CCN2/Connective tissue growth factor seems to be involved in development of cardiac hypertrophy and fibrosis, but a possible cardioprotective role in left ventricular (LV) remodelling following myocardial infarction has also been suggested. The main objectives of the study were therefore to investigate whether circulating CCN2 levels were associated with infarct size, LV function, adverse remodelling or clinical outcome in two cohorts of patients with ST-elevation myocardial infarction (STEMI). CCN2 was measured in 988 patients 18 hours after PCI and clinical events were recorded after 55 months in the BAMI cohort. In the POSTEMI trial, serial measurements of CCN2 were performed in 258 STEMI patients during index hospitalisation and cardiac magnetic resonance imaging was performed in the acute phase and after 4 months. Clinical events were also recorded. There were no significant associations between levels of CCN2 and infarct size, LV ejection fraction, changes in LV end-diastolic or end-systolic volume, myocardial salvage or microvascular obstruction. There were no significant associations between CCN2 levels and clinical events including mortality, in either of the study cohorts. In conclusion, circulating levels of CCN2 measured in the acute phase of STEMI were not associated with final infarct size, left ventricular function or new clinical events. Adverse left ventricular (LV) remodelling, impaired myocardial salvage and heart failure development remain unresolved issues in patients with acute ST-elevation myocardial infarction (STEMI) despite modern reperfusion therapy. Although the underlying mechanisms are extensively studied, specific therapeutic approaches remain challenging.2, is a member of the CCN family of matricellular proteins3. CCN2 is involved in a variety of biological processes including extracellular matrix synthesis, cell proliferation and angiogenesis. It has been implicated in the pathogenesis of cardiac hypertrophy and fibrosis7, and has been found to be upregulated in models of cardiac pressure-overload induced heart failure8 and myocardial infarction (MI)10, suggesting a role in cardiac remodelling. Although it is mainly described as a pro-fibrotic marker, some experimental models involving cardiac-restricted overexpression of CCN2 and post-ischaemic administration of recombinant CCN2 have suggested that CCN2 may be cardioprotective by attenuating LV remodelling12, increasing tolerance to ischaemia-reperfusion (IR) injury13 and reducing infarct size14. Circulating levels of CCN2 have been shown to be associated with heart failure in clinical studies15, however, the role of endogenous CCN2 in acute MI in humans remains unclear. Patients with increase in serum levels of CCN2 after MI were reported to have improved LV function and possibly attenuated LV remodelling in a small human study11. There is however, a lack of information from clinical studies with adequate sample size on circulating levels of CCN2 during the acute phase of MI, the effect of reperfusion therapy on CCN2 levels and any possible associations between CCN2 and IR-injury, ischaemic postconditioning, adverse remodelling, as well as later clinical outcome.CCN2/Connective tissue growth factor, which is upregulated in response to transforming growth factor beta 1 (TGF-β1)We therefore wanted to investigate, whether levels of circulating CCN2 were associated with myocardial injury, remodelling, and clinical outcome in two separate cohorts of STEMI patients treated by primary percutaneous coronary intervention (PCI). Possible associations with myocardial IR-injury, including myocardial salvage and ischaemic postconditioning, adverse remodelling and final infarct size assessed by cardiac magnetic resonance imaging (CMR) were explored in the Postconditioning in ST-Elevation Myocardial Infarction (POSTEMI) study, while studying associations between circulating CCN2 levels and clinical outcome was the main objective of the Biobanking in Acute Myocardial Infarction (BAMI) study.Data were obtained from 258 (POSTEMI) and 988 (BAMI) patients from the two study populations, respectively. Median values of CCN2 measured at Day 1 (median 18 hours after PCI in both populations) were 23.3 ng/ml in the POSTEMI cohort and 27.1 ng/ml in the BAMI cohort. Characteristics of the study populations according to high or low CCN2 levels at Day 1 (dichotomised at median) are shown in Table There was a significant decline in CCN2 levels during PCI, while there was a significant increase from after PCI to Day 1, and a further increase to 4-month follow-up , change in indexed LV end-diastolic volume (LVEDVi) and LV end-systolic volume (LVESVi), myocardial salvage or microvascular obstruction (MVO), respectively, neither in correlation analyses with CCN2 analysed as a continuous variable , ∆LVEDVi  and ∆LVESVi , but these associations were present only at one sampling point . There were no associations between change in CCN2 levels and final infarct size or myocardial salvage.Change in CCN2 levels  from hospitalisation to 4-month follow-up was weakly correlated with LVEF at 4 months  and creatinine, than patients without events.The median follow-up time in the BAMI population was 55 months, and the median time to first clinical event was 16 months (1.3 years) after the index infarction. A total of 200 patients experienced an event, 66 deaths, 61 reinfarctions, 6 strokes, 52 urgent unscheduled PCI procedures and 15 hospitalisations with heart failure. In addition, 16 patients died after first having experienced a non-fatal event. As previously reportedThere was no difference in CCN2 levels in patients who experienced a clinical event compared to patients without, nor was there any difference between patients who died compared to survivors Table . Also, nFewer adverse clinical events were registered in the smaller POSTEMI cohort. 20 patients  experienced an event during 12 months of follow-up , and 26 deaths were registered  after median 70 months of follow-up. In line with the results from the BAMI cohort, CCN2 levels at all sampling points were similar in patients with and without clinical events Table .Table 5AThe main findings in the present study were that circulating CCN2 levels measured in the acute stages of STEMI were not associated with myocardial injury, impaired function or long-term prognosis.We did not find any associations between CCN2 levels and various indices of myocardial injury and function, neither in the acute phase nor when measured 4 months after the index infarct. Furthermore, no associations were found between CCN2 and later cardiovascular adverse events or all-cause mortality in two different cohorts of STEMI patients. In accordance with this, CCN2 levels were similar in patients who experienced an adverse clinical event including all-cause mortality, compared to patients without.17, the role of CCN2 in MI and post-infarction remodelling remains unclear. In fact, previous reports have suggested both a pathological and protective role of CCN2. After an acute infarction, CCN2, activated by various mediators including TGF-β1, plays a role in regulation of fibroblast phenotype and function in the injured area18. Increased expression of CCN2 in cardiac myocytes and fibroblasts following MI has been demonstrated in several experimental models10, indicating a role of CCN2 in post-infarction fibrosis. One experimental study showed increased CCN2 expression in viable myocardium as late as 180 days after MI suggesting a role in late remodelling following MI4. Recent reports from animal models of IR-injury have discussed a cardioprotective role of CCN2. Both transgenic mice with cardiac-restricted overexpression of CCN2 and Langendorff-perfused hearts treated with recombinant human CCN2 showed enhanced tolerance towards IR-injury14. Moreover, one experimental study demonstrated that transgenic mice with overexpressed CCN2 had smaller infarcts, less LV dilatation and hypertrophy, and lower mortality, suggesting protective, anti-remodelling characteristics of CCN2 in MI11. In contrast to these results, we did not find any associations between circulating levels of CCN2 measured both before and after reperfusion and surrogate markers of IR-injury or LV remodelling including myocardial salvage, MVO and change in LVEDV in patients with STEMI. Neither was there any association with the iPost procedure used in the POSTEMI study19.While there is extensive evidence of CCN2 being a key mediator in cardiac fibrosis11. There was, however, no information about CCN2 levels during the first 2 days after admission11. In the present study, we found a significant overall increase in CCN2 levels from hospitalisation to 4-month follow-up and delta CCN2  was weakly correlated with changes in LV volumes. However, these associations were weak, not consistent across all the sampling points, and importantly, we did not find any associations with final infarct size or myocardial salvage.In a small human study of 42 STEMI patients, no overall changes of CCN2 levels from 2 days to 2 months and 1 year were found. However, when analysing patients according to increase or decrease during this period, patients with increasing CCN2 to follow-up had lower LV end-systolic volume and higher LVEF, suggesting that CCN2 activity after MI may attenuate remodelling20, in contrast to the hypothesis that high levels of CCN2 should be cardioprotective. It must be emphasised that this was a completely different patient population compared to our acute MI populations. The present results are based on CCN2 measured in the circulation. The lack of associations with myocardial injury and function obviously does not exclude an important role of locally acting CCN2 in the myocardium, both at the cardiomyocyte and the fibroblast level, which has been shown in numerous experimental studies13.Despite a potential role of CCN2 in the pathogenesis of post-infarction remodelling, we did not find any associations with adverse clinical events or all-cause mortality in either of the two cohorts. The consistent lack of associations between CCN2 and adverse clinical events in both the BAMI cohort, which had a relatively large number of adverse events and long-term follow-up, and the POSTEMI cohort with multiple sampling points, indicate that circulating CCN2 measured in the acute stages of STEMI does not add prognostic information for development of myocardial injury, heart failure, and later cardiovascular events. There are, to our knowledge, no other reports from large STEMI cohorts on CCN2 and long-term prognosis. A recent report, however, demonstrated that high baseline plasma levels of CCN2 were associated with increased risk of mortality and cardiovascular events, in patients with manifest, but stable, vascular diseaseThere are very few studies on circulating CCN2 in STEMI patients, and mainly with small cohorts. The strengths of this study are the relatively large cohort and long-term follow-up, the