The beneficial effects of cardiac resynchronization therapy (CRT) are thought to result from favorable left ventricular (LV) reverse remodeling, however CRT is only successful in about 70% of patients. Whether response to CRT is associated with a decrease in ventricular arrhythmias (VA) is still discussed controversially. Therefore, we investigated the incidence of VA in CRT responders in comparison with non-responders.In this nonrandomized, two-center, observational study patients with moderate-to-severe heart failure, LV ejection fraction (LVEF) ≤35%, and QRS duration >120 ms undergoing CRT were included. After 6 months patients were classified as CRT responders or non-responders. Incidence of VA was compared between both groups by Kaplan-Meier analysis and Cox regression analysis. ROC analysis was performed to determine the aptitude of LVEF cut-off values to predict VA.In total 126 consecutive patients  were included, 74 were classified as responders and 52 as non-responders. While the mean LVEF at baseline was comparable in both groups  only the responder group showed an improvement of LVEF  under CRT. In total in 56 patients VA were observed during a mean follow-up of 28±14 months, with CRT responders experiencing fewer VA than non-responders . Secondary preventive CRT implantation was associated with a higher likelihood of VA. As determined by ROC analysis an increase of LVEF by >7% was found to be a predictor of a significantly lower incidence of VA (AUC = 0.606).Improvement of left ventricular function under cardiac resynchronization therapy goes along with a reduced incidence of ventricular arrhythmia. Cardiac resynchronization therapy (CRT) has become an integral component of systolic heart failure (HF) therapy. Up to date there is a bulk of evidence for the beneficial effect of CRT in patients with moderate-to-severe clinical impairment, which includes improved quality of life, fewer hospitalizations and decreased mortality To address the impact of an improved LV function on the occurrence of ventricular arrhythmias we analyzed the incidence of VA in CRT responders in comparison with non-responders.126 consecutive heart failure patients who underwent implantation with a combined CRT and cardioverter-defibrillator device (CRT-D) were included. Eligibility for CRT was based on 1) moderate-to-severe HF  despite optimal conventional therapy, 2) LVEF ≤35% as demonstrated by echocardiographic assessment and 3) left bundle branch pattern on the electrocardiogram (ECG) with a QRS duration >120 ms This study was conducted with approval of the ethics review committees (ERC) appointed by each centre . Data collection for scientific purposes was covered under a written consent given by the subjects upon admission to a teaching hospital.CRT systems were implanted as previously described All patients were seen for outpatient clinic visits at 4 weeks post CRT implantation and in 3-month intervals after implantation. A physician contacted patients who failed to present to the prescheduled routine visits by phone. All follow-up visits included an interview, physical examination, an ECG, and a device interrogation. From the device printouts incidence and type of arrhythmias were determined by two trained electrophysiologists. Analysis of the printouts was blinded. Shocks or antitachycardic pacing (ATP) were classified as appropriate when they occurred in response to VT or VF and as inappropriate when triggered by sinus or supraventricular tachycardia, T-wave oversensing, or electrode dysfunction As described before the cycle length of the first ventricular arrhythmia triggering defibrillator (ICD) therapy and the average cut-off rate of the VT detection zone were standardized Heart failure symptoms were classified using the New York Heart Association (NYHA) score. Resting 2-dimensional echocardiography was performed at baseline and 6 months follow-up The primary end point was the occurrence of spontaneous sustained VT or VF leading to appropriate ICD intervention. Continuous data are expressed as mean ± standard deviation (SD). Categorical data are presented by frequencies and percentages. Differences in baseline characteristics and 6-month follow-up were evaluated using unpaired Student t-test and Fisher's exact test as appropriate. Data within patient groups (to compare the effect of CRT) were compared by the use of paired Student t-tests. Survival curves were calculated and graphically presented using the Kaplan-Meier method for censored failure time data. Cox regression analysis was performed to evaluate associations between risk factors at enrollment and appropriate VT/VF therapy. Variable selection process was performed in two steps. Starting with the univariate analysis of the potential association of baseline findings with the occurrence of sustained VT or VF. This step was used as a model building process with factors showing a p-value of less or equal to 0.2 being used in the corresponding multivariate statistical model. The resulting multivariate Cox regression models were stratified by responders, non-responders and ICM or DCM respectively. In this last step, factors were assessed as significant, if the p-value was less than 0.05. ROC analysis was conducted after prior testing by multivariate analysis. All analyses were performed using SAS® statistical software, V9.1.3 .The baseline characteristics of patients are shown in Mean LVEF increased within 6 month after CRT device implantation from 25±7% to 31±8% (p<0.001), with a reduction in LVESV from 174±73 ml to 138±69 ml (p<0.001). There were 74 (59%) patients, among our collective of 126 individuals, fulfilling the criteria for positive CRT response as established above . In the The mean duration of follow-up was 28±14 months (range 9 to 48 month). There were 10 (8%) deaths in our whole collective. Of those 3 occurred in the responder group and were all due to non-cardiac causes, the remaining 7 deaths occurred in the non-responder group and were all attributed to worsening heart failure. There were 8 hospitalizations due to worsening heart failure among 7 Patients in the responder group (11%) and 43 such hospitalizations among 22 patients in the non-responder group (42%). There were no heart transplantations in the responder group whereas there were 2 transplantations among the non-responders.2 = 7.5, p<0.0061, 2 = 5.7, p<0.0168). By employing ROC analysis an EF increase by >7% during CRT was determined as a significant cut-off value  against with first event beyond this period (late events). In this analysis patients with early events had a lesser increase in LVEF during the first 6 months (11.7±27.9% vs. 5.9±24.1%), although the number of patients in those groups was small (n = 28 vs. 24) and the effect was statistically not significant (p = 0.435).Cox Regression analysis of clinical baseline parameters indicates that patients on therapy with an ACE inhibitor or an angiotensin receptor antagonist, as well as females a significantly have a reduced risk of VA . Also response to CRT therapy by 6 months after implantation is associated with an reduced risk for VA . Secondary preventive indication for device implantation is associated with a significantly higher risk of such events  .Twelve patients (9.5%) experienced inappropriate ICD shocks. The trigger for inappropriate therapy was atrial arrhythmia in 3 patients, sinus tachycardia in 1 patient, T-wave oversensing in 7 patients, and sensing of diaphragm potentials in 1 patient. Of these 12 patients 7 belonged to the responder group and 5 to the non-responder group, representing 9.5 respectively 9.6% of each group (p = 1.0).The key findings of this study are: (1.) the incidence of VA is reduced in patients responding to CRT during long-term follow-up. (2.) An increase of LVEF during the first 6 months after commencement of therapy goes along with a decreased incidence VA.Although there is some evidence favoring antiarrhythmic effects of CRT In a recent study Lin et al. The time course of VA incidence in our study appears to be in line with reports from other investigators, delineating a period from 3 to 12 months after implantation in which electrical reverse remodeling seems to occur We emphasize that the population of our uncontrolled non-randomized observational study is smaller than that included in recent hallmark trials looking for benefit from CRT responding. However, our study design pursued a different aim and was conducted to investigate the incidence of VA in association to improved cardiac function in daily clinical practice.Contradictory to evidence from previous studies Also we chose a definition of reverse remodeling that diverged in some points from the definition used in other current studies. This might impede the comparability of our results.For the assessment of functional myocardial remodeling under CRT we monitored the development of LVEF during patient follow-up visits. Although LVESV has been shown to be a good indicator of reverse remodeling in previous publications, LVEF was chosen as it is well established and can be measured with comparably low intra- and inter-observer variation during routine echocardiography Defining a positive response to CRT is still crucial. Defining a response as >10% increase of LVEF and/or an improvement of NYHA functional class by ≥1 may limit the number of patients fulfilling these criteria. Also there exist more elaborate classifications of HF, which might aid in the better discrimination of HF stages , for responders and non-responders Click here for additional data file.Supplement S2. Ding cardiovascular risk factors and history of coronary revascularisation for responders and non-responders .(DOCX)Click here for additional data file.Supplement S3Table containing medication  at time of implantation for responders and non-responders .(DOCX)Click here for additional data file.


