We aimed to establish whether αvβ3 integrin expression determines myocardial recovery following MI.Maladaptive repair contributes towards the development of heart failure following myocardial infarction (MI). The α18F-Fluciclatide (a novel αvβ3-selective radiotracer) positron emission tomography (PET) and CT imaging and gadolinium-enhanced MRI (CMR) were performed in 21 patients 2 weeks after ST-segment elevation MI . CMR was repeated 9 months after MI. 7 stable patients with chronic total occlusion (CTO) of a major coronary vessel and nine healthy volunteers underwent a single PET/CT and CMR.18F-Fluciclatide uptake was increased at sites of acute infarction compared with remote myocardium (tissue-to-background ratio (TBRmean) 1.34±0.22 vs 0.85±0.17; p<0.001) and myocardium of healthy volunteers . There was no 18F-fluciclatide uptake at sites of established prior infarction in patients with CTO, with activity similar to the myocardium of healthy volunteers . 18F-Fluciclatide uptake occurred at sites of regional wall hypokinesia  and subendocardial infarction. Importantly, although there was no correlation with infarct size  or inflammation , 18F-fluciclatide uptake was increased in segments displaying functional recovery  and associated with increase in probability of regional recovery.18F-Fluciclatide uptake is increased at sites of recent MI acting as a biomarker of cardiac repair and predicting regions of recovery.NCT01813045; Post-results. Ischaemic heart disease remains the leading cause of death globally, with over 1 million people suffering acute myocardial infarction (MI) per year in the USA alone. As the acute management of MI improves, the number of patients surviving acute myocardial injury is higher than ever before. In this population, adverse cardiac remodelling and the syndrome of delayed heart failure represent the major cause of morbidity.Repair following MI is triggered by a complex interaction of neurohormonal activation and upregulation of angiogenic and pro-fibrotic transcription factors that initiate the restoration of a capillary network through angiogenesis and re-endothelialisation, as well as extracellular matrix (ECM) remodelling through macrophage accumulation and fibroblast activation. This interplay of angiogenesis, inflammation and fibrosis determines the extent of preservation and restoration of myocardial integrity.vβ3 integrin is a transmembrane cell surface receptor that facilitates migration, proliferation and interaction with the ECM, thereby allowing cells to respond to, and in turn modify, their extracellular environment. Expressed at low levels by quiescent endothelial cells, αvβ3 integrin is markedly upregulated in states of angiogenesis within the myocardium after infarction.vβ3 integrin expression by both activated cardiac myofibroblasts and macrophages during margination and chemotaxis. Thus, αvβ3 integrin expression appears central to the coordination of repair following MI.The αvβ3 integrin following MI using the novel αvβ3 integrin-selective radiotracer, 18F-fluciclatide, combined with cardiac positron emission tomography (PET), CT and cardiovascular MRI (CMR). The study aims to describe and characterise the uptake of this radiotracer and to correlate it with clinical markers of disease severity and functional recovery in patients with recent MI.In this study, we investigated the expression of α18F-fluciclatide and CMR were performed in three groups of participants recruited from Royal Infirmary of Edinburgh between July 2013 and February 2015. Exclusion criteria were age <40 years, women of childbearing potential not taking contraception, severe renal failure (serum creatinine >2.8 mg/dL) or hepatic failure (Child-Pugh grade B or grade C), atrial fibrillation, contrast allergy, inability to undergo scanning and inability to provide informed consent. Studies were performed with approval of the local research ethics committee, in accordance with the Declaration of Helsinki, and with the written informed consent of each participant.PET/CT scanning with 18F-fluciclatide 14±7 days after their initial presentation. CMR was performed within 7 days of PET/CT scanning. Patients were then invited to return for a second PET/CT scan with 18F-fluciclatide 10 weeks after MI and for a follow-up CMR at 9 months.Patients with recent acute ST-segment elevation MI and peak high-sensitivity cardiac troponin I (hs-cTnI) >10 000 ng/L were invited to attend PET/CT scanning with 18F-fluciclatide and CMR.Patients with an angiographically documented complete occlusion of a major epicardial artery and stable cardiac symptoms for >6 months were invited to attend for a single PET/CT scan with 18F-fluciclatide and CMR.Volunteers with normal left ventricular (LV) systolic function, no structural heart disease and no symptoms of heart failure or MI underwent a single PET/CT scan with For histological analysis, myocardial biopsy samples were obtained from patients undergoing coronary artery bypass grafting following recent MI. Patients with large ST-elevation MI  were considered for inclusion, forming a separate cohort from the acute MI group.18F-fluorobenzaldehyde at pH 3.5 to form 18F-fluciclatide. Full description of this synthesis has been published.5–7The radiotracer was manufactured at the Clinical Research Imaging Centre, University of Edinburgh on an automated module  by coupling an amino-oxy-functionalised peptide precursor (AH111695) with 4-18F-fluciclatide  after administration of a target dose of 230 MBq 10.1136/heartjnl-2016-310115.supp1supplementary data18F-fluciclatide uptake within the myocardium (see online 18F-fluciclatide uptake was assessed by an experienced observer (WSAJ) by drawing regions of interest (ROIs) in each myocardial segment using the standardised 