serial measurements in the acute phase of STEMI, the use of repeated CMR to evaluate myocardial function and injury, and the testing of any association with survival post-MI in two separate cohorts of STEMI patients.Only one blood sample at Day 1 in the BAMI cohort and the lack of sampling between Day 1 and 4 months in POSTEMI are major limitations of this study. We may have missed the peak value, and it is possible that the main effects of CCN2 occur during the first weeks/months rather than hours/days after the infarction. The majority of previous research on CCN2 in MI has been experimental and on the cellular level. Although it seems that CCN2 is not a good circulating biomarker, we cannot exclude that locally released CCN2 in the myocardial tissue plays an important role in fibrosis and in the remodelling process of the infarcted myocardium. The relatively small number of adverse events in the cohort with serial blood sampling (POSTEMI cohort) increases the probability of a type 2 error. However, the similar results in the BAMI cohort with a larger number of events strengthen the conclusions. The relatively small infarct size judged by troponin T levels, few in-hospital deaths and relatively low incidence of heart failure in the BAMI population may indicate that this was a low-risk STEMI population, which may have influenced the results.Circulating levels of CCN2 measured early after STEMI were not associated with myocardial IR-injury, infarct size, adverse remodelling, impaired function or new adverse clinical events. The role of circulating CCN2 as a potential prognostic biomarker for adverse remodelling, heart failure development and long-term prognosis in STEMI patients appears to be limited.21 and STROBE 22 checklists, respectively.All parts of this study were approved by the Regional Committee for Medical Research Ethics, South-East Norway, and conducted in accordance with the ethical principles of the Declaration of Helsinki. All participants were included after providing written informed consent. The results from the POSTEMI and BAMI studies are reported in accordance with the CONSORT  201023, and the study flow-chart is available as Supplementary Figure 24. CMR was performed median 2 days after the index event in the acute phase and repeated after 4 months’ follow-up, allowing assessment of infarct size, LVEF, LV volumes, myocardial salvage, and MVO. Estimation of myocardial salvage (%) was based on CMR measurements of myocardium at risk in the acute stage and final infarct size at 4 months’ follow-up, as previously reported19. Clinical end points were recorded at follow-up visits 4 and 12 months after the index infarction, and long-term mortality data were acquired from clinical records median 70 months after inclusion. The effect of iPost on the primary endpoint of the study, final infarct size measured by CMR after 4 months, was neutral19.Two different cohorts of STEMI patients were studied in the present study. The Postconditioning in ST-Elevation Myocardial Infarction (POSTEMI) trial was a prospective, randomised, single-centre, open-label clinical trial investigating the effect of ischaemic postconditioning (iPost) on infarct size in STEMI patients. The trial was approved by the Regional Committee for Medical Research Ethics, South-East Norway, on July 30, 2008, and following a pilot period including 20 patients and evaluation of safety by the Data and Safety Monitoring Board the trial was registered at clinicaltrials.gov on June 16, 2009 (registration number NCT00922675). The study design including detailed CMR protocol has previously been reported in detail25. A total of 2760 patients with STEMI were admitted to the hospital in the inclusion period between July, 2007 and July, 2011, and 1025 patients were included in the BAMI cohort after written informed consent. The exclusion criteria were age below 18 years and patients who were otherwise unable (sedated) to sign written informed consent. STEMI was defined and treated according to current guidelines24. For recording of adverse clinical events, 988 patients were followed from inclusion until December 31, 2013, with a median follow-time 4.6 years. The clinical endpoints were registered by telephone contact or mail between June 1 and December 31, 2013. The remaining 37 patients were excluded as a result of not responding on contact (32) or a final diagnosis other than STEMI (5). For each endpoint, the hospital records were collected and then further evaluated by an Endpoint Committee. Deaths were obtained from the Cause of Death Registry, administered by the Norwegian Institute of Public Health. Questionnaires and hospital records at admission were used for basic clinical information.The other cohort included patients from the Biobanking in Acute Myocardial Infarction (BAMI) study which was an observational cohort study of stable patients with acute STEMI admitted to Oslo University Hospital UllevålIn both cohorts, a composite clinical endpoint was defined as death, MI, unscheduled revascularisation > 3 months after the index infarction, rehospitalisation with heart failure or stroke. PCI or coronary artery bypass grafting as a consequence of the index infarction, or repeated coronary angiography without a PCI procedure, were not considered as clinical events.In the POSTEMI population, blood sampling was performed before (median 2.8 hours after symptom onset) and immediately after the primary PCI procedure and further at Day 1 at approximately 8 a.m. (median 18.3 hours after PCI), and at 4-month follow-up. In the BAMI population, blood samples were collected at Day 1 the following morning after an overnight fast, median 18 hours after PCI and 24 hours after symptom onset. Serum was prepared by centrifugation for 10 min at 2000 × g and samples were stored at −80 °C until analysed. Circulating levels of CCN2 were analysed by ELISA . Inter assay coefficient of variation (CV) was 10%, and samples from both cohorts were analysed simultaneously with the same lot number. Routine biochemical analyses, including C-reactive protein (CRP), NT-proBNP, and cardiac-specific troponin T were determined by conventional laboratory assays. Peak CRP and peak troponin T were defined as the maximum value measured during hospitalisation.Continuous variables are presented as median values  and categorical variables as proportions. Associations between CCN2 and clinical variables were assessed by both correlation analyses (Spearman’s rho) and group analyses (dichotomised or split into quartiles). Non-parametric tests were used throughout due to marked skewness in the distribution of CCN2. Mann-Whitney U test and Kruskal-Wallis test were used for group comparisons of continuous variables, while categorical variables were analysed using Chi-square test. Friedman test followed by Wilcoxon signed rank test were used to compare CCN2 levels at different sampling points. To investigate possible associations between CCN2 and adverse clinical events, the variable was split into quartiles (Qs) because linear effect could not be assumed. First, Qs 2, 3, and 4 were compared to Q1 in univariate Cox regression models. Next, patients with CCN2 above or below median were compared. A two-sided p-value < 0.05 was considered to be statistically significant. Due to the explorative nature of the study, no correction for multiple comparisons was performed. All analyses were performed by IBM SPSS Software, version 23.0 for Windows .The datasets generated during the current study are available from the corresponding author on reasonable request.Supplementary Information


Ebstein anomaly is a kind of congenital defect of tricuspid valve mainly affecting the right ventricle, recent evidence have suggested the LV geometry remodeling in patient with Ebstein anomaly due to potential RV-LV coupling. The aim of this study-we investigated the interaction between abnormal right ventricle and left ventricle and whether myocardial fibrosis is the basis of abnormal left ventricle remodeling in ebstein abnomaly by using T1 mapping technique of cardiac magnetic resonance.Twenty patients with ebstein's anomaly and twenty matched normal controls were prospectively included in this study. All subjects received a comprehensive cardiac MRI scanning according to a standard protocol, which consisted of pre- and post-contrast T1 mapping for calculating ECV to quantify myocardial fibrosis of left ventricle. LV geometry and function data. Bi-ventricular volume, function and severity of ebstein anomaly were also analyzed.In patients with Ebstein anomaly, LV volume was mildly decreased and EF also mildly reduced .ECV of LV myocardium in ebstein was larger than that of normal controls (28.76 ± 4.40 vs 23.39 ± 3.56 p = 0.003). ECV correlated well with severity index of RV malformation and LVEF in Ebstein's patients group. The native-T1 value of LV myocardium in ebstein's was longer than that of in normal controls with p = 0.04.LV myocardial fibrosis and remodeling evidently existed in patients with ebstein's anomaly which was strongly correlated to the severity index of ebstein. Myocardial fibrosis plays a role in LV remodeling which directly results from LV deformity in ebstein' patients.


National data estimate a prevalence of 0.14%to 0.35%, mortality of 3 to 35 per 100,000 individuals and an annual average of30,000 hospital admissions in Brazil.th century, with alterations on cardiac output.4 With new information on theextra-hepatic repercussions of cirrhosis, cirrhotic cardiomyopathy (CCM) has beendescribed as a spectrum of chronic morphofunctional alterations in the heart ofcirrhotic patients with no previous cardiac diseases.7 Thecardiomyocyte lesion is provoked by an imbalance in hemeostasis that occurs in theprogression of cirrhosis, with exhaustion of beta-adrenergic receptors, cytoplasmicimpregnation by endocannabinoids, and imbalance of nitric oxide andendothelin.7 CCM isasymptomatic; however, systolic and diastolic structural alterations are describedin the electrocardiogram (ECG) and Doppler echocardiogram (ECHO).8Cardiac manifestations of hepatic cirrhosis were first reported in the209 Today, it ispossible to identify myocardial compromise in up to 50% of cirrhosispatients,10 but, in mostcases, without clinical expression.Because CCM is asymptomatic, except during situations of stress, prevalence studiesare limited. Heart failure (HF) secondary to CCM is frequent in patients who undergoliver transplant, in which half the patients presents HF, and up to 21% die fromcardiac causes.The objective of this review is to describe recent findings of the pathophysiology ofthe cardiovascular system in hepatic cirrhosis, and show the importance ofbiomarkers and cardiac imaging methods in the identification of a new clinicalphenotype of CCM.Hepatic cirrhosis evolution is insidious, being at times asymptomatic oroligosymptomatic until advanced stages. Signs and symptoms of liver failure tendto appear late, with subtle