diastolic function of the LV21, whereas pathological LVH might not present with a QRS high voltage pattern. Pathological LVH is accompanied by not only increases in levels of certain cardiomyocyte proteins, but also an altered extracellular matrix composed of fibroblasts, cardiac steatosis, and vascular smooth muscle cells22. This can explain the discrepancy between anatomical LV mass and electrically active LV mass. In a report of LVH patients without coronary stenosis, the electrocardiographic findings of echocardiographic LVH presented as various electrical manifestations, including a flat T wave without increased QRS voltage23. Indeed, it has recently been shown that myocardial fibrosis measured by cardiovascular magnetic resonance imaging (MRI) is associated with reduced QRS voltage regardless of LV mass on ECG24.The mechanisms underlying the association between NSSTTA with impaired LV relaxation and echocardiographic LVH are not fully understood. We demonstrated a higher prevalence of echocardiographic LVH in the context of NSSTTA without ECG LVH. Most of the ECG LVH criteria include high electrical voltage with the assumption that thicker myocardium has more electrical activity. Indeed, the ECG characteristics of physiological LVH include QRS high voltage25. The reasons for the stronger association of NSSTTA with impaired LV relaxation in this patient subgroup are unclear, but cardiac fibrosis as a cause of diastolic dysfunction can be more prevalent in the higher risk group, serving as one possible explanation26.In the present study, the association between NSSTTA and impaired LV relaxation was stronger in individuals at an intermediate to high risk for CVD. A previous community-based study demonstrated that a higher prevalence of diastolic dysfunction was observed as the number of cardiovascular risk factors increased27. Lindsay et al. reported a significant elevation in level of TIMP-1, a biomarker of cardiac fibrosis, in patients with hypertension and ECG ST-T changes28. In addition, level of TIMP-1 was related to the E/A ratio and DT on echocardiography, indicating the possibility of a correlation between the expression of this protein with LV diastolic function28. Moreo et al. reported an association between cardiac fibrosis and diastolic dysfunction using cardiac MRI and echocardiography29.Cardiac fibrosis is responsible for electrical disturbances that can lead to ST-T wave abnormalities. Increased myocardial interstitial fibrosis and collagen accumulation commonly accompany LVH, which affects conduction disturbances, myofibrillar disarray, and heterogeneous gap junction distribution30. Second, other ECG parameters related to LV diastolic dysfunction reported in previous studies were not available in our study. However, our study was the first to find an association between NSSTTA and impaired LV relaxation, explaining the poor cardiovascular prognosis of NSSTTA from prior studies. Our findings in apparently healthy, young, and middle-aged Korean adults might limit generalizability to other ethnic populations or patients with comorbid conditions. However, subjects with fewer comorbidities minimize the presence of potentially unmeasured confounders that could affect ECG signals or LV diastolic function.Our study had some limitations. First, we measured mitral annulus velocity only in the septal area. The current guideline recommends the use of a mean value by measuring both septal and lateral mitral annulus velocities; however, septal E′ can predict LV longitudinal myocardial relaxation and diastolic functionIn this large sample of apparently healthy Korean adults, NSSTTA were associated with increased prevalence of impaired LV relaxation and LVH on echocardiography. In particular, clinicians should be mindful of impaired LV relaxation in the presence of NSSTTA on ECG when the conventional cardiovascular risk is intermediate to high. This suggests that NSSTTA can reflect subclinical cardiac dysfunction and geometric abnormalities, possibly explaining the unfavorable prognosis of NSSTTA with regard to cardiovascular outcomes.Supplementary Information


Cardiovascular magnetic resonance (CMR) T1 mapping has recently been shown to be highly sensitive for detecting myocardial iron overload. Furthermore, T1-mapping can be used to quantify relative concentrations of contrast agents that shorten T1. We hypothesized that T1 mapping can detect and quantify the myocardial distribution of a clinically available intravenous iron substitution agent.CMR imaging was performed in healthy male volunteers . T1 of blood and myocardium was quantified using a modified Look-Locker inversion recovery (MOLLI) sequence for T1-mapping in a mid-ventricular short-axis slice at 1.5T (Siemens Aera). Images were acquired before and at regular intervals up to 50 minutes after onset of a 15 minute long injection of 20 ml (50 mg iron/ml) ferric carboxymaltose (Vifor Pharma). T1, R1 and ΔR1 of myocardium and blood, and the partition coefficient (lambda) for myocardium were measured over time.Both myocardial and blood T1 were shortened after intravenous injection of ferric carboxymaltose (Figure 1, thus indicating that ferric carboxymaltose distributes to a greater extent into the myocardium than extracellular agents, most likely by distribution also into the intracellular space. The described technique opens up the new possibility for using CMR to study in vivo myocardial iron physiology in health and disease.T1 mapping can be used to detect and quantify the myocardial distribution of ferric carboxymaltose figure . Further