16-segment approach.mean). SUVmax and TBRmax values were also calculated alongside the corrected SUV values, where blood pool activity was subtracted from myocardial uptake  and T1 mapping was performed at 3 T  with calculation of LV function, wall motion index (WMI), transmurality of LGE and extracellular volume (ECV) fraction (see online vβ3 antibody clone LM609 (Millipore) before digital imaging  and histopathological examination.Briefly, a core cardiac biopsy was taken from the peri-infarct zone, fresh-frozen and sectioned in cryosection medium  and JMP , where appropriate. A two-sided p value<0.05 was considered statistically significant.We explored myocardial radiotracer uptake in three groups of patients, comparing them with CMR and clinical indices of cardiac function. Continuous data were tested for normality with the D'Agostino and Pearson Omnibus test. Continuous normal variables were expressed as mean±SD and compared using Student’s t-test or analysis of variance test when comparing more than two groups. Continuous non-normal variables were presented as median (IQR) and compared using the Mann-Whitney or Kruskal-Wallis test when evaluating two or more than two groups. Interobserver reproducibility was calculated by Bland-Altman method and presented as mean bias ±2 SDs and intraclass correlation coefficients (ICC) with 95% CI. The χ18F-fluciclatide: 21 patients with acute MI, 7 patients in the chronic total occlusion (CTO) group and nine healthy volunteers ) and featured the anterior (n=16) and lateral (n=4) territories predominantly, while one patient had an inferior MI. All subjects received emergency coronary angiography with successful revascularisation 197 min (148–342 min) from the onset of symptoms (see online There were no areas of infarction in control subjects. All patients within the acute MI cohort (n=21) had visible infarction on CMR 13±5 days after MI. These infarcts were large (infarct size 12±7 g/m2) between MI and CTO groups (p=0.34), the LV ejection fraction (LVEF) was reduced with a larger WMI score in those with recent MI  and regional wall motion . In total, 43 of 272 myocardial segments (16%) showed an improvement in regional wall motion, while 226 segments remained unchanged and three segments displayed functional deterioration. Infarct size and LV mass also improved . The optimum contrast between 18F-fluciclatide uptake in the site of infarction and the blood pool was observed at 40 min ) and a high ICC value (0.94 (95% CI 0.83 to 0.98)). This measure was therefore preferentially used for subsequent analysis. Quantification of the regional 18F-fluciclatide TBRmean in individual myocardial segments also proved reproducible with no fixed or proportional biases (mean % difference −8.97 (95% CI −31.6 to 13.6)) and a high ICC value (0.90 (95% CI 0.590 to 0.975), see online Using static PET images, the interobserver reproducibility assessing 18F-fluciclatide on baseline PET/CT scanning (12±4 days after MI), which co-localised to regions of infarction on CMR . Indeed, no focal increase in 18F-fluciclatide uptake was observed in regions of chronic infarction, with similar PET uptake measurements compared with control subjects . In regions of myocardium remote to the site of acute infarction, 18F-fluciclatide activity was modestly but uniformly increased when compared with comparative regions in patients with CTO . Across our population, there were no age-related , p=0.31) or sex-related  differences in 18F-fluciclatide uptake.All patients in the acute MI cohort had increased focal myocardial uptake of n on CMR . Hepatic10.1136/heartjnl-2016-310115.supp3supplementary video 218F-fluciclatide PET/CT 76±19 days post-MI, with similar results noted. All these patients were clinically stable between the scans. 18F-Fluciclatide uptake remained elevated at the site of infarction , although the intensity was reduced compared with earlier imaging  and interestingly remained equivalent in terms of intensity compared with the initial PET scan .Seventeen subjects agreed to return for a second  p=0.01; . Increas18F-fluciclatide uptake following MI was compared with clinical and imaging measures of MI severity and subsequent repair , it did not correlate with many of the standard measures of infarct severity; in particular, there were no associations with infarct size on CMR , LVEF , hs-cTnI  or C reactive protein  . Rather, 18F-fluciclatide activity was highest in segments with hypokinesis  per 10% increase in TBRmean, p=0.003), which persisted after adjustment for age and sex (OR 1.27 (95% CI 1.07 to 1.51) per 10% increase in TBRmean, p=0.005). This effect was however attenuated following additional adjustment for the transmurality of LGE (OR 1.03 (95% CI 0.83 to 1.26) per 10% increase in TBRmean, p=0.80) and ECV (OR 1.02 (0.91 to 1.32) per 10% increase in TBRmean, p=0.35).18F-fluciclatide, we have for the first time described the temporal expression of myocardial αvβ3 integrin receptor in patients with recent acute MI. We demonstrate intense early uptake attributable to regions of recent infarction, in particular subendocardial, hypokinetic infarcts that appeared to demonstrate subsequent functional recovery. Our data suggest that αvβ3 integrin receptor expression can be readily quantified in the infarct zone and that 18F-fluciclatide PET may hold promise as a clinical biomarker of healing activity with application to novel pharmacological or cell-based therapies aimed at improving outcome after MI.Using the novel radiotracer vβ3 integrin by vascular endothelial cells facilitates myocardial salvage through angiogenesis in the peri-infarct zone, while also mediating the activated macrophage response to inflammatory signals and governing myofibroblast differentiation through the activation