There were 90 articles published in the Journal of Cardiovascular Magnetic Resonance (JCMR) in 2012, which is an 8% increase in the number of articles since 2011. The quality of the submissions continues to increase. The editors are delighted to report that the 2011 JCMR Impact Factor (which is published in June 2012) has risen to 4.44, up from 3.72 for 2010 (as published in June 2011), a 20% increase. The 2011 impact factor means that the JCMR papers that were published in 2009 and 2010 were cited on average 4.44 times in 2011. The impact factor undergoes natural variation according to citation rates of papers in the 2 years following publication, and is significantly influenced by highly cited papers such as official reports. However, the progress of the journal's impact over the last 5 years has been impressive. Our acceptance rate is approximately 25%, and has been falling as the number of articles being submitted has been increasing. In accordance with Open-Access publishing, the JCMR articles go on-line as they are accepted with no collating of the articles into sections or special thematic issues. For this reason, the Editors have felt that it is useful once per calendar year to summarize the papers for the readership into broad areas of interest or theme, so that areas of interest can be reviewed in a single article in relation to each other and other recent JCMR articles. The papers are presented in broad themes and set in context with related literature and previously published JCMR papers to guide continuity of thought in the journal. We hope that you find the open-access system increases wider reading and citation of your papers, and that you will continue to send your quality manuscripts to JCMR for publication. CMR is used widely for research into the vessel wall It is most frequently used for the carotid arteries where it characterizes plaque content ,2, vulneHigh intensity signals in carotid plaques seen on TOF-MRA MIP images acquired at 3.0 Tesla was shown to be associated with increased intraplaque haemorrhage and lipid-rich necrotic core volumes . This isMorphology and composition of carotid plaques were evaluated in patients undergoing chronic lipid apheresis (LA) who suffered recent stroke using spin-echo images obtained at 3T . DespiteIntravascular CMR using 3T and loopless CMR detector was used to obtain in vitro and in vivo high resolution images of atherosclerotic plaques and the findings were compared with histology . The autFurther to previous papers in JCMR on MRA techniques , and mulMagnetization Transfer Contrast (MTC) and Diffusion Weighted Imaging (DWI) were used for ex vivo thrombus imaging at 11.7T. MTC estimated more accurately the thrombus area compared to T1W and T2W images the rabbit aortic specimens . The quaThis is a well written and well illustrated review of CMR in inflammatory vasculitis with an extensive bibliography . As suchThe authors provide a comprehensive review of the current and emerging clinical and research applications of CMR in systemic hypertension which is a highly prevalent potentially modifiable cardiovascular risk factor . CMR proThe clinical importance of pulmonary hypertension is being increasingly recognised and new treatments are being evaluated. Pulmonary embolism remains a major problem during in-patient episodes, and evaluation has been improved using computed tomography, although CMR also shows flow abnormalities which can be useful .Interventricular mechanical dyssynchrony is a mark of pulmonary hypertension. The authors showed that L-R dyssynchrony in peak strain recovers to normal values after pulmonary endarterectomy in patients with chronic thromboembolic pulmonary hypertension . The RV Late gadolinium enhancement (LGE) occurs at the right ventricular insertion point in patients with pulmonary hypertension and has been shown to correlate with CMR derived RV indices but the prognostic role of LGE is not well established. This study showed that LGE is a marker of advanced disease and poor prognosis . RVEF waCMR was shown to be a useful alternative to echocardiography in the evaluation of suspected pulmonary hypertension . The resThis is a comprehensive review of the role of CMR in assessment of patients with pulmonary hypertension . CMR is Diffusion tensor imaging (DTI) is an MR technique which uses diffusion weighting to identify components of tissue architecture. It has most commonly been applied to the brain, where larger diffusion values occur along nerve fibres in comparison to across fibres. This is interpreted to mean that diffusion occurs more freely along nerve fibres than between nerve fibres. Spectacular colour coded images showing the nerve fibre directions and long distance connections in brain white matter can be generated. The technique can also be used for the heart , however-3 mm2/s and HA was epicardium -34.3 ± 7.6°, mesocardium 3.5 ± 6.9° and endocardium 38.9 ± 8.1°. Comparison of initial and repeat studies showed global interstudy reproducibility for FA  = 7.2%), MD  and HA . Reproducibility of FA was superior to MD (p = 0.003). Global MD was significantly higher in the septum than the reference lateral wall . Septal HA was significantly lower than the reference lateral wall in all 3 transmural layers . This is the first study to assess the interstudy reproducibility of DTI in the human HCM heart in-vivo and the largest cDTI study in HCM to date. The results showed good reproducibility of FA, MD and HA which indicates that current technology yields robust in-vivo measurements that have potential clinical value. The interpretation of regional differences in the septum requires further investigation.The authors report the reproducibility of using a stimulated-echo single-shot-EPI sequence with zonal excitation and parallel imaging in 10 patients with HCM scanned on 2 different days . FractioThe aim of this study was therefore to develop a technique for quantitative 3D diffusion CMR tractography of the heart, and to apply this method to quantify fiber architecture in the remote zone of remodeled hearts . DiffusiCMR of congenital heart disease has become relatively mature, although quality interpretation requires training. There has been interest in assessing ventricular mechanics in congenital disease , compariThis study using 4D CMR velocity acquisitions studied flow through the right heart of patients with repaired tetralogy of Fallot (rTOF) compared with healthy volunteers . This teIn this study, whole-heart 4D velocity acquisitions as well as five 2D flow acquisitions per study were obtained in patients with single ventricle physiology, 14 with bidirectional cavopulmonary connection [BCPC], and 15 with Fontan connections . Good agIn this study, ECG- and navigator-gated high-resolution MRA sequence (HR MRA) with slow infusion of extracellular contrast agent was implemented at 3 Tesla for the assessment of congenital heart disease and compared to standard first-pass MRA (FP MRA) in 34 patients, median age 13 years, with congenital heart disease . HR-MRA In this study, CMR phase contrast measurements of flow were obtained in key parts of circulations of 12 late gestation human foetuses during late pregnancy . As no EMeasurements of volume flow by phase-contrast velocity acquisitions can be compromised by background or phase offset errors . This stThe left atrial appendage (LAA) can be a source of thrombi that can cause embolic stroke, and impaired LAA function is thought to predispose to thrombosis. This study explored the feasibility of assessing LAA emptying by velocity encoded CMR, comparing it with trans esophageal echo (TEE) measures, in 18 patients with sinus rhythm and 12 with atrial fibrillation . It was Wave intensity analysis, traditionally derived from invasively acquired pressure and velocity data, were here derived from non-invasive CMR measures of velocity and area from a high-resolution breath hold spiral phase-contrast acquisition. Ascending and descending aortic flows were recorded in healthy adult volunteers and compared with results from 15 patients with coronary heart disease . PatientThis study used velocity encoded CMR to establish whether cardiac index  decreases with age in healthy volunteers and compared the CI values of athletes and patients with congestive heart failure (CHF) . CI was CMR is widely used for assessment of the aorta in both congenital and acquired conditions and is particularly well suited for functional of compliance , and lonThe Bramwell-Hill model describes the relation between vascular wall stiffness expressed in aortic distensibility and the pulse wave velocity (PWV) . In thisThis study provides normal CMR values for cross-sectional areas, distensibility and pulse wave velocity of the thoracic aorta in children and young adolescents and may serve as a reference for the detection of pathological changes of the aorta .CMR is being used increasingly to investigate 4D flow patterns in the heart and great vessels . In thisT1 mapping is the technique of the moment, and there has been a large expansion in papers since 2011 published on this subject in JCMR ,52 and oThis manuscript describes the development and evaluation of a method of pixel-wise mapping of extracellular volume (ECV) fraction . The metAs a follow up to “Extracellular volume fraction mapping in the myocardium, part 1: evaluation of an automated method" , the purThis work investigates the intra-individual variations in T1 mapping and extracellular volume at different field strengths, myocardial regions and cardiac phases . The papT1 mapping of the myocardium: intra-individual assessment of post-contrast T1 time evolution and extracellular volume fraction at 3T for Gd-DTPA and Gd-BOPTA.This manuscript focuses on the impact of the contrast agent in the determination of normal ECV and T1 values for healthy volunteers and also assesses stability of ECV over time . The resIn this work, the authors’ introduced the use of a single breath-hold T1 mapping technique (ShMOLLI) for the equilibrium contrast method they had initially described and validated for the measurement of ECV . The resThe authors used an EP catheter’s own irrigation system for cooled-tip ablation and assessed the use of this to reduce the temperature at the blood-tissue interface . InitialIn this review article a presentation is made of the various strategies which have been introduced for remotely steering vascular catheters within the MRI environment . FollowiIn this study the emphasis was again aimed at safety. The authors’ describe a guide-wire design based on a loopless antenna . ImportaThe value of CMR in transarterial aortic valve implantation (TAVI) is under exploration ,62. In tThe phenotyping of cardiomyopathy is a major success story for CMR, and has led to gene discovery , and ideHypertrophic cardiomyopathy (HCM) is characterised by asymmetric hypertrophy, increased fibrosis and myocyte disarray. It represents the most common genetic disorder of the myocardium. There is a wide range of clinical expression, ranging from asymptomatic mutation carriers , to suddIn this review article, Maron considers the incremental role of CMR in patients with HCM . ComplemIn this review, the current evidence base to support the role of CMR in the evaluation of cardiomyopathies is discussed . The uniThis study was undertaken to detect and quantify diffuse myocardial fibrosis HCM patients using a histologically validated CMR post-contrast myocardial T1 mapping technique . FurtherIn this study, the authors found that myocardial fibrosis is seen in about 75% of patients with asymptomatic or mildly symptomatic ‘pure’ apical HCM patients . They obIn this study, the authors assessed the effect of co-medication with a typical protein binding drug (Ibuprofen) on contrast enhanced T1 mapping . The autMyotonic dystrophy type 1 (MD1) is a neuromuscular disorder with potential involvement of the heart and increased risk of sudden death. It is an autosomal dominant inherited disorder caused by an unstable expansion of a repetitive trinucleotide sequence (CTG) on chromosome 19. The prevalence varies from 2.1-14.3 per 100 000. MD1 is characterized