Detailed quantitative analysis of the effect of left ventricle (LV) hypertrophy on myocardial ischemia manifestation in ECG is still missing. The associations between both phenomena can be studied in animal models. In this study, rabbit isolated hearts with spontaneously increased LV mass were used to evaluate the effect of such LV alteration on ischemia detection criteria and performance.Electrophysiological effects of increased LV mass were evaluated on sixteen New Zealand rabbit isolated hearts under non-ischemic and ischemic conditions by analysis of various electrogram (EG) parameters. To reveal hearts with increased LV mass, LV weight/heart weight ratio was proposed. Standard paired and unpaired statistical tests and receiver operating characteristics analysis were used to compare data derived from different groups of animals, monitor EG parameters during global ischemia and evaluate their ability to discriminate between unchanged and increased LV as well as non-ischemic and ischemic state.st-3rd min) of ischemia. Besides ischemia, these parameters reflect increased LV mass as well (with sensitivity reaching approx. 80%). However, the sensitivity of the parameters to both phenomena may lead to misinterpretations, when inappropriate criteria for ischemia detection are selected. Particularly, use of cut-off-based criteria defined from control group for ischemia detection in hearts with increased LV mass may result in dramatic reduction (approx. 15%) of detection specificity due to increased number of false positives. Nevertheless, criteria adjusted to particular experimental group allow achieving ischemia detection sensitivity of 89–100% and specificity of 94–100%, respectively.Successful evaluation of both increased LV mass and ischemia is lead-dependent. Particularly, maximal deviation of QRS and area under QRS associated with anterolateral heart wall respond significantly to even early phase  and other methodological aspects . Results of this study might be helpful for developing new clinical diagnostic strategies in order to improve myocardial ischemia detection in patients with LV hypertrophy. Despite the intensive clinical and preclinical research, both morbidity and mortality associated with myocardial ischemia remain high. Diagnosis of myocardial ischemia might be complicated by co-incidence with other diseases, e.g. myocarditis, hypertension or left ventricular (LV) hypertrophy. The association between myocardial ischemia and LV hypertrophy has been intensely discussed during the last few decades. Particularly, the studies elucidated such important aspects as mechanisms of development and prevalence of myocardial ischemia in LV hypertrophy patients, specific character of analysis of ECG with ischemia-like patterns recorded in LV hypertrophy patients with and without evidence of myocardial ischemia, and others –3. NeverIn cardiovascular research, particular aspects can be successfully studied on animal models, frequently on isolated heart perfused according to Langendorff . AlthougThis paper presents the comprehensive study, where the effect of increased LV mass fraction on assessment of myocardial ischemia in electrocardiographic signals was addressed for the first time. Particularly, rabbit isolated heart model was used to: a) evaluate suitability of electrogram (EG) parameters for detection of increased LV mass fraction; b) quantify possible effects of increased LV mass fraction on the heart response to ischemia ; c) assess an impact of LV mass on efficiency of ischemia detection in EG. Besides the anatomical and electrical characteristics of the heart, the effect of mutual spatial orientation of the heart and electrode system on EG morphology was investigated, too. As a consequence, present work contributes to improving the quality and reliability of ischemia studies on animals and brings new information potentially useful for assessment of increased LV mass and myocardial ischemia.All experiments were carried out with respect to recommendations of the European Community Guide for the Care and Use of Laboratory Animals and according to the experimental protocol approved by the Committee for Ensuring the Welfare of Experimental Animals, Faculty of Medicine, Masaryk University.3, 24 mM; KCl, 4.2 mM; KH2PO4, 1.2 mM; MgCl2, 1.2 mM; CaCl2, 1.25 mM; glucose, 5.5 mM) aerated by pneumoxyd [Sixteen adult New Zealand