of latent transforming growth factor-β1.vβ3 integrin contains a binding site for an RGD peptide subunit (the arginine-glycine-aspartate motif) and this is the target for a number of molecular imaging probes. In murine and human studies of acute MI, RGD-based radiotracers accumulate at the site of infarction as early as 3 days, peaking at 1–3 weeks post-MI18F-fluciclatide. Moreover, given the study sample size and comprehensive imaging assessment, we have been able to make several significant observations as well as incorporate a number of important controls and comparisons.Expression of α18F-fluciclatide uptake in patients with recent acute MI with healthy control subjects and patients with established infarction. We have demonstrated that 18F-fluciclatide uptake is specific for acute infarction and does not bind to old established infarcts. Perhaps more importantly, we did not see a correlation with acute infarct size, quantified as the mass of LGE on CMR. Indeed binding of 18F-fluciclatide in akinetic infarcts was relatively low and was instead highest in subendocardial infarcts associated with hypokinesia. This would suggest that 18F-fluciclatide uptake is not a surrogate of infarction but relates more to the tissue-healing response to injury.We have compared 18F-fluciclatide to subendocardial infarcts. It is possible that microvascular obstruction in larger infarcts prevented tissue penetration by 18F-fluciclatide or that the presence of tissue necrosis resulted in loss of tissue architecture. However, a number of our observations suggest that 18F-fluciclatide uptake reflects novel αvβ3 integrin expression due to re-endothelialisation and angiogenesis in the peri-infarct zone. First, ex-vivo histological examination 2 weeks following MI demonstrated that αvβ3 integrin expression predominantly co-localises within endothelial cells of the microvasculature. Second, increased 18F-fluciclatide uptake was associated with functional recovery of hypokinetic infarcts. Third, we did not observe 18F-fluciclatide uptake in patients with CTO who have chronic and well-established collateral vasculature. Fourth, we did not observe large regions of microvascular obstruction on CMR imaging. This suggests that only newly forming vessels or repopulation of vessels with endothelial cells will result in αvβ3 integrin expression and 18F-fluciclatide uptake. This is consistent with similar observations in other diseased states such as angiogenesis associated with malignancy.18F-fluciclatide identifies areas of re-endothelialisation and angiogenesis, it is perhaps not surprising that 18F-fluciclatide uptake appeared to localise to segments that demonstrated subsequent functional recovery. Taken together, our data suggest that assessing αvβ3 integrin expression in the acute phase of repair might be of use in investigating the healing processes that occur following acute MI. Larger studies are required to confirm these initial findings and assess whether 18F-fluciclatide PET provides incremental benefit to CMR (our study was not sufficiently powered). However, as a marker of activity, 18F-fluciclatide may be of particular use in assessing the effects of novel therapies aimed at accelerating repair post-MI.There are a number of potential explanations for the preferential binding of 18F-fluciclatide uptake persisted in the region of infarction but was reduced compared with the 2-week assessment. This delayed phase of repair is characterised pathologically by a reduction in inflammation and angiogenesis and a more moderated reorganisation of the ECM through myofibroblast-driven type I and type III collagen production.18F-fluciclatide uptake reflects the waning of re-endothelialisation and angiogenesis or represents a switching to myofibroblast cell types indicative of an enhanced fibrotic response. There was some heterogeneity in the time course of 18F-fluciclatide uptake since uptake increased at 10 weeks in six subjects. However, we detected no adverse effects of this increase in uptake and there was no corresponding increase in LGE or ECV on T1 mapping.At 10 weeks following MI, vβ3 integrin in remote myocardial regions has been reported up to 6 months following MI.18F-fluciclatide activity was consistently increased in the remote myocardium at both 2 and 10 weeks when compared with comparative myocardial regions in patients with CTO and healthy controls.Modification of the ECM following MI is limited to the site of infarction. Indeed, the myofibroblast-driven fibrotic expansion seen in the remote myocardium influences global myocardial recovery.vβ3 integrin expression.vβ3 integrin expression in humans post-MI. Fortunately, inference can be drawn from extensive animal models of infarction but, for future application of 18F-fluciclatide, a more extensive histological assessment would be preferred. Third, our study was not powered to address the incremental value of 18F-fluciclatide PET over established predictor markers of cardiac recovery such as CMR. This will require larger patient populations. Instead this study provides the first description of increased 18F-fluciclatide in the myocardium following MI, indicating that it provides important information about the LV remodelling response. Further studies will be required to establish the clinical utility of this approach.There are some limitations in our study that we should acknowledge. First, despite accounting for systolic motion using ECG gating, cardiac PET is also limited by respiratory motion and this may affect sensitivity in particular due to the high activity in the closely adjacent blood pool and hepatic tissue. This is likely to be a particular problem for inferior infarcts (present in only one of our study subjects), although these less commonly lead to