by slowly progressive weakness of skeletal muscles, myotonia and involvement of several organ systems. An earlier age of onset and increased severity of clinical symptoms has been observed in subsequent generations and is related to degree of CTG expansion. Patients with MD1 usually die from respiratory or cardiac complications. Sudden death is considered to be the result of atrioventricular block or ventricular arrhythmias. Recent studies showed that severe electrocardiographic (ECG) abnormalities and atrial arrhythmias are independent risk factors, although with moderate sensitivity, for sudden death in MD1 patients. Although death from progressive heart failure is uncommon in patients with MD1 compared to other muscular dystrophies, left ventricular systolic dysfunction is associated with an increased risk of overall mortality and sudden death. Therefore, the picture emerges that MD1 patients have a complex cardiac phenotype including both the myocardium and the conduction system. The principal finding of this study is that structural and functional myocardial abnormalities are frequent in MD1 patients . The preThe aim of this study was to determine the reproducibility and sample size of CMR fibrosis measurements that would be applicable in clinical trials . Mean ECParticipation in strenuous aerobic physical activity is increasing among the aging population. The cardiovascular effects of acute strenuous exercise, specifically marathon running, have demonstrated a transient increase in cardiac biomarkers and right ventricular (RV) systolic dysfunction using multimodality cardiac imaging, including transthoracic echocardiography (TTE) and cardiovascular magnetic resonance (CMR). Little is known, however, on the cardiovascular effects of repeated marathon running in individuals over the age of 50. The aims of the current study were two-fold: 1) To assess the extent and severity of cardiac dysfunction after the completion of full marathon running in elite individuals >50 years of age using cardiac biomarkers, TTE and CMR; and 2) If there is evidence of LGE on CMR, to detect the presence of silent coronary artery disease using cardiac computed tomography (CCT) . MarathoWith the development of the T2* technique , and theSeveral echocardiographic and CMR measurements have been proposed to diagnose LVNC. There has been an association between adult patients with isolated LVNC and depressed left ventricular function; however the reason for this remains unclear. In adults, it has been found that some of these measurements such as NC/C ratio and NCMA are well correlated with systolic dysfunction. However, in children these relations have not been yet established. In this study the authors investigated the relation between different anatomical measurements with ventricular performance using CMR in a pediatric population . They foThe application of CMR to the assessment of valvular heart disease continues to increase, notably with respect to aortic stenosis . This isThis excellent review summarises and discusses the additive value of CMR in the investigation of valve disease, highlighting not only its many advantages as an adjunct to echocardiography, but addressing also the limitations of the technique . The abi2 = 0.012, P = 043), adaptive response of the ventricle (P = 0.22) and the severity of aortic stenosis as assessed by CMR. Although concentric hypertrophy was the most commonly observed response , six patterns of LV adaptation were observed. Asymmetric patterns of wall thickening were frequently noted (n = 14) with some phenotypic overlap with hypertrophic cardiomyopathy.This manuscript describes the novel application of CMR quantification of indexed left ventricular volumes and mass index to investigate and characterise the impact of the pressure loading in aortic stenosis on left ventricular remodelling and hypertrophy in 91 patients with echocardiographic moderate or severe aortic stenosis . There wFurther consideration of the utility of CMR in the assessment of aortic stenosis is made in this study seeking to validate novel CMR estimation of valve effective orifice area (EOA) by a single plane method using jet shear layer detection (JSLD) against CMR estimation of EOA by the continuity equation and the customary echocardiographic measure of EOA by the continuity equation . JSLD anAlthough myocardial perfusion CMR has been possible for many years, the clinical sequence and data processing remain variable between centres. The papers below help to close the gap between research and clinical practice including reports from the large MR-INFORM and the MR-IMPACT trials. Recent developments in accelerated acquisitions, quantification perfusion acquisition techniques , and eveIn patients with stable coronary artery disease (CAD), decisions regarding revascularisation are primarily driven by the severity and extent of coronary luminal stenoses as determined by invasive coronary angiography. More recently, revascularisation decisions based on invasive fractional flow reserve (FFR) have shown improved event free survival. Perfusion CMR has been shown to be non-inferior to nuclear perfusion imaging in a multi-centre setting and superior in a single centre trial. In addition, it is similar to invasively determined FFR and therefore has the potential to become the non-invasive test of choice to determine need for revascularisation. This paper describes the rationale and study protocol for the MR-INFORM trial comparing MR and FFR . The MR-Superior diagnostic performance of perfusion-cardiovascular magnetic resonance versus SPECT to detect coronary artery disease: The secondary endpoints of the multicenter multivendor MR-IMPACT II .Perfusion-cardiovascular magnetic resonance (CMR) is generally accepted as an alternative to SPECT to assess myocardial ischemia non-invasively. However its performance vs gated-SPECT and in sub-populations is not fully established. In this multicenter study, the diagnostic performance of perfusion-CMR and gated-SPECT was compared for the detection of CAD in various populations using conventional x-ray coronary angiography (CXA) as the standard of reference . In 33 UExercise electrocardiography (ECG) is frequently used in the work-up of patients with suspected coronary artery disease (CAD), however the accuracy is reduced in women. CMR stress testing can accurately diagnose CAD in women. This study reports a direct comparison of CMR to ECG . The autAdenosine perfusion CMR can quantify myocardial perfusion reserve. While regadenoson is increasingly employed due to ease of use, imaging protocols have not been standardized. The authors sought to determine the optimal regadenoson CMR protocol for quantifying myocardial perfusion reserve index (MPRi), and whether regadenoson stress imaging should be performed before or after rest imaging . Twenty First-pass myocardial perfusion is often imaged with a tailored hybrid centric interleaved echo-planar-imaging sequence, providing rapid image acquisition with good contrast enhancement. The centric interleaved phase-encode order minimises the effective time-of-echo but it is sensitive to frequency-offsets. This article aims to show possible artefacts that might originate with this sequence, in the context of first-pass perfusion imaging, when frequency-offsets are present . NumericTechnical advances in perfusion CMR, particularly accelerated data acquisition methods, allow myocardial perfusion imaging with unprecedented spatial resolution. However, it is not clear how implementation of these recent advances affects perfusion image quality, signal and contrast to noise ratios (SNR & CNR) and the occurrence of important artefacts in routine clinical imaging. The objective of this study was therefore to compare a standard and an advanced, high-resolution perfusion sequence . A standIn the conventional approach to arterial spin labeling in the rodent heart, the relative difference in the apparent T1 relaxation times corresponding to selective and non-selective inversion is related to perfusion via a two compartment model of tissue. But accurate determination of T1 in small animal hearts is difficult and prone to errors due to long scan times and high heart rates. In this study, the authors introduce the theoretical frame work for an alternative method based on the signal intensity of slice-select and non-select inversion recovery images at a single inversion time at short repetition time . A modifCMR is invaluable to the study of patients with ischaemic heart disease and has made a major impact on this field since the first reports of inversion-recovery techniques to delineate myocardial infarction. The use of CMR in the acute cardiac setting has been reviewed , and recMicrovascular obstruction (MVO) or the ‘no-reflow’ phenomenon is an established complication of coronary reperfusion therapy for acute myocardial infarction. It is increasingly recognized as a poor prognostic indicator and marker of subsequent adverse LV remodeling. Klug reported the relation between microvascular obstruction (MVO) on first-pass gadolinium images and outcomes in 129 patients treated with primary angioplasty for ST-segment elevation myocardial infarction (STEMI) . At a meDue to their inherent susceptibility to field inhomogeneity, T2* sequences have been used to assess intramyocardial hemorrhage (IMH) . The metKatherine Wu’s excellent review of MVO and hemorrhage in myocardial infarction summarized the underlying pathophysiology behind this common clinical problem as well as the CMR techniques used for its diagnosis, the clinical implications, and future directions needed for improving the understanding of the issues involved .Quantification of the area at risk (the region of viable but ischemic myocardium) after an acute coronary syndrome can be used to determine the amount of myocardial salvage following intervention. In a similar way to the assessment of late enhancement, there is debate as to the best measurement technique. As a result, studies have relied upon either manual delineation or threshold methods  but these techniques have inherent limitations. Sjögren et al. report an automatic segmentation algorithm for quantification of area at risk (AAR) which defines the continuous region most likely to represent AAR by estimating the intensities of normal myocardium and AAR with an expectation maximization algorithm, restricting the AAR region according to an a priori model of the maximal expected extent for the culprit artery . In a stAlthough T2-weighted sequences have been widely used to assess myocardial oedema, quantitative T1-mapping is also sensitive to changes in free water content. The Oxford group in collaboration with Matthias Friedrich in Calgary compared 21 healthy controls and 21 patients with Takotsubo cardiomyopathy or acute regional myocardial edema without infarction. Wall motion, myocardial T1 values (ShMOLLI T1) and T2 signal intensity ratio relative to both skeletal muscle and remote myocardium (with both dark-blood T2-STIR and bright-blood ACUT2E) were compared on CMR scans performed at 1.5T within 7 days of the index event . ReceiveIn response to reportedly variable image quality associated with STIR sequences for the detection of myocardial oedema, the Leeds group studied image quality and diagnostic performance of STIR using a set of pulse sequence parameters dedicated to edema detection . STIR imIn a paper closely related to the group’s previous manuscript on the assessment of myocardial oedema, Dall’Armellina et al. reported the utility of pre-contrast T1-mapping for delineating the extent of ischemic injury and myocardial damage in the setting of acute myocardial infarction . In 41 pMultiContrast Delayed Enhancement (MCODE) imaging simultaneously provides a T2-weighted image with a phase sensitive inversion recovery (PSIR) LGE image and can be used to discriminate subendocardial infarction more clearly. With standard LGE techniques, this can be challenging especially if there is poor contrast between the blood pool and the infarct itself. Bandettini and colleagues reported a prospective comparison between MCODE and