rabbits  were included in the study. After premedication , the rabbits were anaesthetized by mixture of xylazin  and ketamin . To prevent ischemia during heart preparation, trachea was cannulated and the animal was artificially ventilated . Then the chest was opened, heart was rapidly excised and placed into cold (4 °C) Krebs-Henseleit (K-H) solution. The heart was fixed to a Langendorff apparatus and perfused with K-H solution , the rotation of the heart (5 min), global ischemia (induced by cessation of perfusion), and reperfusion (each 10 min long). In stabilization period, the hearts were rotated around their longitudinal axis from 0° to 90° in 10° steps, where 0° was considered as initial heart position in recording system  of each animal was assessed. Immediately after the isolated heart experiment, the whole heart was weighted . Both atria and right ventricle were then separated and LV with septal wall was weighted . Free lateral wall of LV was cut and the wall thickness (LVT) was measured.p < 0.001, Mann-Whitney U test; n = 8 for both groups).To assess spontaneously changed anatomical characteristics of the heart, following indexes were calculated: the heart weight to body weight (HW/BW) ratio, the LV weight to body weight (LVW/BW) ratio and LV weight to heart weight (LVW/HW) ratio. According to the results of retrospective analysis, LVW/HW ratio – representing the LV fraction in the whole heart mass – was the only index suitable for dividing the animals into two groups. The discrimination threshold value of LVW/HW ratio (0.57) was found by analysis of receiver operating characteristics (ROC) curve . Thus, aBefore EG parameters calculation, the EG segments with artefacts were excluded from the analyses. The low-frequency baseline wander was suppressed using Lynn’s filter with cut-off frequency of 0.5 Hz. After filtering, QRS complexes were automatically detected using wavelet based detector. For representation of particular lead positions see Fig. , averageD), absolute value of maximal QRS deviation (QRSA), area under whole QRS , and area under positive (+AUCQRS) and negative (−AUCQRS) part of QRS. These parameters were also calculated from EG recorded within the whole ischemia and reperfusion by initially placed lead I and lead II (see above).Following QRS-related parameters were analysed in each rotation position in stabilization period: QRS duration (QRSA) were calculated. The former was chosen empirically as an alternative to ST60 used in human ECG analysis considering the differences in characteristics (mainly QT and ST-T duration) of human ECG and EG of rabbit isolated heart.Besides abovementioned parameters, level of ST segment at J + 20 ms point (ST20) and maximal deviation of T wave , specificity (Sp), area under ROC curve (AUCROC), and optimal cut-off point were used to quantify the detection performance. Particularly, AUCROC of 0.5–0.6 and 0.9–1 represents poor and excellent discrimination performance of the parameter, respectively [p < 0.05 was considered as significant.It was found, that data are not normally distributed (Shapiro-Wilk test). The non-parametric Mann-Whitney U-test was then used to test the differences between L and H groups in following data sets: a) EG parameters in different heart positions calculated in stabilization; b) EG parameters calculated from data recorded during ischemia and reperfusion. Additionally, Wilcoxon signed rank test was applied in L and H group separately in order to reveal possible significant changes of the parameters appeared at the end of each minute during ischemia and reperfusion . Correlation between anatomical characteristics was investigated using Spearman’s correlation coefficient ectively . For allA  and in AUCQRS   were: cut-off point 3.3 mV (−45.3 mV·ms), Se 82% (75%) and Sp 83% (82%). Indices calculated for other parameters were significantly lower within the whole recording range  of ischemia. In lead I data, ischemia manifestations were generally indicated with 1–2-min delay as compared to lead II. Values of almost all parameters returned to the control level immediately at the beginning of reperfusion. The exceptions were QRSD and ST20 from H group, where ischemia-induced changes disappeared after 3–4 min of perfusion recovery.Firstly, magnitude and time onsets of ischemia manifestations were evaluated in each group separately. Parameters measured at the end of each minute of ischemia were compared with those from the end of stabilization by paired test. Onsets of significant ischemia-induced changes of different parameters are summarized in Table D (4th–7th min of ischemia) and AUCQRS and +AUCQRS (5th–10th min of ischemia). In Fig. D and AUCQRS in each minute of corresponding experimental period is shown using box plots. It is evident that above differences are due to accentuation of parameters values in H group. No differences were found in values of ST-T parameters during ischemia as well as in all parameters calculated from reperfusion.Secondly, the responses of the hearts with unchanged and increased LV mass fraction to myocardial ischemia and reperfusion were compared via comparison (using unpaired test) of parameters measured in both groups during corresponding experimental periods. Significant differences were found in case of QRSA derived from lead II or AUCQRS derived from lead I or lead II in both groups, etc.), AUCROC reaches 0.8 (indicating good discrimination ability) in approx. The 3rd-5th minute of ischemia  for ischemia detection in the hearts with high LV mass fraction results in prominently decreased Sp (by approx. 