adverse remodelling and heart failure. Novel motion tracking may in the future help to negate some of these issues and enable even greater definition of regional αvβ3 integrin radiotracer in the assessment of myocardial repair following acute MI. We have demonstrated that increased 18F-fluciclatide uptake occurs at sites of acute MI, in particular regions of subendocardial infarction and hypokinesia associated with subsequent functional recovery. Our data suggest that myocardial αvβ3 integrin expression represents a marker of ongoing cardiac repair and that 18F-fluciclatide is a potentially useful imaging biomarker for investigating this healing response post-MI.vβ3 integrin cell surface receptor is intrinsic to angiogenesis, inflammation and fibrogenesis in remodelling myocardium and has been targeted using positron emission tomography (PET) radiotracers in murine and small human studies following MI. However, the role of αvβ3 integrin radiotracers in humans following MI is incompletely defined.Non-invasive imaging of myocardial remodelling may permit understanding, prediction and potential modification of adverse remodelling and the syndrome of delayed heart failure following myocardial infarction (MI). The α18F-fluciclatide binds with αvβ3 integrin receptors in regions of acute MI and in the remote myocardium. 18F-fluciclatide uptake correlates with functional impairment and may predict myocardial recovery.Using PET imaging with kinetic analysis, CT contrast angiography and cardiac MRI, we have demonstrated that vβ3 integrin receptor imaging in humans following MI. This novel characterisation of myocardial remodelling may hold potential as a biological end point in the study of novel therapies following MI.Our study fulfils a key step validating αIn conclusion, we report the largest and most comprehensive analysis of an α


In the setting of reperfused acute myocardial infarction (AMI), the authors sought to compare prediction of contractile recovery by infarct extracellular volume (ECV), as measured by T1-mapping cardiac magnetic resonance (CMR), with late gadolinium enhancement (LGE) transmural extent.The transmural extent of myocardial infarction as assessed by LGE CMR is a strong predictor of functional recovery, but accuracy of the technique may be reduced in AMI. ECV mapping by CMR can provide a continuous measure associated with the severity of tissue damage within infarcted myocardium.Thirty-nine patients underwent acute (day 2) and convalescent (3 months) CMR scans following AMI. Cine imaging, tissue tagging, T2-weighted imaging, modified Look-Locker inversion T1 mapping natively and 15 min post–gadolinium-contrast administration, and LGE imaging were performed. The ability of acute infarct ECV and acute transmural extent of LGE to predict convalescent wall motion, ejection fraction (EF), and strain were compared per-segment and per-patient.Per-segment, acute ECV and LGE transmural extent were associated with convalescent wall motion score . ECV had higher accuracy than LGE extent to predict improved wall motion . Infarct ECV ≤0.5 had sensitivity 81% and specificity 65% for prediction of improvement in segmental function; LGE transmural extent ≤0.5 had sensitivity 61% and specificity 71%. Per-patient, ECV and LGE correlated with convalescent wall motion score  and convalescent EF . ECV and LGE extent were not significantly correlated . In multivariable linear regression analysis, acute infarct ECV was independently associated with convalescent infarct strain and EF , whereas LGE was not .Acute infarct ECV in reperfused AMI can complement LGE assessment as an additional predictor of regional and global LV functional recovery that is independent of transmural extent of infarction.  Following reperfused acute myocardial infarction (AMI), the left ventricle (LV) remodels, with the extent of functional recovery in the infarct zone determined by the proportion of viable, contractile cells Native and post-contrast T1 mapping by CMR allows for estimation of myocardial extracellular volume (ECV). ECV estimation provides the potential for quantitative assessment of severity of tissue disruption and loss of myocytes within the infarct zone, potentially providing an additional dimension of infarct characterization to LGE-derived assessment of transmural extent. ECV mapping has been applied to chronic MI with a range of values in the infarct zone, suggesting that it may be sensitive to severity of tissue damage in myocardial infarction We hypothesized that ECV estimation by CMR in reperfused ST-segment elevation AMI offers additional predictive value for functional contractile recovery as compared to transmural extent of LGE hyperenhancement.2, cardiomyopathy, or contraindications to CMR. The study protocol was approved by the institutional research ethics committee and complied with the Declaration of Helsinki; all patients gave written informed consent. Clinical management (including anticoagulation and use of aspiration catheters during primary percutaneous coronary intervention) was at the discretion of the responsible clinician, reflecting contemporary practice and guidelines, and performed blind to CMR results. All patients were considered for beta-blockade, angiotensin-converting enzyme inhibitors, statins, dual antiplatelet therapy, and cardiac rehabilitation. A venous blood sample for hematocrit was obtained at the start of each scan.Patients with first ST-segment elevation AMI, revascularized by primary percutaneous coronary intervention within 12 h of onset of pain, were prospectively recruited from a single tertiary center. ST-segment elevation AMI was defined as per current guidelines All patients had CMR at 3.0-T  within 3 days of index presentation (acute scan) and the same CMR protocol 