clinical and laboratory manifestations which areoften hard to interpret.11 Considering it is different from a classic presentationof HF, it is necessary to know this syndrome (CCM) and have a degree of clinicalsuspicion for early identification, to prevent its evolution to relatedcomplications, such as suprarenal insufficiency and hepatorenal syndrome(HRS).Cardiologists may be faced with a patient complaining of dyspnea, presenting withascites, without pathological jugular swelling, normal ECG, ECHO with normalejection fraction, but with elevated B-type natriuretic peptide (BNP) - acondition that may be suggestive of CCM.In the past, cardiomyopathy in alcoholic cirrhosis was understood as myocardialdamage concomitant to liver damage, and had dilated cardiomyopathy as aphenotype.It was believed that alcohol aggression to the heart always happened in the formof chronic disease with dilatation of cavities. With the discovery of viralhepatitis B and C, myocarditis from hepatitis B and C viruses was described,with variable clinical phenotypes, from the oligosymptomatic state, associatedor not to dilated cardiomyopathy. The concept of CCM allows us to understand anew clinical phenotype: the asymptomatic patient, with no apparent functionallimitations, but subclinical cellular and structural cardiac disease .12 There isa predominance of arterial vasodilatation, which induces the activation of theautonomic nervous and renin-angiotensin-aldosterone (RAAS) systems, so thatperipheral perfusion is preserved. This hyperdynamic pattern is directlydependent on cardiac reserve (inotropic and chronotropic capacity), so cardiacoutput is preserved.Cirrhotic patients have hyperdynamic circulation from the peripheralvasodilatation imposed by the neuroendocrine imbalance of hepatic cirrhosis,with increased cardiac output at rest and decreased peripheral vascularresistance.1213With the evolution of biochemical studies and morphofunctional cardiacevaluations, the concept of CCM started to represent the suboptimal ventricularresponse to stress, physiological or induced, even though the patient presentsapparently normal cardiac output at rest, in the absence of previous heartdisease.14CMC`s pathogenesis involves cellular, neural and humoral factors, whosepathophysiological basis is in alterations of the plasma membrane ofcardiomyocytes: influence in calcium signaling, hyperstimulation of betareceptors, action mediated by nitric oxide, carbon monoxide andendocannabinoids. There is an increase in circulating levels of vasoactivesubstances  which are usually elevated incirrhosis due to liver failure and the presence of portosystemic collateralvessels.14Concomitant to the progression of the hepatic disease, there is diastolicmyocardial dysfunction  and systolic myocardial dysfunction.5 Diastolic dysfunction usuallyprecedes systolic dysfunction, which is generally observed in situations inwhich there is an increased demand for cardiac output associated to decreasedmyocardial contractility, such as in situations of hemodynamic stress -infectious processes, physical exercise, use of certain medication andsurgery.9It is understood that diastolic and systolic dysfunction is directly related tothe severity of liver dysfunction and portal hypertension.15 Cardiac dysfunction is also manifested in situations ofmyocardial stress, such as preload increase secondary to transjugularintrahepatic portosystemic shunt (TIPS) insertion, generally indicated for preliver-transplant patients.10Cardiac dysfunction can negatively interfere in the prognosis of cirrhoticpatients, reducing survival and participating in the genesis of complications.HRS and post-paracentesis circulatory dysfunction, which a state of systemichypoperfusion secondary to the quick removal of large volumes of ascitic fluidwithout adequate albumin intake, are the main complications associated to bluntmyocardial response to stress.16 Criteria for CCMidentification are described in Considering most patients are asymptomatic in the initial stages of CCM, theymust undergo clinical, laboratory, electrocardiographic and imaging evaluationsfor early diagnosis.18 Troponin I elevation has beenassociated to a decrease in systolic output and left ventricular mass, but withno correlation to the severity of cihrrosis.19 Pro-BNP elevation has been associated tointraventricular septum wall thickness and ventricular wall thickness. BNP andpro-BNP elevation is associated to the severity of cirrhosis and cardiacdysfunction, but not to hyperdynamic cuiculation.21 Theincrease of BNP and pro-BNP in cirrhotic patients, compared to the control groupand healthy individuals, has a direct correlation to the severity of the hepaticdisease (by the Child-Pugh score and the hepatic venous pressure gradient) andto cardiac dysfunction markers .16 Elevatedlevels of BNP and pro-BNP in cirrhotic patients indicate a myocardial origin ofthese peptides due to the stretching of cardiomyocytes from left ventricularoverload, which increases the expression of the gene responsible for BNPtranscription.17The use of biomarkers has been useful in clinical practice, especially troponinI, BNP, and N-terminal-pro-BNP (NT-pro-BNP), which may be found in abnormallevels in cirrhosis.16Tumor necrosis factor alpha and interleukins 1 and 6 are inflammatory cytokineshyperstimulated in hepatic cirrhosis and HF. The elevation of cardiacdysfunction biomarkers  indicates, in the contextof cirrhosis, myocardial compromise, which is related to the severity of thehepatic disease.Chest X-Ray evaluation is usually normal, or may reveal indirect signs of leftatrial enlargement and, in advanced stages, left ventricular enlargement andcardiomegaly with pleural effusion. ECG may aid in the diagnosis by showing QTinterval prolongation , presence ofmultiple extrasystoles and, in more advanced stages, bundle branch block and STsegment depression. 24-hour holter has better sensitivity to identifybradyarrhythmia and tachyarrhythmia, and can aid in the diagnosis of subclinicalor paroxysmal diseases.5ECHO is a non-invasive method whose findings are correlated to the degree ofhepatic dysfunction: increase of LV diastolic diameter and decrease of peaksystolic velocity, and LV systolic deformity rate evaluated by tissue Doppler.Other findings seen in CCM's diastolic dysfunction are: reduced early (E) andlate (A) ventricular relaxation capacity, and decreased E/A ratio withprolongation of the E-wave deceleration time. In advanced stages, there is LVsystolic dysfunction, with reduction of the ejection fraction. The strain rate(SR) is a new echocardiographic parameter able to identify a reduction in LVsystolic function when the ejection fraction is still normal.8 It canalso help identify simultaneous compromise of both organs, such as inhemochromatosis and amyloidosis.MRIs have been increasingly used in the context of morphofunctional evaluation ofliver and heart diseases. It can determine ejection fraction, volume of cardiacchambers (increase of LV mass and end diastolic volumes in the LA and LV) andmyocardial morphologic alterations, including tissue alterations (areas of edemaand fibrosis), identifying the lesion by using contrast such asgadolinium.19Recognizing the appropriate moment for a therapeutic approach in these patientsis a challenge in the comprehension of CCM. Cardiac compromise is usuallysubclinical, and is manifested as left ventricular insufficiency (LVI) at timesof increased demand, such as in situations of clinical or surgical stress.Congestive HF, with signs of pulmonary congestion, is the final spectrum ofdilated CMPs of any etiology, in which CCM is included - clinical context ofpoor prognosis and high mortality. There is still no specific treatment for CCM.It is currently approached in the same way as HF, which includes water andsodium restriction, use of diuretics, RAAS inhibitors andbeta-blockers.23 The central idea is that HRSis a marker of bad systemic perfusion, and that cardiac output, despite being inthe normal range in the ECHO, is insufficient for the demand. Thus, theinotropic would promote an increase in cardiac output and renal perfusion. Inthe published cases, there was good clinical response with recovery of kidneyfunction.CCM approach in the course of hepatic cirrhosis is still a challenge in clinicalpractice because, when there is the diagnosis of dilated CMP with frankpulmonary congestion, prognosis is reserved. Recently, our group reported, forthe first time, two cases of patients with elevated BNP, X-Ray with no pulmonarycongestion, and ECHO with normal LVEF, but with a progression to HRS refractoryto conventional treatment, in which there was benefit from the use ofdobutamine, as rescue therapy of kidney function, with great clinicalresponse.Myocardial compromise, underdiagnosed in cirrhotic patients, and CCM represent a newclinical phenotype. Once cardiovascular repercussions are understood, thecardiologist should observe its manifestations, be them signs of congestion orclinical complications such as HRS, particularly in situations of clinical orsurgical stress, stimulating its evaluation with cardiac imaging methods andbiomarkers. There is still a lack of understanding of how to apply this knowledge,in daily practice, to benefit patients. There is a need for studies with theobjective of identifying potential treatments that alter the natural history ofcardiac disease in cirrhotic patients, especially in the asymptomatic phase.


The purpose of this study was to analyze the reproducibility of native and contrast-enhanced CMR techniques to measure lesion size after acute myocardial infarction (AMI) using native T1/T2 mapping, T2-weighted (T2w) imaging, contrast-enhanced late gadolinium enhancement (LGE), post-contrast T1 mapping and extracellular volume (ECV) quantification.Lesion size was independently quantified by 2 experienced observers in total of 120 consecutive CMRs obtained in 30 patients within the first 6 months after AMI using native and contrast-enhanced sequences. Lesion sizes were quantified using a threshold method  on basal, midventricular and apical short-axis left ventricular slices. Lesion size is given as the mean of both observers. Bland-Altman analysis was performed to determine the agreement between the two observers. Non-parametric Levene's test was used to compare the variances of the relative differences. Statistical analysis was performed using GraphPad Prism 6.The relative median difference of the native CMR techniques were -1.95% (-12.7% and 9.8%) for T2w, -5.3% (-19.6% and 14.8%) for native T1 and -4.0% (-23.9% and 9.9%) for native T2 (Fig. In general, there was a good agreement between the two observers to measure lesion size after AMI, but all post-contrast sequences had a better agreement compared to the native sequences. The low agreement of native imaging was mainly caused by higher interobserver differences in small lesions with lesion sizes between 0-15 %LV compared to lager lesions >15 %LV.