15%) as compared to detection based on H group cut-off (39 mV·ms) due to increased number of false positives  for ischemia detection in united data results in decreasing of Se (by 5%) and increasing of Sp (by 9%) due to increased number of false negatives and decreased number of false positives, respectively , LVW and BW  and LVW and HW .In contrast to the human, where LV mass assessment is generally based on evaluation of LV volume parameters , in Increased LV mass fraction in group H was accompanied by insignificant but clearly visible increase of collagen content  together with decreased tolerance of such myocardium to ischemic insult, as was previously reported . ConsideOne of the factors influencing the quality and characteristics of ECG is the mutual orientation of electrode system and the heart which can be affected with the subject’s body position or electrode placement during recording procedure. Clinically significant ST segment deviation and changes of QRS complexes  in standard ECG recorded at right and left-side lying position (comparing with supine) in both healthy and subjects with cardiac disease were reported . The draIn the present study, longitudinal rotation of the heart placed in the bath filled with K-H solution was performed in stabilization in order to obtain EGs from different sites of LV. In both animal groups, no significant “pseudo-ischemic” alterations  were found in EGs, including those from initial position of horizontal leads, which is suitable for monitoring the changes in EG morphology caused by global ischemia . Small aIt is known that anatomical changes of the heart such as LV hypertrophy produce the changes in ECG morphology including increased amplitude and QRS complex prolongation, QRS patterns associated with the defects of intraventricular conduction and the left axis deviation , 28, 29.A. Nevertheless, AUCQRS seems to be the most sensitive to the changes in electrical activity caused by LV mass fraction increase  can be accurately detected using easily calculated EG parameters . As in human , one of see Fig. . This isduration . It shouduration ).QRS and -AUCQRS) should be included in the study. Other possible approach is use of data recorded from boundary LV areas  . These cD and AUCQRS parameters between L and H groups revealed in the middle of ischemia  obviously results in increase of false positive or false negative detections and, consequently, in decrease of Sp or Se (or both)  can be considered relevant for clinical practice due to similarities in characteristics of rabbit and human heart. Particularly, results of this study might be helpful for improvement of myocardial ischemia detection in patients with LV hypertrophy.


Collectively, these findings illustrate that LLLT improves LV systolic function in the early post-infarction cardiac remodeling. However, this beneficial effect may be dependent on the maintenance of phototherapy. Long-term studies with LLLT application are needed to establish whether these effects ultimately translate into improved cardiac remodeling.Low-level laser therapy (LLLT) has been targeted as a promising approach that can mitigate post-infarction cardiac remodeling. There is some interesting evidence showing that the beneficial role of the LLLT could persist long-term even after the end of the application, but it remains to be systematically evaluated. Therefore, the present study aimed to test the hypothesis that LLLT beneficial effects in the early post-infarction cardiac remodeling could remain in overt heart failure even with the disruption of irradiations. Female Wistar rats were subjected to the coronary occlusion to induce myocardial infarction or Sham operation. A single LLLT application was carried out after 60 s and 3 days post-coronary occlusion, respectively. Echocardiography was performed 3 days and at the end of the experiment (5 weeks) to evaluate cardiac function. After the last echocardiographic examination, LV hemodynamic evaluation was performed at baseline and on sudden afterload increases. Compared with the Sham group, infarcted rats showed increased systolic and diastolic internal diameter as well as a depressed shortening fraction of LV. The only benefit of the LLLT was a higher shortening fraction after 3 days of infarction. However, treated-LLLT rats show a lower shortening fraction in the 5th week of study when compared