3 months post-AMI . To ensure consistent slice positioning and infarct analysis between time points, modified Look-Locker inversion (MOLLI) T1 mapping, tissue tagging, T2-weighted imaging, and LGE and wall motion cine image acquisition were performed in 3 identical short-axis positions, by acquiring the central 3 slices of 5 parallel short-axis slices spaced equally from mitral annulus to LV apical cap Images were analyzed offline using commercial software . Two types of analysis were performed. To evaluate performance of ECV estimation independent of LGE imaging, segmental analysis was performed using 3 short-axis slices and by analyzing each segment of the modified 16-segment American Heart Association model LGE signal intensity was recorded in arbitrary units as generated by cvi42 analysis software .Regional wall motion anomaly was graded per-segment and per-patient from cine imaging by an experienced cardiologist , blinded to the results of strain and LGE and scored as: 0 = normal; 1 = mild or moderate hypokinesis; 2 = severe hypokinesis; 3 = akinesis; 4 = dyskinesis 2 < 0.95 were rejected.Myocardial ECV was calculated from native and post-contrast MOLLI images Mid-myocardial end-systolic circumferential strain was measured through the infarct and remote zones using tissue tagged imaging .Detailed image analysis techniques are described in the t tests. All tests were 2-tailed; p values <0.05 were considered significant. Qualitative measures were correlated using the Spearman rank test; quantitative measures were correlated with the Pearson coefficient. Regression and power calculation details are outlined in the Statistical analysis was performed using IBM SPSS Statistics 21.0 . Continuous variables are expressed as mean ± SD, and compared using paired Student Recruitment details are given in the Infarct characteristics are shown in Acute infarct ECV correlated with wall motion score acutely  and at 90 days  . ImprovePerformance of acute ECV and acute LGE to predict markers of LV function per patient are shown in Univariable linear regression analysis (examining per-patient the variables in This study shows that the ECV in acute reperfused myocardial infarction is predictive of regional and global LV functional recovery, and adds prognostic value to LGE. ECV adds quantitative information about severity of myocardial injury within the infarct zone to the assessment of infarct extent by LGE. Particularly for infarcts with higher transmural extent, acute infarct ECV appears to be an additional predictor of functional recovery that can complement transmural infarct extent by LGE.ECV provides a continuous measure of tissue composition and thus a potential tool to interrogate the severity of myocardial damage in infarcted myocardium. Acute ECV was a stronger predictor than LGE for convalescent EF and attenuated strain in the infarct zone; when correcting for ECV, LGE was no longer an independent predictor of EF or infarct zone strain. ECV demonstrated utility throughout the range of infarct severity observed in reperfused AMI. ECV-derived measurement of infarct severity also complemented LGE measurements of infarct extent, and increased the sensitivity and specificity to predict functional improvement in patients with >50% transmural LGE that was independent of LGE analysis. ECV had higher accuracy than LGE to predict improvement in regional wall motion score , higher LGE is established as a clinical reference standard for viability imaging following AMI, but accuracy may be reduced when using the technique in this context. Recent European guidelines note that prediction of functional recovery with LGE CMR is “no better than other imaging techniques” ECV estimation by CMR is validated in models of chronic fibrosis rather than acute infarction Despite the clear association of ECV and functional recovery, several potential confounders should be considered. Edema affects both T1 and ECV The sample size in this study is relatively small, but in keeping with similar studies in this demographic PerspectivesCOMPETENCY IN MEDICAL KNOWLEDGE: CMR can be used to predict the amount of contractile recovery after reperfused AMI. The transmural extent of scar as measured from LGE CMR is a well-established predictive marker of functional recovery. The novel quantitative measure of myocardial ECV is compared with LGE for the ability to predict contractile recovery in AMI. Both LGE and ECV at day 2 were predictive of contractile recovery at 3 months. ECV had higher accuracy than LGE to predict improved convalescent wall motion. An acute infarct ECV of >0.5 suggested poor contractile recovery; ECV <0.5 predicted contractile recovery with sensitivity 81% and specificity 65%. After accounting for interactions, ECV was independently associated with measures of convalescent contractility; LGE was not. Measurement of ECV by CMR is a useful additional tool in the setting of reperfused AMI, to help predict the degree of contractile recovery.TRANSLATIONAL OUTLOOK: Further multicenter studies with different CMR vendors are warranted to determine the optimal method to combine the two measures of LGE and ECV. Future work should characterize the pathophysiological correlates of ECV variability in AMI.This study demonstrates that addition of CMR-derived ECV estimation of the infarct zone after AMI offers increased accuracy to predict ejection fraction and functional recovery compared with LGE alone. Acute ECV estimation is feasible in this demographic and can provide clinically relevant information. The potential clinical utility of infarct ECV mapping post-AMI is most pronounced in cases of intermediate LGE transmural extent, and potentially allows for improved early characterization and prognostication of patients post-AMI.