standard PSIR LGE imaging in 73 patients referred for vasodilator stress perfusion by targeted, repeat imaging of slice locations . MCODE hCharacterization of infarcted myocardium using CMR typically relies on late gadolinium enhancement (LGE) techniques as T1 and T2 weighted imaging is relatively insensitive to chronic infarction without the use of a paramagnetic contrast agent. Witschey et al. proposed that T1ρ-weighted rotating frame CMR techniques could be used to measure infarct size in the absence of a contrast agent due to the relatively large change in T1ρ relaxation time between scar and myocardium . In a poAt the edges of a region of infarcted myocardium, the peri-infarct zone (PIZ) contains a mixture of viable and non-viable myocytes, the extent of which is associated with susceptibility to arrhythmia (ventricular tachycardia) and adverse cardiac outcomes. In this study, the group attempted to characterize early temporal changes in scar morphology and regional function in the PIZ. Custom signal density threshold algorithms, based on remote myocardium, were applied to define infarct core and peri-infarct zone in minipigs with reperfused, anteroseptal infarcts . The autFollowing on from the previous paper, the dynamic nature of infarct healing in terms of the amount, the rate and duration was assessed in 66 patients enrolled following reperfusion for acute STEMI . Mean inO’Regan et al. used 3D co-registration of CMR images to assess the long-term effects of ischemia-reperfusion injury on left ventricular structure in 46 patients following primary PCI for acute STEMI . PatientIn this study, 3T blood oxygen level dependent (BOLD) functional MRI was used to assess whether heme arginate could prevent ischemia-reperfusion injury in the calf muscles of 12 healthy male subjects . BOLD caCine, tagging and late gadolinium sequences were used in this study to characterize cardiac morphology, location and extent of MI, and regional mechanics in 6 pigs pre- and post-MI . This waCMR is known to have utility in guiding resynchronization therapy ,139. In It is established that MVO and hemorrhage portend an adverse clinical outcome and it therefore follows that strategies aimed at minimizing these might result in an improved prognosis. In this retrospective study, Zia showed that coronary thrombus aspiration (TA) during primary percutaneous coronary intervention (PCI) was associated with reduced myocardial edema, myocardial hemorrhage, left ventricular remodeling and incidence of MVO after STEMI  . Sixty pThe power of CMR is in no small part due to the additive information that can be gained by the administration of gadolinium based contrast agents (GBCAs), and these are being applied in new situations especially the atria . There i2. Nausea or vomiting were reported as common side effects by 60% of respondents. The manuscript supports awareness by responding cardiac imagers of the immature renal function and physiological differences in paediatric patients that places them at risk of NSF. It also highlights the paucity of data regarding use of such agents in the neonatal and paediatric populations, and the resulting hindrance to licensing and guideline formulation.No GBCA is currently approved for use in children under the age of 2 years. This manuscript reports the results of the 70 replies to a worldwide survey of GBCA use by cardiac imagers with paediatric experience, with an emphasis on studying the use of GBCAs in neonates . The preGrowing awareness of the relationship between gadolinium exposure and the development of NSF led to revised label warnings for GBCAs in 2008. The results of a meta-analysis of gadolinium dosing regimes in 233 peer-reviewed studies published between 2004 and 2010 where gadolinium was employed for CMR in a total of 19,934 patients are reported in this manuscript . In 199 Awareness of NSF and the pre-requisite substrate of severe renal impairment for developing this condition, together with more stable gadolinium chelates has created a somewhat self-limiting problem. Nevertheless, this review elegantly provides an overview of what remains a relevant issue, notably with respect to maintaining the safe use of GBCAs . The ongMeasuring cardiac function is a fundamental for CMR. Myocardial tagging has recently been reviewed , and newFeature tracking (FT) post processing of routinely acquired SSFP cines is an appealing approach to quantification of myocardial strain, and has been used during dobutamine stress . This stThis paper reported the inter-study variation of global and regional strain as measured by feature tracking analyses of CMR SSFP cines in 16 healthy volunteers . AlthougThis study reported k-t undersampled cine 3D tagging in conjunction with k-t principal component analysis (PCA) reconstruction for single breath-hold acquisitions of multidirectional strain of the whole heart . The perThis paper reviews current clinical applications LV torsion measurements by CMR, showing how torsion can give insights into LV mechanics and the influence of LV geometry and myocyte fiber architecture on cardiac function . It offeThis study reported measurements of myocardial strain in the subendocardial and epicardial layers of the LV by resting tagged CMR at 3T in 12 patients with severe chronic coronary artery disease who had been scheduled for coronary artery bypass grafting . MyocardThis study reports measurements of RV mechanics by whole heart three dimensional cine displacement encoding with stimulated echoes (DENSE) CMR in 5 healthy volunteers . The infThis study set out to investigate the incremental value of 3D relative to 1D or 2D harmonic phase analyses of strain by CMR in the assessment of viability in a porcine model of infarction . The 3D Given increasing availability and uptake of CMR, it is ever more important to determine the appropriate application of CMR derived values to clinical use. Although there is correlation between ejection fraction measure by CMR and echocardiography, the values are not interchangeable. Consequently, where an evidence base has been established in one modality, the threshold value cannot necessarily accurately and reliably be transferred across modalities. Additional CMR derived parameters continue to be generated, increasingly from the acquisition of 3D data sets. An emphasis on expanding the collection of robust prospectively acquired multi-centre multi-vendor scientific data is required to generate appropriate clinical and prognostic thresholds for CMR derived parameters. Although the fundamental techniques for measuring ventricular function and mass using the contiguous parallel short axis slices techniques are well established, there are continuing reports of variants of the basic technique , and extThis retrospective single centre study of 52 patients highlights the clinically important discrepancy between left ventricular ejection fraction (LVEF) as measured by CMR compared to echocardiography and investigates the potential impact of applying the echo derived selection criteria for ICD implantation to CMR derived data . The useIn this study, 376 patients with stable coronary artery disease were followed up prospectively for 38 ± 21 months to assess the incremental prognostic value of late gadolinium enhancement (LGE) as an adverse prognostic factor above conventional risk factors including LVEF . LGE andThis manuscript addresses the important issue of how closely small animal myocardial motion resembles and replicates human cardiac physiology and pathology . Using pThis manuscript describes extensive quantification of myocardial motion of the entire left ventricle from 3D tissue phase mapped (TPM) CMR in 12 healthy volunteers and 2 patients . Having There are always papers which defy simple categorization. This section pulls together such varia which includes society reports , and novThe review of JCMR papers in 2011 , and theMetallic skin closure staples and vessel ligation clips were assessed at 3 Tesla for magnetic field interactions, heating, and artifacts in this paper . MRI-relCost evaluation of cardiovascular magnetic resonance versus coronary angiography for the diagnostic work-up of coronary artery disease: application of the european cardiovascular magnetic resonance registry data to the german, united kingdom, swiss, and united states health care systems.CMR has favorable characteristics for diagnostic evaluation and risk stratification of patients with known or suspected CAD. CMR utilization in CAD detection is growing fast. However, data on its cost-effectiveness are scarce. The goal of this study was to compare the costs of two strategies for detection of significant coronary artery stenoses in patients with suspected coronary artery disease (CAD): 1) Performing CMR first to assess myocardial ischemia and/or infarct scar before referring positive patients (defined as presence of ischemia and/or infarct scar to coronary angiography (CXA) versus 2) a hypothetical CXA performed in all patients as a single test to detect CAD . A subgrThe number of MR conditional pacemakers is increasing, which has been reviewed recently , and repThis is the second of 2 reviews , coverinThe authors declare that they have no competing interests.All authors contributed to the writing of this review article. All authors read and approved the final manuscript.


Cardiac structure and function results from complex interactions between genes, molecular regulators and environmental factors. Until recently, imaging-genetics studies had limited power as standard methods of cardiac phenotyping rely on global indices of mass and function, providing only macroscopic descriptors. Manual analysis of large cohorts is time consuming and subject to inter-observer variability.Current cardiac magnetic resonance (CMR) cine imaging techniques are limited by poor through-plane resolution. Here we present a high resolution 3D left ventricular atlas with automated segmentation.Subjects: healthy volunteers (19), patients with dilated cardiomyopathy (DCM) (5) and hypertrophic cardiomyopathy (HCM) (5) from the Genetic Studies of the Heart and Circulation (GenScan) study. Ten volunteers had two studies to assess repeatability. A further five healthy volunteers were imaged to create the atlas.Subjects underwent CMR using a 1.5T Philips Achieva system with a 32 element cardiac phased-array coil. Short axis SSFP images were acquired: 2D: voxel size 2.0 x 2.2 x 8.0 mm, 12 sections, two sections per breath-hold, slice thickness 8 mm with 2 mm gap, 30 cardiac phases. 3D: single breath-hold 3D b-SSFP volumes: voxel size 2 x 2 x 4 mm (reconstructed to 2 x 2 x 2 mm), 48 sections, 20 cardiac phases, SENSE factor 4.The 3D cine atlas was developed using ITKsnap software to manually label each voxel. Novel images were then segmented automatically using multi-atlas simultaneous segmentation and registration Figure .Wall thickness was determined as the distance between each point on the epicardial surface and its closest counterpart on the endocardial surface. To assess accuracy conventional manual volumetry of the 3D images was made using Philips Extended Workspace. The segmentations of the LV were co-registered enabling 3D point-by-point comparisons of wall thickness between the three cohorts using parametric tests Figure .2D manual volumes (geometric means and 95% CIs) were similar to 3D automated volumes. LV end-diastolic volumes - 154mLs (141-169mLs) vs 156mLs (143-169mLs). Differences not statistically significant . Mean automated volumetry (expressed as percentage of the whole) was 1% greater than 2D manual volumetry.High spatial resolution 3D cine imaging provides accurate assessment of LV volumes and mass and enables single breath-hold cardiac phenotyping. Co-registration permits pooling of data from large cohorts and is effective for voxel-wise statistical comparisons of wall thickness. This technique will be used for mapping the effect of genetic variants on regional function, morphology and strain in a high-throughput population based study.Supported by the Medical Research Council, Imperial College Biomedical Research Centre and the British Heart Foundation.