with Sham and non-irradiated rats. A worsening of cardiac function was confirmed in the hemodynamic analysis as evidenced by the higher LV end-diastolic pressure and lower +dP/dt and −dP/dt with five weeks of study. Cardiac functional reserve was also impaired by infarction as evidenced by an attenuated response of stroke work index and cardiac output to a sudden afterload stress, without LLLT repercussions. No significant differences were found in the myocardial expression of Akt Myocardial infarction (MI) is a major cause for heart failure (HF) development  dilation and enlargement of the ischemic tissue . The protocol was approved by the Institutional Research Ethics Committee of the Nove de Julho University, São Paulo, Brazil (number: 0015–2012). Experiments were performed under ketamine (50 mg/kg), and Xylazine (10 mg/kg) mixture anesthesia, and efforts were made to minimize the suffering of animals.n = 7); infarcted rats submitted to LLLT . Sham rats (n = 8) were operated upon similarly, although the coronary occlusion was avoided. The Sham and MI-N groups were submitted to a similar LLLT procedure, yet the device was kept off (placebo). Echocardiographic analyses were carried out on 3 days and 5 weeks post-infarction. We have included in the study only rats with large infarcts, which showed be defined on the 3rd-day post-infarction as a size ≥ 37% of LV  was used for irradiation under the parameters in Table Rats were anesthetized as described above (K-X mixture) and LV echocardiography was performed using a 12-MHz transducer connected to an HP Sonos-5500 . The infarct size was evaluated on transverse 2-dimensional view and reported as percent of the LV perimeter on the basal, mid transversal, and apical planes  and oxygen-enriched ventilation with a closed chest. The left femoral vein was accessed for drug administration, and a 2-F gauge Millar catheter-tip micromanometer  was inserted into the right carotid artery into the LV cavity. Moreover, an ultrasound flow probe  was positioned in the ascending aorta. The following data were analyzed : LV systolic (SP) and end-diastolic pressures (EDP), rate of change of LV pressure (+dP/dt and −dP/dt), heart rate, and cardiac output (CO), and stroke volume (SV). Stroke work index (SWI) was stated as previously described , and Image Pro-Plus software, version 4.0 .Proteins were extracted from the LV remote area as previously described by us . Shapiro-Wilk test was used to verify normality data. Levene test was applied to assess the equality of variances. One-way ANOVA complemented by Newman–Keuls The biometric data are shown in Table As seen in Figure in bolus phenylephrine injection. For suitable homogenization, we carried out experiments to raise the blood pressure of 50–70% over the baseline level   and FAPESP .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.


Accurate prediction of sudden cardiac death due to ventricular arrhythmia remains challenging. Left ventricular ejection fraction has shown an association with increased risk of ventricular arrhythmias and is included in the recommendations for implantable cardioverter defibrillator as primary prevention. However, left ventricular ejection fraction may be normal in a large number of patients who are at risk of ventricular arrhythmias. Echocardiography remains the imaging technique of first choice to rule out the presence of structural heart disease and assess left and right ventricular function. Advances in strain echocardiography and cardiac magnetic resonance have provided important insights into the mechanisms of ventricular arrhythmias, and will be summarized in this review. Accurate prediction of sudden cardiac death (SCD) due to ventricular arrhythmia remains challenging. Predictive models should take into consideration the interaction between vulnerable substrates, defined by the presence of genetic or acquired electrical, functional or structural heart disease, and the multiple transient factors  that may precipitate the ventricular arrhythmia, making almost impossible to obtain one common predictive model for all patients, including individuals without known heart disease. Of the total number of SCD events, almost 50% occur in subjects without known heart disease.Cardiac imaging has developed several indices beyond LVEF that permit the identification of patients at high risk for SCD. Echocardiography remains the imaging technique of first choice to rule out the presence of structural heart disease and assess left and right ventricular functions. Advances in strain imaging have provided important insights into the dispersion of the mechanical activation throughout the left ventricle and the presence of heterogeneous regional function that may increase the risk of ventricular arrhythmias.This review article provides an overview on current evidence showing the additional role of advanced echocardiography and CMR techniques to select patients for ICD implantation for primary prevention. Several