Clinical decision-making in symptomatic patients after mitral valve (MV) repair remains challenging as echocardiographic reference values are lacking. In native MV disease intervention is recommended for mean transmitral pressure gradient (TPG) >15 mmHg or systolic pulmonary artery pressure (SPAP) >60 mmHg at peak exercise. Insight into standard stress echo parameters after MV repair may therefore aid to clinical decision-making during follow-up.Stress echocardiography derived parameters in asymptomatic patients after successful MV repair differ from current guidelines for native valves.In 25 patients (NYHA I) after MV repair stress echocardiography was performed on a semi-supine bicycle. Doppler flow records and MV related hemodynamics at rest and peak were obtained. Linear regression analysis was performed for mean TPG and SPAP at peak, using predetermined variables and confounders.Mean TPG at rest (3.2 ± 1.4 mmHg) significantly increased at peak (15.0 ± 3.4 mmHg) but was always <25 mmHg. Mean SPAP at rest (21.4 ± 3.8 mmHg) significantly increased at peak (41.8 ± 8.9 mmHg) but was never >57 mmHg. Only the indexed MV ring diameter was inversely correlated to mean TPG at peak in a multivariable model.In contrast to current recommendations in native MV disease, our data indicate that the standard value for mean TPG during stress echocardiography in asymptomatic patients after successful MV repair was above the guideline threshold of 15 mmHg in >50%, but always <25 mmHg. For SPAP, patients never reached the guideline cutoff (60 mmHg). Long-term follow-up data are needed to provide insight in clinical consequences. Baseline stress echocardiography may indicate individual reference values to compare with during follow-up.https://clinicaltrials.gov/ct2/show/NCT02371863?term=chamuleau+AND+Mitral&rank=1. Mitral valve (MV) regurgitation is a common valve disease and associated with significant morbidity and mortality worldwide , 2. The Twenty-five randomly selected patients after successful isolated MV repair at the UMC Utrecht were analyzed by use of an echocardiographic assessment at rest and during exercise. The flowchart is depicted in Online Resource 1 in Supplementary Material. Successful MV repair was defined as no or grade 1+ residual of recurrent MV regurgitation and mean TPG ≤ 7 mmHg after MV repair in rest at time of study enrollment . InclusiEchocardiographic measurements were obtained in accordance with current guidelines and the Declaration of Helsinki , 25. ImaPatients underwent a physical exercise test on a semi-supine bicycle. We monitored a 4-lead electrocardiogram during exercise and measured blood pressure (non-invasively) before, during, and after exercise. Symptoms were continuously evaluated. A standard exercise protocol was used, starting with 25 W, which was manually increased by 25 W every 3 min. Echocardiographic recordings were performed at each stage. To determine echo values at peak, stress echocardiography was preferentially performed until >85% of the age-predicted maximal heart rate or exhaustion occurred. Medication was continued to assess exercise tolerance under baseline treatment.T-test for 2 groups, one-way ANOVA for >2 groups, or Mann–Whitney U test in case of non-normal distribution. Categorical data were described using frequencies and percentages, with comparative evaluations performed via the χ2, Fisher’s Exact, or McNemar’s test. A P-value of <0.05 was considered statistically significant. Linear regression for (1) mean TPG at peak and (2) SPAP at peak  was performed based on complete case analysis, with univariable and multivariable linear regression on predetermined variables of interest  and potential confounders .Statistical analysis was done using SPSS . Continuous variables were expressed as mean ± SD and compared with a two-sided via median sternotomy, cardiopulmonary bypass, and cardioplegic arrest with cold blood cardioplegia. Quadrangular or triangular resection of the MV leaflet was performed in 17 (68%), annuloplasty using a Carpentier–Edwards Physio Ring in 15 (60%), and annuloplasty with a Cosgrove–Edwards Annuloplasty Band in 10 (40%) patients. A concomitant procedure, e.g., Maze or coronary bypass surgery, was never performed. The mean TPG measured by echocardiography within the first 5 days after repair was always <5 mmHg (3.1 ± 0.9 mmHg).Baseline characteristics and preoperative profile are displayed in Table Table Exercise characteristics are depicted in Table P = 0.009), and mean change in SPAP was significantly higher  in patients with >15 mmHg mean TPG at peak. No other comparisons reached statistical significance. Univariable regression analysis for the continuous value of mean TPG at peak exercise  showed a significant, positive correlation with change in SPAP , and a negative correlation with indexed diameter MV ring diameter . Mean TPG at peak only remained significantly correlated to the indexed diameter of the MV ring annulus  after correction for other variables and potential confounders.Exploratory comparisons were performed for the 14 subjects (56%) with mean TPG at peak of >15 mmHg and