Accurate assessment of left ventricular function in rodent models is essential for the evaluation of new therapeutic approaches for cardiac diseases. In our study, we provide new insights regarding the role of a 1.5 Tesla (T) magnetic resonance imaging (MRI) device and different anesthetic regimens on data validity. As dedicated small animal MRI and echocardiographic devices are not broadly available, we evaluated whether monitoring cardiac function in small rodents with a clinical 1.5 T MRI device is feasible. On a clinical electrocardiogram (ECG) synchronized 1.5 T MRI scanner we therefore studied cardiac function parameters of mice with chronic virus-induced cardiomyopathy. Thus, reduced left ventricular ejection fraction (LVEF) could be verified compared to healthy controls. However, our results showed a high variability. First, anesthesia with medetomidine, midazolam and fentanyl (MMF) led to depressed cardiac function parameters and more variability than isoflurane gas inhalation anesthesia, especially at high concentrations. Furthermore, calculation of an average ejection fraction value from sequenced scans significantly reduced the variance of the results. To sum up, we introduce the clinical 1.5 T MRI device as a new tool for effective analysis of left ventricular function in mice with cardiomyopathy. Besides, we suggest isoflurane gas inhalation anesthesia at high concentrations for variance reduction and recommend calculation of an average ejection fraction value from multiple sequenced MRI scans to provide valid data and a solid basis for further clinical testing. Myocarditis is an inflammatory disease of the heart which is frequently caused by viral pathogens. Patients present with varying clinical symptoms ranging from mild dyspnea and benign cardiac arrhythmias to cardiogenic shock and sudden cardiac death Against this background, the objective of this pilot study was providing the feasibility of cardiac function evaluation by magnetic resonance imaging with a clinical 1.5 T MR scanner in coxsackievirus B3 (CVB3) infected mice, a mouse model for viral myocarditis and dilative cardiomyopathy. We therefore assessed left ventricular function parameters in coxsackievirus B3 infected mice and compared them to healthy controls. In order to verify our results with a more standardized imaging technique, we compared our data to results obtained with a dedicated small animal echocardiographic device. Furthermore, we compared the anesthetic regimen used in the MRI study with different concentrations of isoflurane to assess the optimal anesthetic conditions for data acquisition.q) male mice  were infected intraperitoneally (i.p.) with 1×105 plaque forming units (pfu) of coxsackievirus B3 (CVB3) SWR/J (H-2Cardiac function of 22 infected mice (SWR/J) was assessed by cardiac magnetic resonance imaging (MRI) eight weeks after CVB3 infection. For comparison of LVEF, 7 healthy mice (SWR/J) were tested as well. For comparison of left ventricular volumes and cardiac output, 4 age matched mice were used respectively.Healthy, 6–8 week old male BALB/c mice were used for evaluation of cardiac function by echocardiography. Animal care and all experimental procedures were performed in strict accordance to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health  and were approved by the local animal care and use committees of the district government of Baden-Württemberg.For reliable electrocardiographic (ECG) synchronization and high resolution imaging, a dedicated small animal ECG device  and a microscopy coil , which is clinically used for finger imaging, were applied. All imaging procedures were performed on a clinical 1.5 T Philips Achieva MR scanner using a clinical gradient system . Animals (SWR/J) were anesthetized with fentanyl (10 µg/kg), medetomidine (1 mg/kg) and midazolam (2 mg/kg) (MMF) and imaged in prone position with the thorax positioned on top of the microscopy single loop surface coil (D = 2.3 mm). High-resolution MRI sequences for assessment of myocardial function and morphology were implemented. Cine MRI was performed with prospective ECG triggering using a spoiled gradient echo technique. Imaging parameters included repetition time/echo time (TR/TE) = 18 ms/6.5 ms, flip angle = 30°, averages = 1, field of view (FOV) = 35 mm, matrix = 128 resulting in a spatial resolution of 0.22×0.22×1 mm at a temporal resolution of 18 ms. Ejection fraction was determined by evaluation of end diastolic volumes (EDV) and end systolic volumes (ESV) in short axis view in seven slices with an in-house developed IDL 6.1 based software package. Calculation of left ventricular ejection fraction (in %) was conducted via the formula ((EDV-ESV)/EDV)*100.3/ and 7*LVID;s3/. Calculation of left ventricular ejection fraction (in %) was conducted via the formula ((EDV-ESV)/EDV)*100. Cardiac index was defined as cardiac output divided by body weight as previously described Anesthesia of 6–8 week old, healthy male BALB/c mice  was performed with 2% isoflurane. As ejection fractions of different mouse strains are comparable Data is shown as mean ± standard deviation (SD). Data was evaluated for normal distribution by the Anderson-Darling-Test. Comparison between two groups was performed using the unpaired t-test, if data was normally distributed. If values were significantly different from normal distribution, Mann-Whitney-U-test was used for statistical testing. Values of p<0.05 were considered statistically significant. Data were analysed using Microsoft Office 2010 and the statistical software PAST v2.17c In this model of cardiomyopathy, cardiac function of 22 CVB3-infected mice was assessed using cine MRI and results were matched with up to 7 healthy controls in order to evaluate the grade of systolic impairment. In Our clinical 1.5 Tesla device included a microscopy coil which is clinically used for finger imaging and resulted in a lower signal-to-noise ratio in comparison to dedicated small animal 7 to 11.7 Tesla MRI devices combined with high-end gradient systems. In practice, this led to an increase of standard deviations. As shown in As shown in Isoflurane gas inhalation anesthesia of the same population revealed higher values for LVEF similar to the values obtained by other groups , indicatData regarding effects of MMF on myocardial contraction and heart rate are scarce compared to data on ketamine/xylazine or isoflurane Next, we studied whether the anesthetic regimen MMF also has an impact on the variability of cardiac measurements. Therefore, we compared cardiac function parameters under MMF, 1.75% isoflurane (isoflurane is commonly used at concentrations of 1.25–2.25% for maintenance of anesthesia) and 3% isoflurane. As depicted in In small animal echocardiography, multiple cycle measurements are commonly used to calculate an average value for LVEF in order to reduce variability of the results Many techniques have been implemented in the past to measure cardiac function in small animals. Pressure-volume loops can be obtained via Millar tip catheterization, but repetitive measurements are not possible in this setting. Echocardiography using clinical echo devices is often used in animal models, but provides a weak spatial resolution and is known to have a high inter- and intra-observer variability In our pilot study we show that clinical 1.5 T MRI driven evaluation of left ventricular function in mice with mild cardiomyopathy is feasible, although some limitations and lessons from small animal echocardiography need to be considered.As our data show, the variability of values obtained using a clinical 1.5 T MRI device is higher than in studies using dedicated small animal MRI or echocardiographic devices. This limitation needs to be considered regarding future study designs, as group sizes need to be increased in order to identify significant changes of left ventricular function parameters.In order to find possible solutions for the high variability and an explanation for the depressed cardiac function of healthy controls, we verified our 1.5 T MRI results with a dedicated small animal echocardiographic device. As demonstrated above, calculation of an average LVEF as known from small animal echocardiography Throughout literature, many anesthetic regimen including thiopental Nevertheless, our study has some limitations. First, we only assessed healthy controls under the mentioned anesthetic regimens. Therefore, we are not able to predict the effects of the anesthetics in mice with severe cardiomyopathies. Eventually, higher isoflurane concentrations might show a distinct cardiodepressive effect in these mice leading to higher dropout rates. Second, the parasternal short axis M-Mode we used to assess cardiac function parameters is not as accurate as e.g. the LV-trace mode, which much more considers regional wall motion abnormalities.To sum up, evaluation of LVEF changes in virus-induced cardiomyopathy with a clinical 1.5 Tesla MRI is feasible for serial monitoring of cardiac function and validation for novel therapeutic strategies. Calculation of an averaged LVEF value reduces variability. Furthermore, choice of the anesthetic regimen has essential influence on the results of cardiac measurements.