Aluminium phosphide (ALP) is widely used as a fumigant pesticide. In case of ALP poisoning, it is responsible for myocardial dysfunction, related to toxic myocarditis, and hemodynamic disorders. We report a case of a 28-year-old female who had intentionally ingested ALP and was admitted with cardiogenic shock. The transthoracic echocardiography (TTE) at the time of admission showed severe global myocardial hypokinesia with the presence of a giant left ventricular thrombus. Cardiovascular magnetic resonance (CMR) revealed extensive toxic myocarditis with a left ventricular systolic dysfunction. All cardiac lesions were reversible after symptomatic treatment, within 6 months. We aim, by reporting this case, to evidence the complete reversibility of cardiac injury due to aluminium phosphide poisoning documented by transthoracic echocardiography and cardiovascular magnetic resonance. In Morocco, ALP poisoning is a serious healthcare problem , with a Few cases of reversible myocardial injury have been described in the literature. None of them has been evaluated by cardiovascular magnetic resonance .A 28-year-old woman was admitted to the emergency department with profuse sweating and dizziness, two hours following intentional ingestion of 1 tablet of aluminium phosphide, of which the confirmation was based on toxic ingestion history reported by the case's relatives. She was immediately transferred to the intensive care unit and received gastric lavage.Physical examination at the time of admission revealed general malaise, pulse rate of 120 bpm, blood pressure of 100/60 mmHg, and oxygen saturation of 97% on room air (pulse oximetry).Chest X-ray was normal. The electrocardiogram showed ST-segment elevation in AVr lead with ST-segment depression in inferior and anteroapical leads .Blood analysis revealed increased cardiac troponin I concentration of 17.5 ng/mL (50 times the ULN), glycemia of 0.90 g/dL, sodium of 140 mEq/L, and potassium of 3.8 mEq/L.One hour after admission, the patient developed signs of cardiogenic shock: hypotension (85/40 mmHg), sinus tachycardia (142 bpm), polypnea (28 cycles/min), and GCS score of 12.μg/kg/min, dopamine 20 μg/kg/min) with remarkable hemodynamic improvement 24 hours later.The patient was assisted by mechanical ventilation and intravenous inotropic and vasopressor agents , beta-blockers (carvedilol 12 increased to 25 mg twice daily), and spironolactone (25 mg increased to 50 mg per day) was introduced.Cardiovascular magnetic resonance was performed using a high performance 1.5-Tesla magnet. It showed an intramyocardial subepicardial signal anomaly in the anterior, inferoseptal, and anterolateral walls in T2 and in late gadolinium enhancement in T1-weighted images (after 10 min of gadolinium injection) suggesting acute toxic myocarditis Figures  and 6. AOn follow-up, there was progressive improvement of the hemodynamic, biologic, electric, and echocardiographic parameters. Both the left ventricule ejection fraction and the global longitudinal strain increased, respectively, to 55% and to −13.5% , after 2The patient remains asymptomatic at one-year follow-up.ALP is one of the most abused suicidal chemical agents in Morocco. It is marketed as dark gray tablets of 3 g, consisting of aluminium phosphide (56%) and ammonium carbamate (44%) [When it comes in contact with gastric hydrochloric acid or with atmospheric moisture, ALP releases a lethal phosphine gas .It is a mitochondrial toxin that causes depression of cardiac contractility, secondary to toxic myocarditis, and hemodynamic disorders.The accurate mechanism of cardiotoxicity of ALP is not well defined . It inclThe clinical presentation depends on the amount of toxin ingested, the route of administration, and the time elapsed since exposure to the poison .Within a few minutes following the toxic ingestion, the patient develops symptoms of cardiovascular, gastrointestinal, respiratory, and nervous systems deterioration. Then, a few hours later, symptoms of hepatic and renal failure and disseminated intravascular coagulation appear .The acute cardiovascular collapse secondary to phosphine-induced myocardial damage is the most common mode of presentation (60–100% of cases) .Several studies noted electric abnormalities, as conduction disorders, cardiac arrhythmias, and nonspecific ST-T wave changes, resulting from focal myocardial necrosis and changes in membrane action potentials . Singh eThe transthoracic echocardiogram of our case showed an important reduction in the left ventricular systolic function with global severe hypokinesia. Similar cases have been reported with a significant decrease in the left ventricular ejection fraction. Bhasin et al. demonstrated a similar pattern of global hypokinesia of the left ventricule walls in 80% of their cases. Elabbassi et al. had reported normalization of echocardiographic findings in aluminium phosphide poisoning survivors by the fifth day . ConcernTo our knowledge, we are reporting the first case of left intraventricular thrombus of ALP poisoning.Cardiovascular magnetic resonance, a noninvasive, nonradiating technique, has been successfully used in the evaluation of both ischemic and nonischemic heart diseases. The ability to detect early myocardial changes missed by other imaging techniques, using tissue characterization, makes CMR an excellent diagnostic tool for early and detailed assessment of cardiovascular diseases. Additionally, CMR is the best noninvasive tool currently used for the detection of myocarditis. It has become actually the leading noninvasive imaging modality of myocarditis. The consensual use of the 3 criteria “Lake Louise Criteria”  has standardized the CMR protocol for myocarditis diagnosis .In our case, CMR showed myocardial edema in the T2-weighted images and myocardial areas of late gadolinium enhancement in the early phase. Follow-up CMR in two months showed favourable evolution with regression of the above finding. Furthermore, CMR provided valuable information about the systolic function of both right and left ventricles and the left intraventricular thrombus. To our knowledge, this is the first report describing finding of CMR in ALP ingestion.Since there is no specific antidote to ALP poisoning, the management of ALP intoxication remains primarily supportive care. The use of different therapeutic modalities was reported in the literature with varied degrees of success, including magnesium sulphate , N-acetyThe majority of poisoned patients die despite intensive medical care . HoweverMyocardial injury following ALP poisoning is responsible for high mortality, mainly due to hemodynamic failure attributable to toxic myocarditis . However


LV) function can be difficult to characterize using traditional volume‐based echocardiography measures. Myocardial strain imaging is a sensitive, quantitative marker of myocardial deformation that can measure ventricular function. Recent advances allow layer‐specific measurement of endo‐ and epicardial strain, enhancing the ability to evaluate myocardial ischemia. This study investigates the effects of apical ischemia on LV function using epi‐ and endocardial strain. We hypothesize that myocardial strain will identify changes in regional and global myocardial function associated with focal apical ischemia as compared to ejection fraction (EF), and that longitudinal strain will be a better indicator of myocardial dysfunction compared to circumferential or radial strain. In a porcine model (n = 9), acute ischemia was induced by left anterior descending coronary artery occlusion. Echocardiograms were performed at baseline, during 15‐min ischemia, and after reperfusion. Global longitudinal strain decreased with acute focal ischemia of the left ventricular apical region , with no change observed in global circumferential and radial strain or EF. Both endocardial and epicardial longitudinal strain decreased by 68% (P < 0.001) in the ischemic and peri‐ischemic zone, while circumferential and radial strain only decreased in endocardium of the ischemic zone. Longitudinal strain was more sensitive to ischemia, being able to detect changes in global LV function and thus may confer clinical diagnostic advantage in the evaluation of acute LV apical ischemia.Early detection of acute myocardial ischemia is critical to prevent permanent myocardial damage. The impact of apical ischemia on global left ventricular ( Early detection of acute myocardial ischemia is critical for prevention of irreversible myocardial damage. Subtle changes in endocardial deformation can now be measured quantitatively with speckle tracking strain imaging  weighing 40–50 kg were anesthetized intramuscularly with telazol (8–10 mg/kg), intubated, and mechanically ventilated. General anesthesia was maintained with isoflurane (1–2%). The electrocardiogram was monitored from limb and precordial leads. A femoral artery was cannulated for blood pressure measurement and a jugular vein was cannulated for drug infusion. A median sternotomy exposed the heart; the heart was suspended in a pericardial cradle and the second diagonal branch of the left anterior descending artery was isolated. After a 30‐minute equilibration phase, the second diagonal branch of the left anterior descending coronary artery was occluded with a 4.0 silk suture for 15 minutes followed by 30 minutes of reperfusion, with reproducible apical ischemia  and complied with National Institutes of Health guidelines on the care and use of laboratory animals. Yorkshire pigs , while measures of left ventricular diastolic function included the minimum rate of left ventricular pressure change (dP/dtmin) and the isovolumetric relaxation time constant (tau).A 5‐French Millar conductance pressure‐volume catheter  was inserted via the left common carotid artery into the left ventricular, with echocardiography confirmation, and connected to a conductance processor  to continuously measure left ventricular pressure and volume. Segmental volume signals were examined to ensure proper electrode position. Measures were acquired from steady‐state pressure‐volume loops during sinus rhythm. Left ventricular systolic function was assessed by stroke work (SW) and the maximum rate of pressure change . A bovine liver tissue offset was used to enhance image quality; all images were optimized for speckle tracking analysis by manually adjusting sector widths to optimize speckle quality and maintaining frame rates 55–90 frames/sec. Echocardiographic and hemodynamic data were acquired simultaneously at baseline and 1, 5, and 15 minutes after induction of ischemia. Measurements were repeated 1, 15, and 30 minutes after reperfusion. All images were obtained by the same echocardiographer (EM).Strain analysis was completed offline using speckle tracking software . All measurements were obtained using the average of three cardiac cycles and recorded for subsequent offline analysis. Apical and mitral annular points were identified in end‐diastolic and end‐systolic frames. The software's automated border tracking algorithm automatically defined the contour of epicardial and endocardial layers. The integrity of automated tracking was confirmed by inspection of speckle tracking and strain curves; if needed, the region of interest was adjusted manually to optimize tracking . Segments with persistently inadequate tracking were excluded from the analysis.Peak systolic longitudinal (LS) global and segmental strain was measured from the apical window using 4‐chamber, 2‐chamber, and long‐axis images. Representative 4‐chamber strain tracing demonstrating global LS output is shown in Figure The myocardial segments of the left ventricle were divided into three zones a priori based on direct visualization of myocardial tissue injury during occlusion of the second diagonal branch of the left anterior descending artery (LAD): nonischemic, ischemic, and peri‐ischemic. The ischemic zone was defined as the area of myocardial ischemia, and the peri‐ischemic zone contained the surrounding two centimeters of myocardium in LAD