the 11 patients (44%) with mean TPG ≤ 15 mmHg. The mean indexed MV annuloplasty ring diameter was significantly smaller . In a multivariable regression model correcting for other variables and potential confounders, no parameters remained independently correlated.Since no patients reached an SPAP > 60 mmHg, an exploratory comparison of subgroups with SPAP lower and above the guidelines reference value could not be performed. In a univariable analysis , SPAP at peak exercise was significantly correlated to both Our study concerning stress echocardiography in asymptomatic patients to identify the reference values after successful MV repair, revealed three major findings. Surprisingly, >50% of the patients showed a mean TPG at peak beyond the guideline recommendation (15 mmHg); however, mean TPG at peak was never >25 mmHg. Second, SPAP was always <57 mmHg at peak exercise, and therefore never reached the recommendation for intervention in native valve disease (>60 mmHg). Finally, only the indexed MV ring diameter remained independently correlated to the mean TPG at peak in a multivariable regression model.The significant increase of mean TPG from 3.2 ± 1.4 mmHg at rest to 15.0 ± 3.4 mmHg at peak exercise in our study corresponds to previous literature , 27. TheElevated TPG during exercise is due to an obstruction that can occur at the mitral annulus and/or leaflet level , 29. TheOur study showed a significant increase in SPAP during exercise; however, values were always within normal ranges , 4. The Exercise testing is the ideal way to evaluate symptoms in patients with mild-to-moderate MV stenosis . AnnulopThe idea of early surgery in patients with MV regurgitation is to prevent occurrence of myocardial dysfunction preceding heart failure. Nevertheless, previous literature suggests unnoticed diastolic and systolic dysfunction due to myocardial stiffness and decreased fillings rates, as a result of enhanced LV filling and increased chamber compliance already in the early stages of MV regurgitation , 37. In Strain analysis has been used as a quantitative approach to estimate regional myocardial contractility and predict LV dysfunction. By using speckle tracking Goebel et al. revealed the impairment of regional myocardial deformation rate and LV systolic and diastolic twist rate, as proof of early myocardial damage in patients with arterial hypertension but still preserved EF . Candan Potential LV dysfunction in patients after MV surgery may lead to tissue deoxygenation, in particular during exercise. Decreased microvascular tissue perfusion has been demonstrated in patients with no global hemodynamic compromise or laboratory signs of hypoperfusion, using the new Sidestream Dark Field imaging technique . The assE/E′) has been shown to correlate with LV filling pressures (Assessment of LV filling pressures in symptomatic patients after MV surgery may prove or refute a cardiac cause for the shortness of breath. Lower LV filling rates as a result from increased LV stiffness (increased LV diastolic pressures) can lead to lower MV gradients and therefore an underestimation of the postoperative severity of functional MS. Normal LV filling pressures in patients with normal MV gradients suggest a non-cardiac cause for the symptoms. In patients with preserved LV function, the ratio of early transmitral velocity to tissue Doppler mitral annular early diastolic velocity , although the change in SPAP during exercise may serve as an important parameter in case of symptoms. We think that baseline assessment of exercise derived echo parameters after MV repair may serve as an individual reference, and therefore could possibly be of additional value in clinical decision-making when symptoms occur. Future studies should clarify the relationship to adverse clinical outcomes in this cohort.The protocol was approved by the “Research Ethics Board” of the UMC Utrecht . All subjects gave written informed consent in accordance with the Declaration of Helsinki.All authors  substantially contributed to the conception and design of this work, the analyses and interpretation of the data; critically revised this work for important intellectual content; approved the final version to be published; and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Mitral valve prolapse (MVP) is the most common mitral valve disorder affecting 2%–3% of the general population. Two histological forms for the disease exist: Myxomatous degeneration and fibroelastic disease. Pathological evidence suggests the disease is not confined solely to the valve tissue, and accumulation of proteoglycans and fibrotic tissue can be seen in the adjacent myocardium of MVP patients. MVP is diagnosed by demonstrating valve tissue passing the annular line into the left atrium during systole. In this review we will discuss the advantages and limitations of various imaging modalities in their MVP diagnosis ability as well as the potential for demonstrating extra associated valvular pathologies. MVP is a common cardiovascular disorder, originally described in the 1960s and is considered today the most common cause of mitral