Tissue velocity echocardiography is increasingly used to evaluate global and regional cardiac function. Previous studies have suggested that the quantitative measurements obtained during ejection are reliable indices of contractility, though their load-sensitivity has been studied in different settings, but still remains a matter of controversy. We sought to characterize the effects of acute load change (both preload and afterload) and change in inotropic state on peak systolic velocity and strain as a measure of LV contractility.Thirteen anesthetized juvenile pigs were studied, using direct measurement of left ventricular pressure and volume and transthoracic echocardiography. Transient inflation of a vena cava balloon catheter produced controlled load alterations. At least eight consecutive beats in the sequence were analyzed with tissue velocity echocardiography during the load alteration and analyzed for change in peak systolic velocities and strain during same contractile status with a controlled load alteration. Two pharmacological inotropic interventions were also included to generate several myocardial contractile conditions in each animal.Peak systolic velocities reflected the drug-induced changes in contractility in both radial and longitudinal axis. During the acute load change, the peak systolic velocities remain stable when derived from signal in the longitudinal axis and from the radial axis. The peak systolic velocity parameter demonstrated no strong relation to either load or inotropic intervention, that is, it remained unchanged when load was systematically and progressively varied , with the single exception of the negative inotropic intervention group where peak systolic velocity decreased a small amount during load reduction (beat 1–3.98 ± 0.92 with beat 8–2.72 ± 0.89 cm/sec). Systolic strain, however, showed a clear degree of load-dependence.Peak systolic velocity appears to be load-independent as tested by beat-to-beat load reduction, while peak systolic strain appears to be load-dependent in this model. Peak systolic velocity, in a controlled experimental model where successive beats during load alteration are assessed, has a strong relation to contractility. Peak systolic velocity, but not peak strain rate, is largely independent of load, in this model. More study is needed to confirm this finding in the clinical setting. Since its introduction tissue velocity echocardiography (TVE) has opened new possibilities for non-invasive quantification of myocardial function . Tissue An ideal index of myocardial contractility should be independent of loading conditions (preload and afterload), heart size and mass, and sensitive to changes in inotropy . In thisThe issue of load-dependency and tissue velocities during systole has been raised earlier, and clinical findings have been published that support the idea that load reduction can lead to decrase in systolic velocities  or alterWe hypothesized that TVE systolic measures of the left ventricular function, peak systolic velocity (PSV) and systolic strain, would change in relation to loading changes. We further hypothesized that PSV and strain would behave in the same fashion during pharmacologically altered contractile status. We aimed to test these hypotheses in an experimental large animal model, which included exposure to positive and negative inotropic drugs and carefully controlled transient load changes. We also aimed to compare tissue velocities and strain measured from different directions with respect to myocardial axis.After approval from the Umeå Regional Animal Experimental Ethics Committee, and in conformation with the Guide for the Care and Use of Laboratory Animals , 13 juvenile Yorkshire/Hampshire pigs with a mean weight of 36.7 kg (SD = 4.1) were anaesthetized and instrumented, using methods that have been well described previously .-1, xylazine 2.2 mg·kg-1, and atropine 50 μg·kg-1. Anaesthesia was induced with pentobarbital 12 mg·kg-1 i.v. and maintained by a continuous infusion of pentobarbital 5 mg·kg-1·h-1, midazolam 0.3 mg·kg-1·h-1 and fentanyl 20 μg·kg-1·h-1. After tracheotomy, animals were intubated and ventilated in volume-controlled mode  to achieve normoxia and normocapnea  with a mixture of oxygen and room air. During the entire experiment IV fluids were administered: Ringer’s Acetate 15 ml·kg-1·h-1. Arterial and venous catheters were placed through cut downs in the cervical region to access the jugular and carotid vessel systems. Arterial and venous catheters, including a 7 F Swan-Ganz catheter  were advanced to appropriate position. A combined pressure-conductance catheter, with 12 electrodes and 8 mm spacing , was placed in the long axis with the pigtail tip in the apex of LV with the help of fluoroscopy. A 7.5 F balloon occlusion catheter  was placed in the inferior vena cava in order to facilitate a controlled transient restriction of venous return (VCBO maneuver) leading to a beat-by-beat progressive reduction in preload and afterload over a restricted range of normal operating pressures and volumes. Selected sequences from these load reduction periods were then further analyzed.The animals were premedicated with ketamine 10 mg·kges), maximal rate of pressure change (dP/dtmax), and load-independent LV function parameters as the linear slope of the end-systolic PV relationship, defined as end-systolic elastance (Ees) [ed), isovolumic relaxation time constant (tau), minimal rate of LV pressure change (dP/dtmin) and the ratio for end-systolic elastance/arterial elastance (Ees /Ea) [The method of left ventricular volume measurement with dual field conductance volume measurements is well described before elsewhere . The conce (Ees)  and prelce (Ees) . DiastolEes /Ea) .Echocardiographic recordings, long axis and apical four chamber, were recorded with a frame rate of 100–140 frames per second using an ultrasound system . Digitally stored data were analyzed offline using commercial software . Peak systolic velocities and strain was estimated by measuring the spatial velocity gradient over a computation area of 6x6 mm or 6x12 mm. The region of interest (ROI) was continuously positioned within the LV inferior wall when measuring radial measurements and within basal part of septum for longitudinal measurement. The strain length was chosen as 6 mm for posterior wall and 12 mm for septum . The tis2O airway pressure. The inferior vena cava balloon was inflated, and progressive beat-to-beat decreases in left ventricular pressure and volume were recorded. Beats selected for analysis from the balloon inflation period were those where there was a progressive beat-by-beat decrease in both LV end-diastolic and end-systolic volume and pressure at the beginning and end of the sequence. At least 8 consecutive beats, from the point where load reduction began to be noted were used for further analysis.Each measurement sequence was recorded during a period of apnea with 0 cm HConcerning measurement sequences after inotropic interventions, a measurement was collected at baseline before the inotropic intervention was started, and then during adrenaline infusion with target pulse rate raise of approximately 20% from the baseline. After a second rest period, 30 minutes after discontinuation of adrenaline infusion, a negative inotropic intervention was administered, which consisted of an intravenous injection of metoprolol 40 mg and then verapamil 15 mg , with a brief infusion of phenylephrine to counterbalance the immediate vasodilatatory effects of verapamil, which was quickly weaned off as soon as it was not needed.Data are expressed as mean ± SEM or ± 95% confidence intervals. The effects of load alterations were analyzed using repeated measurements analysis of variance (repeated measures ANOVA). Comparison of the first beat (baseline) with the last (eighth) beat in an unloading sequence was performed using the paired Student t-test. A p value <0.05 was considered to be statistically significant.The anaesthetized pigs all demonstrated central circulatory parameters consistent with health during rest before the start of the protocol. All 13 animals completed the protocol, with simultaneous tissue velocities echocardiography measurements together with LV pressure volume results for each sequence. Load changes were achieved by the VCBO, where the first eight beats in the sequences Figure .Hemodynamic results show that the animals had their VCBO sequences with start and end ventricular pressures and volumes not in extreme ranges Figures  and 2. IThe PSV results during the unloading sequence of 8 consecutive beats remained relatively unchanged in both short and long axis at baseline Figure , and behSystolic strain findings Figure  showed tThe inotropic interventions led to differences in the tissue\ velocity parameters Table , where PWhen the radial and longitudinal axes for PSV were compared, there were no differences between the longitudinal axis and radial axis measurements for the resting control and negative inotropic measurements. For the positive inotropic measurement, the PSV average for the longitudinal axis measurement was greater than for the radial axis measurement.The main findings in this study were that PSV was load-independent in this model. The tissue velocity parameter PSV increased with inotropic status increase, and decreased with the negative inotropic intervention. It has been recognized for many decades that there is a strong relation between load and ventricular performance, though it is not yet clear how strongly related tissue velocities are on ventricular performance. These results support the idea that PSV changes, increases or decreases, reflect changes in contractile status (for example as brought about by inotropic interventions in this model).Previous reports have been mixed concerning the relation of tissue velocity to load: some pulsed Doppler velocities in the AV plane during load alteration results have supported the idea that PSV is load-independent ,25-27, oThe results for strain in relation to load supported the idea that strain is load-dependent, in contrast to PSV. Though not reaching statistical significance for all the inotropic conditions, strain appeared to increase generally with decreasing load, in this model, and this agrees with some previously published results ,30. TherThere are measurement-technical aspects which can affect the quality of the signals. We analyzed velocities which were measured in the basal aspect of the interventricular septum. Signal from the ventricular lateral wall was also acquired, but there was often inadequate imaging quality during the VCBO, so that we could only consistently use the septal assessment for futher analysis. It is possible that there was some minimal drift of the strain curves over time, since the (Echopac) proprietary software uses drift compensation. We examined signals both with and without drift compensation. Without this software-driven compensation the baseline was consistently drifting. We are confident that the absolute amount of strain was adequately assessed. Strain rate was examined for all VCBO sequences, thought the signal had enough ‘noise’ that clear maximum strain rates were not reliably identified. Therefore, no strain rate results are shown Figure .This study was conducted with an undisturbed thorax. In cases where the thorax and pericardium are open, it is likely that there is an effect on wall motion and tissue velocities . There hThe clinical relevance  of theseThis type of assessment is needed today in settings where myocardial dysfunction is suspected, or where inotropic drug intervention is contemplated. Peak systolic velocity shows promise as a relatively load-independent parameter, which reflects systolic mechanical myocardial function, and more clinical experience needs to be gathered.In summary, these results showed that peak systolic velocities showed a strong load-independence during acute load reduction, though this was not so for strain. We conclude that PSV is a clinically robust parameter of LV regional and global performance under changing load. Peak systolic strain seems to be load-dependent, and has no clear relation to inotropic changes in serial measures. These findings support a broader use of PSV in serial measures in patients to assess changes in ventricular function.All authors declare that they have no competing interests concerning this study.All authors participated in the initiation and design of the study. All authors execpt JP paricipated in the experiments and data collection. All authors participated in the analysis of the results. All authors contributed to the manuscript, as well as read and approved the final manuscript.