territory. The nonischemic zone included segments greater than two centimeters removed from ischemia.P < 0.05 was considered statistically significant. All statistical analyses were performed in JMP Pro v12.0 .Hemodynamics, Millar catheter measurements, and myocardial strain measures are reported as means with standard deviation at each condition. The change in myocardial strain between each condition and baseline are reported as mean change expressed as percentage. Global myocardial strain measured at 15‐minute ischemia was compared to baseline using a paired t‐test. Hemodynamics and myocardial strain measures during ischemia and reperfusion were compared to baseline within ischemic, peri‐ischemic, and nonischemic zones using repeated measures ANOVA and Tukey's HSD stratified by myocardial layer . For zones with significant changes from baseline during ischemia, segmental analysis was performed using paired t‐tests to identify segments affected by ischemia. Bonferroni correction was used to account for multiple hypothesis testing and All nine animals completed study protocol with adequate images for speckle tracking strain analysis. Two animals experienced ventricular tachycardia (VT) at <1 min reperfusion. VT was nonsustained, no treatment was necessary, and all strain measurements were able to be analyzed at each time point.P < 0.001) and CS  measures. Endocardial LS also had a baseline gradient of increasing values from base to mid  and mid to apex , radial (RS), and circumferential (CS) strains were taken at baseline Fig. . RegionaP < 0.001, Fig. P < 0.0001). Focal ischemia also affected the adjacent peri‐ischemic zone  and epicardium (P < 0.038), respectively. Within the ischemic zone, partial recovery was present after 1‐minute reperfusion, but was attenuated thereafter, with LS remaining below baseline in the endocardium (P < 0.0001) and epicardium (P < 0.002) after 30‐minute reperfusion. LS did not change significantly in the nonischemic zone.Global LS decreased with acute ischemia of the left ventricular apex Table . Regionaone Fig. A, where P < 0.009). The nadir in CS occurred at 5‐minute ischemia and in the endocardium CS was 53% below baseline (P < 0.001) with no change in the epicardium , with no other significant changes observed.Global CS and RS were not significantly affected by acute ischemia Table . Regionaium Fig. B. CS recP = 0.02) before recovering partially at 5‐ and 15‐min ischemia  Global LS was reduced with acute LV apical ischemia, whereas global CS, RS, and EF were not; (2) In the ischemic zone, LS was reduced throughout ischemia in both the endocardium and epicardium, whereas CS and RS were reduced only transiently in the endocardium; (3) In the peri‐ischemic zone, endocardial and epicardial LS were both depressed while no changes in CS or RS were observed; (4) Apical rotation was also reduced transiently at 1‐min ischemia and then recovered. These results demonstrate that acute LV apical ischemia has a greater effect on LS, as compared to other measures of LV function, and therefore global LS may be a better clinical measure of LV ischemic apical dysfunction.In this study, we have importantly shown that acute regional apical ischemia has differential effects on global long‐ and short‐axis myocardial function of the left ventricle. During LV, apical ischemia LS was affected to a greater degree than CS or RS. Traditionally, global LV ventricular function has been most commonly measured by EF, which uses changes in volume to indirectly determine ventricular function. Recent technological advancements in speckle tracking imaging allow direct measurement of myocardial deformation or strain  layer‐specific changes in fiber orientation and coronary perfusion predisposing endocardial and longitudinal fibers to ischemia. Circumferential fibers, which predominate in the midwall of the myocardium, become less concentrated toward the LV apex (Bogaert and Rademakers Previous studies in both clinical and experimental models support our observed results; they show that LS is affected earliest in subendocardial infarction and is a more sensitive marker after acute myocardial infarction as compared to CS or RS (Chan et al. The differences demonstrated in both global and regional strain measures during apical ischemia have important clinical implications. Left anterior descending coronary artery disease is the most common pathology encountered clinically and can lead to LV apical dysfunction (Altiok et al. Taken together, these findings suggest the use of global longitudinal strain in the evaluation of early LV apical ischemia. Changes in global LS may precede changes in hemodynamics or other ventricular function measurements. In our study population of healthy animals, without evidence of prior myocardial dysfunction, induction of acute LV apical ischemia caused no significant changes in hemodynamics or EF. Yet, significant changes were seen in global longitudinal strain, while CS and RS remained unchanged. The importance of LS as a predictor of outcomes, in comparison with other measures of LV function, has been previously established in several surgical populations. Baseline global LS has been shown to be an independent predictor of long‐term LV dysfunction in patients following mitral valve repair (Witkowski et al. As this study used an animal model without preexisting coronary artery disease in order to see the specific effects of acute ischemia on myocardial function, the generalizability of these results may be limited in subjects with preexisting coronary artery disease and myocardial dysfunction. The majority of previous studies investigating the layer‐specific strain have been performed in chronic infarction models. Therefore, our study is unique in that we are applying this technology to an acute ischemia model. While we did not compare strain to another reference such as MRI in this study, layer‐specific strain has been validated by invasive sonomicrometry during acute ischemia (Langeland et al. Myocardial strain measures are able to detect changes in global LV function during apical ischemia. LV apical ischemia had a greater effect on LS as compared to CS or RS and changes in global LS were demonstrated to be associated with LV apical dysfunction. Layer‐specific strain provides new insight to the changes in myocardial deformation associated with acute ischemia. The global strain findings in this study are likely directly related to the changes observed in regional myocardial function. LS may thus confer clinical diagnostic advantage in the evaluation of acute myocardial ischemia over traditional short‐axis analysis of wall motion abnormalities or EF.No conflicts of interest, financial or otherwise, are declared by the authors.


Almost all attempts to improve patient selection for cardiac resynchronization therapy (CRT) using echo-derived indices have failed so far. We sought to assess: the performance of homemade software for the automatic quantification of integral 3D regional longitudinal strain curves exploring left ventricular (LV) mechanics and the potential value of this tool to predict CRT response.L,peak) were automatically measured and calculated for all 17 LV-segments.Forty-eight heart failure patients in sinus rhythm, referred for CRT-implantation  were prospectively explored. Thirty-four patients (71%) had positive responses, defined as an LV end-systolic volume decrease ≥15% at 6-months. 3D–longitudinal strain curves were exported for analysis using custom-made algorithms. The integrals of the longitudinal strain signals  for all 17 LV-segments was greater in CRT responders than non-responders . The optimal cut-off value of SDIL,peak to predict response was 1.037%.s−1. In the 18-patients without septal flash, SDIL,peak was significantly higher in the CRT-responders.The standard deviation of longitudinal strain peak (SDIThis new automatic software for analyzing 3D longitudinal strain curves is avoiding previous limitations of imaging techniques for assessing dyssynchrony and then its value will have to be tested in a large group of patients. Cardiac resynchronization therapy (CRT) has emerged as a relevant therapeutic intervention for the treatment of chronic heart failure –5. BasedSeveral 2D echocardiographic indices of mechanical dyssynchrony have been proposed to better identify therapy responders, yet the lack of reproducibility and the non-optimal quantification of LV mechanical dyssynchrony (LVMD) achievable with these 2D echocardiographic indices in multicenter trials have cast some doubt on the techniques’ clinical applicability –10.In a further advancement, 3D speckle-tracking echocardiography (STE) has been proposed as an alternative and potentially more accurate method for quantifying LVMD and for identifying patients suitable for CRT –13.These different approaches are typically based on analyzing differences in either myocardial velocity timing, by means of tissue Doppler imaging (TDI), or in myocardial deformation using 2D/3D STE. To describe the complexity of LV mechanics, we believe it is essential to perform a combined assessment of LV dyssynchrony and LV regional contractility using STE, particularly by means of longitudinal strain analysis.We hypothesized that a new approach, based on automatic quantification of the integrals pertaining to 3D regional longitudinal strain signals, could provide valuable additional information about regional LV mechanics and function prior to any CRT procedure. The aims of this pilot study were to describe LV mechanics using 3D echocardiography integral-derived longitudinal strain parameters in patients eligible for CRT and to test the relevance of this new tool for predicting CRT response.n = 5).48 patients referred for CRT device implantation at two institutions, the Saint Philibert Catholic University Hospital  and the Rennes University Hospital , were included in the study. Indications for CRT implantation were based on the 2010 ESC guidelines for CRT device use in heart failure . The patIschemic etiology was defined by a history of previous myocardial infarction or prior coronary revascularization or if a > 75% stenosis was observed in ≥1 of the major epicardial coronary arteries . The NYHThe devices were implanted by a standard procedure. The electrophysiologist was blinded with respect to the localization of scar and the main aim during the implantation was to obtain the narrowest QRS at the end of the procedure.All patients provided informed consent to participate in this study, which was performed in accordance with the principles outlined in the Declaration of Helsinki on research in human subjects (CNIL declaration no. 1620030 V. 0).Baseline echocardiography was performed prior to CRT implantation . Digital, routine, gray-scale, 2D Doppler TDI cineloops were obtained from three consecutive cardiac cycles, along with speckle tracking echocardiographic cineloops from one cardiac cycle, all from the apical view . Off-line analyses were performed on digitally stored images .The echocardiography examination was conducted according to the American Society of Echocardiography guidelines . The LV Atrio-ventricular delay was calculated as the ratio between LV filling time and the RR interval. Atrio-ventricular dyssynchrony (AVD) was considered significant when the duration of LV filling time resulted <40% of the RR interval . InterveBaseline 3D–echocardiography was performed in each patient prior to CRT implantation using a commercially available echocardiographic system , equipped with a 4 V phased-array matrix transducer. Consecutive 6-beat ECG-gated sub-volumes were acquired from the apical approach, using second-harmonic imaging during end-expiratory apnea, to generate the full-volume data set. We paid particular attention to encompassing the entire LV cavity within the data set, which was digitally stored in a raw-data format and was exported to a separate workstation equipped with the 4D–AutoLVQ package  for off-line analysis of STE LV myocardial longitudinal deformation.The end-diastolic