echocardiographic and CMR-derived parameters characterizing the arrhythmogenic substrate and transient factors that may increase arrhythmogenicity in ischemic and nonischemic cardiomyopathies will be reviewed.In ischemic cardiomyopathy, the most frequent underlying mechanism of ventricular arrhythmia/fibrillation is reentry. The presence of unexcitable dense scar tissue (core infarct) forms an area of fixed conduction block whereas the surrounding areas with viable myocardium intermingled with fibrous tissue (border or peri-infarct zone) increase the nonuniform anisotropy, favors electrical uncoupling and leads to areas of unidirectional conduction block and slow conduction forming the substrate for reentry.P = 0.001), whereas LVEF was not.P = 0.04) whereas LVEF and total infarct size were not associated.P < 0.001).In patients with myocardial infarction, gadolinium-based contrast agents accumulate in the increased extracellular space with a subendocardial or transmural distribution within the left ventricular wall reflecting the ischemic-necrotic wave-front phenomenon during myocardial infarction. On T1-weighted CMR acquisitions, myocardial scarring appears hyperintense (white) in contrast to the normal viable myocardium .P < 0.001).Advanced echocardiography can also assess the tissue heterogeneity of myocardial infarction focusing on the mechanical and electrical properties. Echocardiographic speckle tracking analysis informs about the deformational capacity of the LV myocardium, representing the contractile status of the myocardium. The 3-dimensional disposition of the myocardial fibers changing continuously from a right-handed helix in the subendocardium to a left-handed helix in the subepicardium determines the specific deformation of the left ventricle: shortening-lengthening in the longitudinal and circumferential directions and thickening-thinning in the radial direction.] Figure . More spP < 0.01), whereas LV GLS was not significantly associated. In the study by Ersboll et al above mentioned, LV mechanical dispersion was also associated with increased risk of ventricular arrhythmias .P < 0.001).In addition, the dispersion of the LV mechanical activation measured with speckle tracking echocardiography as the standard deviation of the time to peak longitudinal strain of 16 LV segments has been proposed as a surrogate to characterize the tissue heterogeneity that may predispose to ventricular arrhythmias .Furthermore, in ischemic heart failure patients, assessment of myocardial ischemia and viability with dobutamine stress echocardiography is of importance and has been associated with the occurrence of ventricular arrhythmias. In 90 patients with ischemic heart disease and treated with an ICD for primary or secondary prevention, the presence of inducible ischemia during dobutamine stress echocardiography was associated with 2-fold increased risk of death or appropriate ICD therapy at follow-up .The association between the presence of LGE (replacement fibrosis) and risk of SCD, aborted SCD, or appropriate ICD therapy for ventricular tachycardia was demonstrated in a recent meta-analysis of 7 studies including 1194 patients with nonischemic cardiomyopathy .Few studies have associated echocardiographic global LV longitudinal strain and mechanical dispersion  with ventricular arrhythmias and SCD.P = 0.002).P = 0.001).P = 0.35) probably due to the inclusion of 5 studies that included patients with a mean LGE extent <10%.Hypertrophic cardiomyopathy is the most frequent genetic heart disease, usually caused by mutations of genes encoding sarcomeric proteins, transmitted with an autosomal dominant inheritance but with incomplete penetrance and variable expression.P = 0.03).Speckle tracking echocardiographic LV strain analysis has demonstrated to correlate with the amount of replacement fibrosis in hypertrophic cardiomyopathy patients, and therefore it could be hypothesized that the assessment of LV strain may be also associated with increased risk of ventricular arrhythmias Figure .60 In 92Arrhythmogenic right ventricular cardiomyopathy (ARVC) is also an autosomal dominant inheritance disease with variable penetrance and phenotype expression characterized by replacement of ventricular myocardium by fibrous and fatty tissue.P < 0.001 for both).Finally, primary electric disorders or channelopathies, such as long QT syndrome, Wolff-Parkinson-White syndrome or Brugada syndrome are characterized by preserved LVEF without structural abnormalities. The prolongation of the action potential and repolarization that occur in these disorders may increase the risk of afterdepolarizations and polymorphic ventricular arrhythmias. Speckle tracking echocardiography has demonstrated to identify mechanical disturbances as a consequence of the electric derangements.Left ventricular ejection fraction assessed with any imaging technique remains as an important criterion to identify the patients at risk of having ventricular arrhythmias or SCD.