Adequate depth of cement penetration and cement mantle thickness is important for the durability of cemented cups. A flanged cup, as opposed to unflanged, has been suggested to give a more uniform cement mantle and superior cement pressurization, thus improving the depth of cement penetration. This hypothesis was tested experimentally.The same cup design with and without flange (both without cement spacers) was investigated regarding intraacetabular pressure, cement mantle thickness, and depth of cement penetration. With machine control, the cups were inserted into open-pore ceramic acetabular models  and into paired cadaver acetabuli  with prior pressurization of the cement.No differences in intraacetabular pressures during cup insertion were found, but unflanged cups tended to migrate more towards the acetabular pole. Flanged cups resulted in thicker cement mantles because of less bottoming out, whereas no differences in cement penetration into the bone were observed.Flanged cups do not generate higher cementation pressure or better cement penetration than unflanged cups. A possible advantage of the flange, however, may be to protect the cup from bottoming out, and there is possibly better closure of the periphery around the cup, sealing off the cement-bone interface. The main cause of aseptic loosening is inadequate surgical techniques and inferior prosthetic implants . SufficiAbsence of postoperative demarcation at the acetabular cement-bone interface has been related to a reduced risk of aseptic cup loosening . The useAccordingly, we decided to compare the intraacetabular pressures, cement mantle thickness, and depth of cement penetration obtained using flanged and unflanged cups inserted in an open-pore ceramic acetabular model as well as in paired cadaveric acetabuli, using pressurization of the cement before implantation.20 ceramic acetabular models with a diameter of 49 mm were produced from Sivex ceramic foam filter plates . 2 custom-made pressure sensors  with a diameter of 3.6 mm and a 100-mm shaft were inserted through a standardized drill hole located at the acetabular pole, and 2.5 cm from the rim, respectively . The tip of each sensor was covered with tape to protect it from polymer-induced damage, and it was made level with the acetabular surface. 20 cross-linked-polyethylene XLPE Opera cups  with a 43-mm outer diameter (flange excluded), a 28-mm inner diameter, and no orientation wire were used . 10 cups10 human cadaver pelvises embalmed in 5% (v/v) formalin, 45% ethanol, 27% glycerine, and 5% glyoxide-glutaraldehyde were obtained from the Anatomical Institute, Aarhus University, Aarhus, Denmark. All pelvises were from male donors (median age 83 (65–102) years) without any previous hip surgery or signs of osteoarthritis. The left and right acetabulum was randomly allocated to receive a cup either with or without a flange. The flange was either trimmed to fit inside the acetabulum (flanged cup) or cut off (unflanged cup). All acetabuli were over-reamed according to the manufacturer's recommendations using a conventional reamer, to provide a final cement mantle between 2.5 and 3.5 mm, depending on the size of the last reamer, and the most suitable cup size . Every acetabulum in a pair was equally over-reamed, and the same cup size was inserted on both sides. During reaming, the aim was to remove at least 75% of the subchondral bone plate area in order to maximize the possibility of cement penetration by exposing cancellous bone . 9 anchoAfterwards, every acetabular bone was potted into Vel-Mix Stone  to ensure horizontal alignment of the acetabular opening during further handling. Finally, 2 additional channels for the later application of pressure sensors were drilled at the pole and 10 mm from the iliac rim . All acetabuli were then cleaned with pulse lavage, and before cementation the acetabular bone bed was dried with gauze . SubsequInsertion forces and intraacetabular pressure measurements were obtained during position-controlled cup insertion within the last 3 mm before the final cup position. Resulting intraacetabular pressures and cup displacements were also assessed during force-controlled pressurization. Area under the curve (AUC) was computed for every insertion force and pressure measurement (with use of the trapezoid rule), and subsequently the calculated value was divided by the observed time period . Cup disA hemisphere template was created in Adobe Photoshop 7.0 to divide the acetabulum into three 60° segments . Each segment was divided into 12 subregions by adding a radial test line for every 5 degrees . Cement The total cement volume (mantle thickness plus penetration depth) was estimated using Cavalieri's direct estimator . BasicalA minimum sample size of 8 in the cadaveric study was calculated to achieve sufficient power (> 80%) based on published pressure variation data  and assuForces, pressures, and cup displacements were measured for 3 flanged cups and 3 unflanged cups . During Mantle thickness, penetration depth, and the respective areas were measured in 10 flanged and 10 unflanged samples . The cenDuring position-controlled cup insertion, forces and pressures were collected for 10 paired samples . The insTotal cement volume and penetration were measured in 10 paired samples. Flanged cups were found to be enclosed by more cement than unflanged cups (70 (58–76) cm3 as opposed to 57 (46–76) cm3; p = 0.005), whereas the cement penetration was similar between the two cup types (0.92 (0.30–2.61) mm as opposed to 0.99 (0.21–2.34) mm; p = 0.9).Increased cement penetration into the acetabular bone improves cup stability . HoweverThe possible advantage of a flanged cup has mainly been related to its hypothesized ability to increase cement pressurization at the time of implantation, thus improving cement penetration . When weIt has been suggested that there may be a correlation between the use of a flanged cup and a lower incidence of bottoming out . We knowThe porosity and preparation of the acetabular bone bed is related to the degree of interdigitation of cement, and removal of the subchondral bone plate has been observed to improve the cement-bone interface and to lower the interfacial stresses without impairing prosthetic stability . We knowThe overall amount of cement penetration was higher in the ceramic study than in cadaveric bone. The reason may lie in the larger pore diameters and a completely open porous structure in ceramic. According to Poiseuille's law (R = 8 ηL × (π r4) – 1) where R denotes flow resistance, η viscosity, and L the length of the pores with radius r . Larger We found no differences in depth of cement penetration between the cups that were tested when inserted in either ceramic or paired cadaveric acetabuli, which confirms earlier findings that cement penetration occurs mainly during cement pressurization before cup insertion . Thus, wIn conclusion, we argue that as flanged cups do not appear to generate higher cement pressure or induce an increased degree of cement penetration, this is not the reason for the superior clinical outcome reported for some flanged cups . Flanged


Heart failure with a normal or nearly normal left ventricular (LV) ejection fraction (HFNEF) may represent more than 50% of heart failure cases. Although HFNEF is being increasingly recognized, there is a relative lack of information regarding its incidence and prognostic implications in intensive care unit (ICU) patients. In the ICU, many factors related to patient's history, or applied therapies, may induce or aggravate LV diastolic dysfunction. This may impact on patients' morbidity and mortality. This paper discusses methods for assessing LV diastolic function and the feasibility of their implementation for diagnosing HFNEF in the ICU. Diastolic heart failure (DHF) has been described since 1998 . Nowaday2), and evidence of LV diastolic dysfunction [E/E′ > 15 . If this ratio is inconclusive, (15 >  E/E′ > 8), then additional echocardiographic information relevant to LV diastolic dysfunction can be derived by Doppler interrogation of mitral valve or pulmonary veins or left atrial volume index. Finally, elevated levels of plasma natriuretic peptides may aid in the diagnosis of DHF [Diagnosis of HFNEF requires the presence of heart failure symptoms and signs, with normal or mildly abnormal LVEF,  diastolic dysfunction, the mitral E/A ratio is <0.8, and the deceleration time of the E wave (DT) is >200 ms. In moderate (Grade II) diastolic dysfunction, the mitral E/A ratio is 0.8–1.5 and DT is 160–200 ms. In severe (Grade III) diastolic dysfunction, the mitral E/A ratio is ≥2 and DT<160 ms. The severity of diastolic dysfunction predicts mortality in longitudinal followup of outpatients [Nagueh et al. provide a simple recommendation for grading LV diastolic dysfunction by using pulsed Doppler at the mitral valve and at the mitral annulus . This isWhile useful, there are several problems with this classification. A reduced mitral E/A ratio may be seen in hypovolemia. The majority of people >60 years old have E/A ratios <1 and DT >200 ms and in the absence of other indications of cardiac disease should be considered normal . TrainedIn the ICU, there are many scenarios where factors influencing LV relaxation, diastolic distensibility, and filling pressures coexist. These factors may be linked to underlying disorders , to patients' history , or to applied therapies (volume resuscitation and positive end-expiratory pressure (PEEP)). Despite the fact that HFNEF has been increasingly identified, its incidence and impact on prognosis in critically ill patients in the ICU remain uncertain. The ICU-specific literature is reviewed below, but due to its sparse nature, extrapolations sometimes have to be made from the non-ICU cardiology literature. This is not only due to lack of extensive research in this setting, but also due to practical differences in patient populations. The clinical signs and symptoms of HF required for the diagnosis of HFNEF may be difficult to recognize in the ICU patient . The preThe typical patient seen in the MICU or surgical ICU differs from a CCU patient. In the CCU, diastolic dysfunction is often seen in the context of coronary artery disease, valvular disease, or arrhythmias. While these may be present in the MICU or SICU patient, there will be a higher percentage of sepsis, renal failure, and hypoxemia. In the MICU or SICU patient there will be a higher incidence of noncardiac comorbidity; so differentiating cardiac from noncardiac causes of dyspnea is of great importance. Finally, there will be a higher percentage of applied therapies that may affect diastolic heart function such as fluid resuscitation and positive pressure ventilation.Importantly the methods used to assess LV relaxation, diastolic distensibility, stiffness, and filling pressure suffer from many drawbacks in the ICU setting. Hence, even invasive measurements may produce inconclusive results, and finding a clinically hypovolemic patient with “normal” pulmonary artery catheter wedge pressure (PCWP) or a normovolemic patient with