frames required for contour detection were automatically displayed in quad view. Manual alignment, achieved by pivoting and translating the four-chamber plane, was undertaken to align the three apical views so that the corresponding intersection line of all of the planes was placed in the middle of the LV cavity, crossing the LV apex and center of the mitral valve in each view. We subsequently used the semi-automated option to identify a fitting geometric model. Importantly, the software required only two single points to be input manually  on the end-diastolic and end-systolic frames of the four-chamber view slice. The software automatically detected the LV cavity endocardial border in 3D and provided the measured LV volumes. If the endocardial border detection was judged inadequate by the examiner, the LV endocardial borders were manually adjusted in multiplanar layout  with a point-click method, immediately followed by secondary automated refinement of boundary detection according to the results. Following assessment of the LV volumes and ejection fraction, an automatic trace of the epicardial border was displayed to identify the region of interest required for LV mass and myocardial deformation measurements by means of 3D STE. This epicardial trace was manually adjusted in order to include the entire LV wall thickness using the same point-click method. The longitudinal deformation parameters were reported as global (both peak and end-systolic) and regional (only end-systolic) and were presented as color-coded polar maps and time-strain traces of an LV 17-segment model ; and 2), strain integrals from the QRS onset to the instant of aortic valve closure  . This analysis included a regional characterization of the longitudinal strain integrals and extended to the 3D case of a set of methods initially developed by our group for 2D strain analysis . The strt,peak” (standard deviation of time to strain peak), along with novel measurements as detailed below.L,peak and mean IL,avc represented the mean of IL,peak and IL,avc of all 17 LV segments, respectively.mean IL,peak and SDIL,avc were the standard deviation of the integrals of the strain signals IL,peak and IL,avc of all 17 segments, respectively. SDIL,peak and SDIL,avc corresponded to the energy dispersion for all 17 segments at the longitudinal strain peak and at the instant of aortic valve closure, respectively.SDIL,avc and IL,peak for each segment. This value could be considered an indicator of the wasted energy developed by the ventricle after aortic valve closure.DiffInt was calculated as the average of all 17 LV segments in terms of the difference between IMSDI  was calculated as the ratio of the time difference between the last and first strain peaks occurring during the cardiac cycle and the duration of the cardiac cycle.We tested the integral-based indicators of the regional longitudinal strain signals, all of which were automatically calculated, revealing standard parameters such as “peak strain” (amplitude), “mean strain peak”, and “SDAt 6-months post-implant, all of the patients were reassessed with 2D echocardiography. Response to CRT was defined as a ≥ 15% reduction in LV end-systolic volume, compared with baseline , 24.p-value <0.05 was considered statistically significant. Sex, non-ischemic etiology, LBBB morphology, QRS ≥ 150 ms, GLS, atrioventricular dyssynchrony, IVMD >40 ms, LVPEI, DTI septo-lateral delay, septal flash, SDt,peak, SDIL,peak, DiffInt, and MSDI were covariates entered into the univariate model.All of the normally distributed data are displayed as the means and standard deviations, with non-normally distributed data expressed as medians and interquartile ranges (IQRs). Normality was evaluated by the Shapiro-Wilk test. Comparisons between the groups were performed using Student’s t-test or the Welch two-sample t-test, with the Mann–Whitney U test applied for normally and non-abnormally distributed data. Categorical variables, expressed as counts and percentages, were compared using the chi-square test or Fisher’s exact test, as appropriate. A p < 0.1 were inserted in the multivariable logistic regression analysis (stepwise entry method). Variables with a p-value <0.1 in the multivariate model were considered possible contributors (according to the fact that this is a pilot study). For all of the variables in the multivariate model, the net odds ratio (OR) was reported, along with its 95% confidence interval (CI) and p-value. Receiver-operating characteristics curves were individually constructed for dyssynchrony parameters to determine the optimal threshold (closest to the top-left corner), sensitivity, specificity, positive and negative predictive values, and diagnostic accuracy. To explore the value in predicting response to CRT, of the tested 3D–strain parameters over the known variables  the ROC curves were traced and a comparison was done. In addition, and for assessing the complementarity or the concordance of the new potential 3D–strain tool vs the previously proposed predictive parameters, a Kappa test was performed. The analyses were performed using R software, version 3.0.3 .All variables showing a A total of 48 heart-failure patients  referred for CRT device implantation were included in this study. 15 patients (31%) had ischemic cardiomyopathy. The mean intrinsic QRS duration was 160 ms (IQR: 160–170), and a typical LBBB morphology was observed in 39 (79%) patients. The mean LVEF was 26 ± 6%.p = 0.033), had and had better LV performance at baseline as indicated by LVEF , and GLS values . The main clinical and echocardiographic characteristics are shown in Table At 6-months follow-up, 34 34 patients 71%) had a LV end-systolic volume reduction ≥15% (responders). Compared to non-responders, the responders were more often female .The classical dyssynchrony parameters were analyzed manually, with the results displayed in Table p = 0.302). The same relationship was observed for SDt,peak .In the overall population, the median strain peak was −10.2% , with no significant difference between CRT responders and non-responders , and only Mean IL,peak was significantly higher in CRT responders than in non-responders .In the study population, mean IL,peak of all 17 LV segments differed significantly between CRT responders and non-responders . DiffInt and MSDI parameters were comparable between CRT responders and non-responders , SDIL,peak , and non-ischemic etiology . Among the 18 patients without septal flash, the SDIL,peak values were higher in CRT responders than in non-responders   of 70.6% and specificity (Sp) of 78.6%  increased the test specificity to 100%, although it decreased its sensitivity and NPV. The Kappa test testing the concordance between septal flash and SDIL,peak was 0.26 confirming that SDIL,peak is exploring another kind of mechanical dyssynchrony than septal flash. In addition combining the septal flash and the SDIL,peak > 1.037% s−1 lead to an area under the curve: AUC = 0.86.All of the multiparametric associations were tested, and they are displayed in Table L,peak and SDIL,peak of all 17 LV segments were higher in CRT responders than in non-responders; 3) While marginally significant in this study, SDIL,peak could have an independent value for predicting CRT response; and 4) combining a SDIL,peak value >1.037% s−1 and interventricular dyssynchrony appeared to be a promising multi-parametric approach for best predicting CRT response, and it was feasible and robust in patients with sufficient acoustic windows and a sinus rhythm. And perhaps the most important finding was that 3D strain-derived parameter could differentiate responders from non-responders among 18 patients without septal flash.Our study investigated a new quantitative computation method for longitudinal strain curves. Integral-derived parameters were generated and described for the first time, and they were applied in heart failure patients eligible for CRT, producing the following primary findings: 1) automatic analysis of longitudinal strain curves provided new complementary data on LV mechanics by combining information on timing and LV regional performance; 2) the mean ISince the publication of the disappointing PROSPECT study results , severalt,peak). We thus proposed a new 3D automatic assessment of regional LV mechanics, avoiding as much as possible potential human error.The first source of error is undoubtedly related to the lack of standardized data-processing methods. Numerous parameters have been proposed . After dL,peak was significantly higher in CRT responders, suggesting that this new predictor could provide additional information for the optimal selection of CRT patients. After the performing of a multiparametric evaluation of mechanical dyssynchrony that considers the three levels of dyssynchrony , it appeared rather clear that this imaging approach could be of additive value to ECG [L,peak > 1.037% s−1 and interventricular dyssynchrony appeared to be an interesting multiparametric approach for predicting a good CRT response.Mechanical dyssynchrony assessment could have 2 steps. As the first step, septal flash should be searched for using a simple visual and/or M-mode approach. If septal flash  is not found, 3D echo should be performed in the next step as an attempt to detect a novel predictor of volumetric response. In the present study, we confirmed such results but also that the septal flash is highly relevant . That ise to ECG . A combiL,avc was lower than the mean IL,peak, in our patients, indicating that most segments reached their maximal deformation after aortic valve closure. SDIL,peak, corresponding to the energy dispersion for all 17 segments at the longitudinal strain peak, appeared to be promising for the assessment of LV dyssynchrony and the prediction of LV reverse remodeling following CRT.This “second step” three-dimensional STE appeared promising for several reasons : (I) allThat is a first pilot study, using one kind of echo-machine in a limited number of patients but in two centers. The goal was to ‘validate’ a tool that was planned to be use in largest population. Since a large intervendor variability has been demonstrated in 3D strain systems, the cut-off values identified are valid only for GE technology . Only thAnother limitation is related to fact that it is a pilot study with the use of an endpoint that is questionable. LV-remodeling is not a perfect surrogate marker of the hardest clinical endpoints. The Endpoint proposed by Packer will have to be considered .This new automatic analysis of 3D longitudinal strain curves, using integral-derived parameters, provided original information on LV mechanics by combining timings and LV regional contractility data. This approach could be of value for improving patient selection for CRT.


In vivo left-ventricular hemodynamics/pressure-volume relationships assessed before/during a 30 min IV infusion of CXL-1020 demonstrated acute load-independent positive inotropic, lusitropic, and vasodilatory effects in normal rats. In rats with only diastolic dysfunction due to bilateral renal wrapping (RW) or pronounced diastolic and mild systolic dysfunction due to 4 weeks of chronic isoproterenol exposure (ISO), CXL-1020 attenuated the elevated LV filling pressures, improved the end diastolic pressure volume relationship, and accelerated relaxation. CXL-1020 facilitated Ca2+ re-uptake and enhanced myocyte relaxation in isolated cardiomyocytes from ISO rats. Compared to milrinone, CXL-1020 more effectively improved Ca2+ reuptake in ISO rats without concomitant chronotropy, and did not enhance Ca2+ entry via L-type Ca2+ channels nor increase myocardial arrhythmias/ectopic activity. Acute-therapy with CXL-1020 improved ventricular relaxation and Ca2+ cycling, in the setting of chronic induced diastolic dysfunction. CXL-1020's lusitropic effects were greater than those seen with the cAMP-dependent agent milrinone, and unlike milrinone it did not produce chronotropy or increased ectopy. HNO is a promising new potential therapy for both systolic and diastolic heart failure.The nitroxyl (HNO) prodrug, CXL-1020, induces vasorelaxation and improves cardiac function in canine models and patients with systolic heart failure (HF). HNO's unique mechanism of action may be applicable to a broader subset of cardiac patients. This study investigated the load-independent safety and efficacy of CXL-1020 in two rodent (rat) models of diastolic heart failure and explored potential drug interactions with common HF background therapies.  Acute decompensated heart failure (ADHF) is the leading cause of hospitalization in the United States with ~1 million hospital admissions per year  , has been shown to improve cardiac function in canine models of systolic heart failure by directly enhancing inotropy and lusitropy, and by venous and arterial vasodilation (pre-/afterload reduction)   . However, ~50% of HF patients have heart failure where EF is preserved (HFpEF)  were used in these experiments. Animal care and experimental protocols were approved by the Animal Care and Use Committee of QTest Labs.Alzet mini-osmotic pumps , filled with isoproterenol (ISO) to deliver 1 mg/kg/day for 4 weeks at a rate of 0.25 μL/h, were implanted in anesthetized rats (~45/~5 mg/kg) via a ~1 cm in a mid-scapulae subcutaneous pocket to the manufacturer's instructions, as previously described  were positioned in right-lateral recumbence and transthoracic 2D-guided short-axis M-mode examinations were assessed at the mid-papillary level to evaluate left ventricular ejection fraction via echocardiography (Phillips HD11xe). Doppler echo was used to assess the ratio of the early (E) to late (A) ventricular filling velocities (E/A ratio) at the level of the mitral valve from an apical four-chamber view on rats positioned in dorsal recumbence.2/CO2) with an adjustable small animal ventilator (Harvard Apparatus). Anesthesia was maintained with a continuous sodium pentobarbital intravenous (IV) infusion (4 mg/kg/h) via an indwelling catheter placed in a peripheral vein, until completion of the experiment. A micromanometer catheter (Millar Instruments—SPR-407) was inserted into the femoral artery to measure arterial pressure. For left ventricular (LV) mechano-energetic evaluation, a 2F high-fidelity conductance/micromanometer catheter (Millar Instruments—SPR-869) was advanced retrograde across the aortic valve and into the LV chamber by way of the right carotid artery in order to simultaneously determine left-ventricular pressure and volume (via conductivity); despite calibration in blood and parallel-conductance adjustments, volumes are expressed as relative volume units (RVU). A balloon catheter was placed and advanced into the inferior vena cava through the left femoral vein. At specific timepoints during the experiment, this balloon was inflated to acutely decrease myocardial preload in order to generate a family of pressure-volume curves/loops. The resulting left-ventricular pressure and volume data were analyzed offline  in order to generate relationships representing the contractile and energetic state of the myocardium. In all cases, hemodynamic stabilization was allowed for at least 15 min prior to the start of the experiments.Each rat was intraperitoneally (IP) anesthetized with sodium pentobarbital (50–90 mg/kg), positioned in dorsal recumbence, endotracheally intubated and ventilated  were compared with volume/vehicle controls , both with and without intravascular volume expansion with Hextend . In addition, load-independent functional effects of HNO were compared (at matched blood pressure reductions) to those of the clinically-used nitric oxide donor sodium nitroprusside , both with and without concomitant restoration of systemic pressures via phenylephrine .The cardiovascular efficacy and safety of CXL-1020, was compared to the phosphodiesterase 3A (PDE3A) inhibitor milrinone  in the setting of normal and abnormal  cardiac function. Pro-arrhythmia was quantified by the number of LV ectopic beats per minute based on the LV-pressure waveform.2+ channel (LTCC) blockade with verapamil .The interactions of HNO were evaluated in combination with the β –AR antagonist, metoprolol  and the ACE inhibitor enalaprilat . The effects of HNO and MIL were also compared in the setting of L-type CaLV ectopic beats were analyzed using ecgAuto from the LV pressure wave form.2+ free tyrode solution (consisted of (in mmol/L): 140 NaCl, 4 KCl, 1 MgCl2, 10 glucose, 5 HEPES, pH 7.4 adjusted with NaOH or HCl) for 4 min. The solution was then switched to a tyrode solution containing collagenase Type II (59 mg/100 mL) , hyaluronidase (2.4 mg/100 mL) , and protease (3.5 mg/100 mL) . After 30 min, the heart was taken off the Langendorff, the ventricles minced while in a petri dish filled with 0 Ca2+ Tyrode solution via tissue scissors, and myocytes were dissociated by trituration with a transfer pipette. Subsequently the myocytes were filtered through a 200 um nylon mesh filter, briefly centrifuged for ~5 s, and resuspended in tyrode solution containing 200 μmol/L Ca2+. Myocytes were used within 6 h of isolation, as previously described . The heart was cannulated and hung on a Langendorff apparatus. It was then perfused with Ca2+ transient and shortening measurements were performed at room temperature with tyrode solution with 1 mmol/L CaCl2 (2 mmol/L CaCl2 for canine), as previously described . Myocytes were stimulated at 1 Hz via platinum electrodes connected to a Grass Telefactor S48 stimulator . As Mil alone did not elicit a functional effect  via either paired/unpaired Student's Throughout this study, 31 instrumented normal rats received CXL-1020 (100 μg/kg/min for 30 min); a dose determined previously to be effective  was similar to CXL-1020 alone except for a mildly enhanced reduction in MAP Table . ConsistThe activity of CXL-1020 was investigated in two models of cardiac dysfunction: chronic renoprival hypertension secondary to bilateral renal wrapping (RW) and chronic β-AR stimulation (ISO).c) were also evaluated  resulted in pronounced cardiac diastolic dysfunction as assessed by echocardiography , but a minimal effect on systolic function  Table . Invasived Table . In thised Table . The maged Table .2+ cycling.The ISO rats also exhibited cardiac dysfunction as assessed by echocardiography , but more than RW Figure . In agre2+ Transient amplitudes ; and reduced shortening amplitudes ], and slowed relaxation . The RT50 is the time for Ca2+ Transient/myocyte to decline/relengthen to 50% of its max amplitude. Although at a different starting point  in this isolated cardiomyocyte setting, CXL-1020 (50 μM) enhanced myocyte contraction and accelerated relaxation , a clinically relevant drug that has a similar lusitropic inodilator profile, in the s Figure  when asss Figure . These r2+ channel in mediating the effects of MIL vs. CXL-1020 was evaluated by selectively antagonizing that current in vivo with verapamil (VER)  while that of MIL was abolished . In the setting of impaired diastole, the beneficial effects of CXL-1020 were not only greater than observed with the cAMP-dependent inotrope MIL, but more importantly, free of chronotropic and pro-arrhythmic liabilities.The present study is the first to thoroughly evaluate the cardiovascular activity of CXL-1020 in rats. These integrative experiments extend previous studies in humans and other species to confirm that CXL-1020 behaves as a load-independent inotrope/lusitrope, improving CaPrevious studies have demonstrated the positive inotropic and lusitropic effects of HNO, in normal dogs , sheep (unpublished), and human  (26% in ISO rats and ~30% in tachypaced dogs), the reduction in MAP in the ISO rats (~−25%) was significantly greater than the reduction in MAP in the dogs (~−10%). These results demonstrate that the ratio of inotropy to vasodilation in the rat is lower than in the dog. This may be, in part, due to the very high efficiency of cardiac Ca2+ handling and PKA/PKG signaling are involved  . This enhanced efficacy in the disease state was not observed in published studies in the conscious tachypaced HF canine model. Collectively, the results in the present study demonstrate the potential of HNO for the treatment of acute clinical diastolic heart failure.Approximately 50% of patients admitted to the hospital for acute heart failure suffer from diastolic dysfunction (HFpEF) . The corrected Tau  was added due to the disparity between baselines HR between models . Elevated HR changes will also reduce the end diastolic volume, shift the LV end diastolic pressure and the EDPVR   .JR and JH are current employees of Cardioxyl Pharmaceuticals. RM is a prior employee of Cardioxyl Pharmaceuticals.SR and CLdR: preformed research, analyzed data, contributed to writing the manuscript. YU: preformed research, analyzed data. RM: contributed to study design. RH, JH, MZ, and JR: contributed to study design, contributed to writing the manuscript.The authors declare that this study received funding from Cardioxyl Pharmaceuticals, Inc. The funder and employees  were all involved in the study design. JR and JH also contributed to writing the manuscript. QTest Labs performed the experiments under contracts (funding) established between QTest Labs and Cardioxyl Pharmaceuticals, Inc. The other 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.


The amount of blood flow through the lungs is determined by pulmonary by pressure gradient as well as cardiac function in PH. Dynamic contrast-enhanced MRI (DCE-MRI) enables high temporal resolution imaging to track the first transit of contrast material bolus through the pulmonary circulation. First-pass parameters such as pulmonary transit time (PTT), left ventricular (LV) full width at half maximum (FWHM), and LV time to peak (TTP) have been shown to be impaired in PAH compared to controls. Little has been reported regarding the relationship between first pass perfusion parameters in other groups of PH. Our aim was to explore the relationship between first-pass parameters and RV and LV performance in patients with group I (PAH) and group IV (chronic thromboembolic pulmonary hypertension) PHWe prospectively recruited 9 patients with PH  who underwent CMR at 3T. CMR studies included functional (bSSFP) cine imaging for assessment of ventricular function, as well as phase contrast velocity encoded cine imaging obtained perpendicular to the main pulmonary artery (MPA) for assessment of MPA distensibility (%). To assess PTT, FWHM, and TTP, a 1:10 diluted bolus (0.0025 mmol/kg) of Gadobutrol was injected intravenously at 5 mL/s and followed using a single-shot saturation-recovery gradient-echo sequence in the short axis orientation . First-pass bolus kinetic parameters were determined by sampling the signal intensities in the RV and LV cavities and generating time-intensity curves for each ventricle. PTT was defined as the transit time of blood between the RV and LV, while FWHM and TTP were derived from the shape of the bolus in the LV cavity . Differences in first-pass parameters between the two groups were assessed using Mann-Whitney U tests and the relationship between each first-pass and functional parameters were investigated using Spearman's rank correlation (rho).There were no significant differences in first-pass parameters between groups (P>0.05 for each comparison). Significant negative correlations were found between FWHM and LV ejection fraction  and LV cardiac output  and FWHM was positively correlated with MPA distensibility . Trends towards negative correlations between PTT and RV  and LV stroke volume indexed  were also revealed.First pass perfusion parameters are similar in Group I and IV patients with PH. An increase in MPA distensibility is associated with an increase in FWHM. This may be attributed to advanced disease when RV cardiac output is decreased resulting in a paradoxical decrease in pulmonary pressures. Increased first-pass bolus dispersion (FWHM) may be a noninvasive marker of impaired pulmonary hemodynamics and biventricular dysfunction in groups I and IV patients with PH.