an elevated PCWP is not uncommon. Doppler indices of diastolic dysfunction only moderately correlate with invasive parameters , 10. AlsWhile critical care ultrasound is a growing field, the nature of ICU practice leads to several limitations to ultrasound use. Many ICU patients are receiving mechanical ventilation which may impede imaging of the heart. ICU patients sometimes cannot be positioned adequately for all cardiac views. Surgical wounds, dressings, subcutaneous emphysema, tubes, and foreign devices may obstruct views . The (atE/E ′ ratio may prove an extremely valuable tool in the ICU setting for diagnosis of HFNEF [The presence of concentric LV remodeling may have important implications for the diagnosis of HFNEF, and an increased LV wall mass index may provide sufficient evidence for the diagnosis of HFNEF when TD yields nonconclusive results or when plasma levels of natriuretic peptides are elevated . The latof HFNEF , 4. Finaof HFNEF , 4.Recent studies have linked the presence of diastolic dysfunction to weaning failure in the critically ill –19. PapaE′ can be conceptualized as the amount of blood entering the LV during early filling, whereas E represents the gradient necessary to make this blood enter the LV. Therefore, a high E/E′ represents a high gradient for a low shift in volume [Another issue associated with LV diastolic dysfunction, which is largely unstudied, is its possible relation to acute loading and unloading conditions of the LV commonly observed in the ICU. An LV with diastolic dysfunction is considered in cardiodynamic terms volume sensitive hence exploring those echocardiographic indices as aids to guide fluid loading or unloading is of great clinical interest. Tissue Doppler indices might be extremely useful in this regard, as n volume . Addition volume , 23.The concept of isolated diastolic dysfunction is becoming a new trend in cardiodynamic analysis; however, as previously mentioned, cases which have been characterized as isolated diastolic dysfunction may well exhibit “subtle” systolic dysfunction , 4. ThisFurthermore, LV tolerance to fluid loading might be better monitored by ultrasound in common scenarios such as the resuscitation of septic shock. In the latter, experimental models and clinical studies have previously reported that apart from systolic dysfunction, alterations in LV stiffness and various grades of diastolic dysfunction may exist –37. In sConsideration should be given to the issue of training of intensivists in echocardiographic analyses of patients with diastolic dysfunction. In the United States, only 55% of critical care fellowship programs provide training in echocardiography . How manDespite the fact that we have still much to learn about many of the above-mentioned mechanisms, by integrating sophisticated “functional cardiac imaging” techniques with current research our clinical understanding of the specificities encountered in critical care patients who may present with LV diastolic dysfunction will be improved. Knowledge of diastolic dysfunction should not be considered a sophisticated approach designated only for cardiologists but should be familiar to all intensivists.E/E′ with other simply derived echocardiographic parameters like left atrial size, or presence of left ventricular hypertrophy with natriuretic peptides, may prove invaluable tools for studying the role of diastolic LV dysfunction in such patients.Although HFNEF is being increasingly recognized, there is a relative lack of information regarding its incidence and prognostic implications in the critically ill. There may be difficulties in the implementation of criteria for the diagnosis of HFNEF in the ICU. However combination of simple echocardiographic indices of LV diastolic dysfunction like TD-derived


Diabetic cardiomyopathy (DCM) is a disorder of the heart muscle in people with diabetes, which is characterized by both systolic and diastolic dysfunction. The effective treatment strategy for DCM has not been developed.Rats were divided into 3 groups with different treatment. The control group was only injected with citrate buffer (n = 8). The diabetes group and diabetes treated group were injected with streptozotocin to induce diabetes. After success of diabetes induction, the rats with diabetes were treated with  or without  recombinant human Neuregulin-1 (rhNRG-1). All studies were carried out 16 weeks after induction of diabetes. Cardiac catheterization was performed to evaluate the cardiac function. Apoptotic cells were determined by TUNEL staining. Left ventricular (LV) sections were stained with Masson to investigate myocardial collagen contents. Related gene expressions were analyzed by quantitative real-time PCR (qRT-PCR).Diabetes impaired cardiac function manifested by reduced LV systolic pressure (LVSP), maximum rate of LV pressure rise and fall (+dp/dt max and -dp/dt max) and increased LV end-diastolic pressure (LVEDP). The rhNRG-1 treatment could significantly alleviate these symptoms and improve heart function. More TUNEL staining positive cells were observed in the diabetic group than that in the control group, and the rhNRG-1 treatment decreased apoptotic cells number. Furthermore, qRT-PCR assay demonstrated that rhNRG-1 treatment could decrease the expression of bax and caspase-3 and increase that of bcl-2. Collagen volume fraction was higher in the diabetic group than in the control group. Fibrotic and fibrotic related mRNA (type I and type III collagen) levels in the myocardium were significantly reduced by administration of rhNRG-1.rhNRG-1 could significantly improve the heart function and reverse the cardiac remodeling of DCM rats with chronic heart failure. These results support the clinical possibility of applying rhNRG-1 as an optional therapeutic strategy for DCM treatment in the future. Patients with diabetes often develop atherosclerosis and hypertension, both of which are major risk factors to the development of heart disease. However, cardiomyopathy can also be developed in the absence of these established risk factors ,2. In thNeuregulin-1 (NRG-1) is a widely expressed signaling molecule that is involved in cell differentiation, proliferation, growth, survival, and apoptosis. It is encoded by a large gene (1400 Kb) located in chromosome 8p12, with several promoters and alternative splicing isoforms ,8. In adExperiments were performed in compliance with the ARRIVE guidelines on animal research. SpragueTo evaluate the cardiac function, cardiac catheterization was performed as previously described . BrieflySamples were fixed in 10% formalin and paraffin embedded in the surgical pathology facility of Nanchang University. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) analysis was performed with a commercially available kit according to the manufacturer's instructions . Slides were counter stained with hematoxylin (blue). Three midventricular sections (from the apex to the base) of each heart were analyzed. Cardiomyocyte nuclei were quantified by counting randomly 10 fields per section. The apoptotic index (percentage of apoptotic nuclei) was calculated as apoptotic nuclei/total nuclei counted ×100%.LV sections were stained with Masson to measure interstitial fibrosis. Interstitial collagen was quantified at a final magnification of 200× with a microscope  connected to a video camera . Photographs obtained under microscopy were used to calculate the collagen volume fraction of the myocardial interstitium by computer imaging analysis system . The content of interstitial collagen  was averaged on nine fields selected across the wall thickness in the septum and free wall.Tissue samples obtained from the left ventricle free wall were minced. RNA was extracted as reported before . Total Rcollagen type I F: 5'- GTTCGTGGTTCTCAGGGTAG -3';collagen type I R: 5'- TTGTCGTAGCAGGGTTCTTT -3';collagen type III F: 5'- TGCCCACAGCCTTCTACACCCT -3';collagen type III R: 5'- CAGCCATTCCTCCCACTCCAG -3';bcl-2 F: 5'- CGGGAGATCGTGATGAAGT -3';bcl-2 R: 5'- CCACCGAACTCAAAGAAGG -3';bax F: 5'- GCAGGGAGGATGGCTGGGGAGA -3';bax R: 5'- TCCAGACAAGCAGCCGCTCACG -3';caspase-3 F: 5'-AGTCTGACTGGAAAGCCGAA -3';caspase-3 R: 5'- CGGGATCTGTTTCTTTGCAT -3';β-actin F: 5'- TGTGCTATGTTGCCCTAGACTTC -3';β-actin R: 5'-CGGACTCATCGTACTCCTGCT -3'.All data were presented as mean ± SEM. Comparisons between groups were made by one-way analysis of variance (ANOVA) with Fisher protected least significant differences post hoc comparison. Results were considered statistically significant if p < 0.05.Sixteen weeks after induction of diabetes, rat cardiac function was evaluated by invasive hemodynamic measurements. There was no significant difference in heart rate among the three groups. The lower LVSP and higher LVEDP were observed in diabetic group than that in control group. Resting maximum rates of rise (+dp/dt max) and fall (-dp/dt max) in LV pressure were also impaired after induction of diabetes, indicating that the diabetic rat systolic and diastolic functions were significantly impaired. After the administration of rhNRG-1, the hemodynamic abnormalities mentioned above were remarkably attenuated , transforming growth factor-α (TGF-α), and NRG1-4. ErbB3 is expressed in prenatal myocytes, whereas, adult ventricular myocytes express only ErbB1, ErbB2, and ErbB4. It is known that ErbB1, also known as the EGF-receptor, does not bind NRG-1, so only ErbB2 and -4 do serve as NRG-1's receptors in adult cardiomyocytes ,20. NRG-DCM is considered as interstitial and perivascular fibrosis. It was known that myocardial fibrosis could cause myocardial dysfunction in diabetes. Our findings also showed that NGR-1 attenuated heart fibrosis. The precise mechanism was unclear. Recent study showed that TGF-β could contribute fibrosis by binding to ErbB-receptors . EnhanceIt was reported that NRG-1/ErbB expression declined in the later stages when pump failure occurred , The decThe heart function of DCM rats with chronic heart failure was significantly improved by NRG-1, supporting the rationale of replenishing NRG-1 as an optional selection for DCM therapy, although further clinical studies are required. rhNRG-1 seems to be able to protect cardiomyocytes against apoptosis and reduce the extent of myocardial interstitial fibrosis. The exact mechanism will be pursued in the future studies.DCM: diabetic cardiomyopathy; rhNRG-1: recombinant human neuregulin-1; EGF: epidermal growthfactor; STZ: streptozotocin; SD: Sprague-Dawley; LV: left ventricle; HR: heart rate; LVSP: LV systolicpressure; LVEDP: LV end-diastolic pressure; +dp/dt: maximum rate of left ventricle pressure rise; -dp/dt: maximum rate of left ventricle pressure fall; SEM: standard error of mean.The authors declare that they have no competing interests.All authors fulfill the criteria for authorship. BL, ZZ and YW designed and drafted the protocol, MWand JP contributed to the design and coordination of the study, XH and JX contributed to the statistical analysis and coordination of the study, TK, YL and ZL interpreted the findings and drafted the manuscript. All authors read and approved the final manuscript.