Clinical data indicating a heart rate (HR) target during rate control therapy for permanent atrial fibrillation (AF) and assessing its eventual relationship with reduced exercise tolerance are lacking. The present study aims at investigating the impact of resting HR on the hemodynamic response to exercise in permanent AF patients by means of a computational cardiovascular model.4, VCI6 and VCI8).The AF lumped-parameter model was run to simulate resting  and various exercise conditions , considering different resting HR . To compare relative variations of cardiovascular variables upon exertion, the variation comparative index (VCI)—the absolute variation between the exercise and the resting values in SHR simulations referred to the absolute variation in HHR simulations—was calculated at each exercise grade , while for systemic arterial pressure the opposite is true .Pulmonary venous pressure underwent a greater increase in HHR compared to SHR simulations (VCIThe computational findings suggest that a slower, with respect to a higher resting HR, might be preferable in permanent AF patients, since during exercise pulmonary venous pressure undergoes a slighter increase and systemic blood pressure reveals a more appropriate increase. Atrial fibrillation (AF), the most common cardiac arrhythmia, is a major healthcare burden, whose prevalence is constantly rising. In case of permanent AF, a rate control approach combined with an oral anticoagulant therapy (OAT) is generally adopted to decreReduced exercise tolerance is, together with chest pain, palpitations and shortness of breath, one of the major symptoms of AF. The decline in exercise capacity during AF is typically on the order of 15% to 20%, 7. DropThis topic is still widely debated, and the relationship between AF and exercise tolerance remains uncertain. The underlying mechanisms are not clear, but most probably rapid and irregular rate plays a key role, together with the consequent reduced passive ventricular filling in early diastole. Being likely that a greater increase in HR (given the same amount of exertion) is related to a worse tolerance, it is sStarting from a lumped mathematical algorithm , 16, 17 The hereby adopted mathematical model is able to measure the effects of AF on the cardiovascular system and it has extensively been validated in resting conditions through systematic comparison with more than thirty clinical studies providing AF hemodynamic data. The prelaed), left atrial volume (Vlaed), left ventricular pressure (Plved), left ventricular volume (Vlved). End-systolic values refer to the instant defined by the closure of the aortic valve, while end-diastolic values correspond to the closure of the mitral valve. Left ventricular performance was evaluated through the following hemodynamic parameters: stroke volume, SV = Vlved—Vlves [ml], ejection fraction, EF = SV/Vlved x 100% [%], stroke work, SW/min [J/min], measured as the area within the left ventricle pressure-volume loop per beat, and cardiac output, CO = SV x HR [l/min]. Oxygen consumption was also estimated through the tension time index per minute, TTI/min = Plv x RR x HR [mmHg s/min]. In addition, systemic arterial , pulmonary arterial  and venous (Ppvn) pressures [mmHg] were evaluated.Left heart dynamics were evaluated in terms of volume [ml] and pressure [mmHg], also considering end-diastolic (ed) and end-systolic (es) values: left atrial pressure , resting simulation corresponds to 1 MET, while exercise simulations were designed to resemble, respectively, a light effort , a moderate effort (6 METs—e.g. skiing) and a vigorous effort (8 METs—e.g. running). Starting from 1 MET see , exercislv,max) and maximum right ventricular elastance  were increased, given the enhanced cardiac inotropism, CQ: flow coefficient [ml/(s mmHg0.5)], K: valve coefficient. List of subscripts. la: left atrium, lv: left ventricle, ra: right atrium, rv: right ventricle, mi: mitral, ao: aortic, ti: tricuspid, po: pulmonary, un: unstressed, min: minimum, max: maximum, sas: systemic aortic sinus, sat: systemic artery, sar: systemic arterioles, scp: systemic capillary, svn: systemic vein, pas: pulmonary artery sinus, pat: pulmonary artery, par: pulmonary arterioles, pcp: pulmonary capillary, pvn: pulmonary vein, p: effect of pressure force, f: frictional action, b: velocity effect on the valve dynamics, due to blood motion, v: vortex effect on the valve dynamics.Lumped-model parameters at baseline. P: pressure [mmHg], V: volume [ml], Q: flow rate [ml/s], ϑ: valve opening angle [rad]. E: elastance [mmHg/ml], C: compliance [ml/mmHg], R: resistance [mmHg s/ml], L: inductance [mmHg s(DOCX)Click here for additional data file.S2 Tablesas, Ppvn, Ppas,dias, SV) are reported in SHR.Cardiovascular parameters in (DOCX)Click here for additional data file.


Left ventricular (LV) diastolic dysfunction occurs earlier in the ischemic cascade than LV systolic dysfunction and electrocardiographic changes. Diastolic wall strain (DWS) has been proposed as a marker of LV diastolic stiffness. Therefore, the objectives of this study were to define the relationship between DWS and coronary revascularization and to evaluate other echocardiographic parameters in patients with stable angina who were undergoing coronary angiography (CAG).Four hundred forty patients  undergoing CAG and with normal left ventricular systolic function without regional wall motion abnormalities were enrolled. Among them, 128 (29%) patients underwent revascularization . All patients underwent echocardiography before CAG and the DWS was defined using posterior wall thickness (PWT) measurements from standard echocardiographic images [DWS = PWT(systole)-PWT(diastole)/PWT(systole)].p < 0.001). Age was comparable between the two groups , but the proportion of males was significantly higher among patients who underwent revascularization . The LV ejection fraction was similar but slightly decreased  and the E/E’ ratio was elevated  among patients who underwent revascularization. In multiple regression analysis, lower DWS was an independent predictor of revascularization .Patients who underwent revascularization had a significantly lower DWS than those who did not (0.26 ± 0.08 vs. 0.38 ± 0.09, DWS, a simple parameter that can be calculated from routine 2D echocardiography, is inversely associated with the presence of coronary artery disease and the need for revascularization. Conditions causing chest pain or discomfort, such as an acute coronary syndrome or angina, have a potentially poor prognosis, emphasizing the importance of a prompt and accurate diagnosis . For patAn echocardiographic study published in 1972 showed abnormal motion of the LV posterior wall during angina pectoris . Recentln = 128) and no revascularization group (n = 312). Patients with ACS, chronic kidney diseases, LV EF < 50%, regional wall motion abnormalities, arrhythmia, severe valvular heart diseases, pericardial diseases, thyroid disease, moderate to severe pulmonary hypertension, sepsis, or haemodynamic instability were excluded from this study. We also collected participant data regarding demographic, anthropometric, and laboratory parameters including cardiac biomarkers.Of 2375 patients who underwent CAG from January 2013 to December 2015, 440 patients  who were diagnosed with or suspected to have stable angina were studied retrospectively. Patients were referred for evaluation of chest pain or dyspnoea by their general practitioner or by themselves. The character of the chest pain  was evaluated, and we excluded any patient with resting pain or suspected unstable angina. A variety of risk factors were recorded during the clinical assessment. Patients who had a prior history of CAD were excluded from this study regardless of their history of coronary stenting. All patients underwent CAG and pre-procedural EF by transthoracic echocardiography (TTE) and were sorted into two groups – the revascularization group (3 − (LVEDD)3] − 13.6. Thereafter, the LV mass index (LVMI) was calculated and indexed to the body surface area. DWS was calculated as [(PWTs) - (PWTd)/(PWTs)] using M-mode echocardiography [TTE was performed using standard techniques with a 2.5-MHz transducer. Standard 2-D and Doppler echocardiography was performed using a commercially available echocardiographic machine  with the same setup interfaced and a 2.5-MHz phased-array probe. With the study participants in the partial left decubitus position and breathing normally, the observer obtained images from the parasternal long and short axes as well as from the apical four chamber and two-chamber and long-axis views. The depth setting was optimized to display the LV on the screen as large as possible and the same field depth was kept for both the four and two-chamber apical views. The sector width was reduced to increase the spatial and temporal resolution. The LV end-diastolic dimensions (LV EDD), end-diastolic interventricular septal thickness (IVSTd), and end-diastolic LV posterior wall thickness (PWTd) were measured at end-diastole according to the standards established by the American Society of Echocardiography . LV EF wThe mitral flow velocities were recorded in the apical four-chamber view. The mitral inflow measurements included the peak early (E) and peak late flow velocities (A) as well as the E/A ratio. The tissue Doppler of the mitral annulus movement was also obtained from the apical four-chamber view. A 1.5-mm sample volume was placed sequentially at the septal annular sites. An analysis was performed for the early diastolic (E’) and late diastolic (A’) peak tissue velocities. As a noninvasive parameter for LV stiffness, the LV filling index (E/E’) was calculated by the ratio of the transmitral flow velocity to the annular velocity. Adequate mitral and tissue Doppler image (TDI) signals were recorded in all patients.The mean longitudinal global strain (GS) of LV was calculated from the apical 4,3,2-chamber views by speckle-tracking 2D–strain imaging .A high-resolution B-mode ultrasound  equipped with a 7.5-MHz linear array transducer was used for carotid ultrasonography. In the longitudinal view, the carotid intima-media thickness (IMT) was determined as the distance from the media adventitia interface to the intima lumen interface on the far wall in a region free of plaque . The exap value of 0.05 or less were considered statistically significant. The performance of continuous tests was assessed by receiver-operating-characteristic (ROC) curve.All of the continuous data are expressed as the mean ± SD, and all of the categorical data are presented as percentages or absolute numbers. Continuous variables were analysed using Student’s t-test, and dichotomous variables were analysed using the chi-square test. In addition, multivariate analysis  was performed. All variables that had a p = 0.001).The clinical characteristics of the patients are shown in Table p = 0.001). However, the mean DWS was significantly lower in the coronary revascularization group in both men  and women .One hundred twenty-eight patients underwent coronary revascularization  among the 440 patients who underwent CAG. Echocardiographic measurements of the study population are shown in Table Table Table Univariate analysis showed that several clinical, echocardiographic, and other factors had predictive value for coronary revascularization. A lower DWS, decreased GS, diastolic dysfunction, elevated E’ velocity, male gender, diabetes, current smoking, higher IMT and higher maximal plaque thickness were associated with coronary revascularization in patients with clinical suspicion of stable angina in those who underwent CAG Table .Table 5Up = 0.011) and higher IMT  were found to be independently related to coronary revascularization , the most common cardiac arrhythmia, is associated with the LV diastolic dysfunction . Kang etTherefore, decreased DWS ≤ 0.33 or 0.34 is definitely associated with increased LV stiffness and diastolic dysfunction in various diseases , 22, 25 This study has a few limitations. First, few patients showed elevated pre-procedural cardiac biomarkers. Suspected ACS patients  were excluded from this study. Only a few patients who were very stable did not have resting chest pain and showed normal LVEF by echocardiography without discernible RWMA were included. Despite the insensitive and subjective nature of the echocardiographic evaluation of RWMA, the patients included in this study were not high-risk patients. Rarely, cardiac troponin can be elevated if the angina episode is prolonged in patients with chronic stable angina . Second,In summary, decreased DWS is associated with coronary revascularization in patients with stable angina. The important clinical implication of this finding is that lower DWS may be helpful to predict coronary revascularization in patients with normal pre-procedural LV EF. This implies a possible role of echocardiography in the diagnosis of stable angina.