regurgitation ,3. BarloDegenerative processes resulting in regurgitation of the mitral valve have two main phenotypes: Diffuse myxomatous degeneration (or “Barlow disease”), which may present as a genetic disorder, and a markedly different fibroelastic deficiency (FED) ,26, whicPathological processes in MVP are not limited to the valves only. Pathological studies of MVP patients with sudden death or death from other causes have shown proteoglycan depositions similar to the deposition within the leaflet also in the myocardial tissue, fibrous endocardial plaque depositions, and non-specific interstitial fibrosis ,33,34,35Echocardiography can be used to assess pathologies in other valves. Echocardiographic definition for tricuspid valve prolapse is still lacking. With the advent of three-dimensional imaging, authors have suggested that 3D images are more suitable for defining the prolapsing segment of the tricuspid valve as well as better define the regurgitant orifice area .Echocardiography is the most widely used imaging tool for evaluating cardiac function. For clinicians, left ventricular chamber size as well as function, and regurgitation severity are important for clinical decision making.et al. were the first to provide a practical road map for MVP evaluation by MRI [et al. chose a stack of cine SSFP images in the LVOT view spanning the entire mitral valve to evaluate MVP  of the heart has emerged in recent years as valuable tool for noninvasive imaging of the heart. It provides high-resolution volumetric datasets that can be post-processed to provide views suitable for MVP diagnosis. After acquisition, images in planes demonstrating both superior aspect of the saddle shaped annulus of the mitral valve are generated. The relation between valve leaflets and annulus can be studied, and the degree of leaflet displacement can be measured . An impoPatients with MVP often complain of palpitations and chest discomfort. These symptoms have led to a notion of increased prevalence of anxiety disorders in MVP patients. This has been referred to as “mitral valve prolapse syndrome” . The assMVP is diagnosed by imaging modalities by demonstrating valve leaflets ascending into the left atrium passing over the two high points of the saddle shaped annulus into the left atrium during systole. Echocardiography has a central role in diagnosis of MVP and is used as the main tool for this purpose. High special resolution imaging modalities such as MRI and CT can also demonstrate the anatomical relation between the mitral valve annular line and leaflet excursion needed for appropriate diagnosis. The now well-established criteria for definition of MVP based on proper understanding of the mitral valve three-dimensional anatomy and shape has allowed better definition of the disease culminating in finding gene and biological pathways leading to myxomatous degeneration and prolapse. Pathological findings in MVP are not confined to the valve tissue only. Some imaging modalities, such as MRI and, to a lesser, extent nuclear imaging, have demonstrated pathologies in muscle tissue of MVP patients. The pathological correlates of these findings, however, as well as their clinical significance are currently uncertain.


Left ventricular diastolic dysfunction is suggested to be associated with higher mortality in severe sepsis and septic shock, yet the methods of diagnosis described in the literature are often inconsistent. The recently published 2016 American Society of Echocardiography and European Association of Cardiovascular Imaging (ASE/EACVI) guidelines offer the opportunity to apply a simple pragmatic diagnostic algorithm for the detection of diastolic dysfunction; however, it has not been tested in this cohort.We sought to assess the applicability in septic patients of recently published 2016 ASE/EACVI guidelines on diastolic dysfunction compared with the 2009 ASE guidelines. Our hypothesis was that there would be poor agreement in classifying patients.Prospective observational study includes patients identified as having severe sepsis and septic shock. Patients underwent transthoracic echocardiography on day 1 and day 3 of their ICU admission. Patients with normal and abnormal (ejection fraction < 52%) systolic function had their diastolic function stratified according to both the 2009 ASE and 2016 ASE/EACVI guidelines.On day 1 echocardiography, of the 62 patients analysed, 37 (60%) had diastolic dysfunction according to the 2016 ASE/EACVI guideline with a further 23% having indeterminate diastolic function, compared to the 2009 ASE guidelines where only 13 (21%) had confirmed diastolic dysfunction with 46 (74%) having indeterminate diastolic dysfunction. On day 3, of the 55 patients studied, 22 patients (40%) were defined as having diastolic dysfunction, with 6 (11%) having indeterminate diastolic dysfunction according to the 2016 ASE/EACVI guidelines, compared to the 2009 guidelines where 11 (20%) were confirmed to have diastolic dysfunction and 41 (75%) had indeterminate diastolic function. Systolic dysfunction was identified in 18 of 62 patients (29%) on day 1 and 18 of 55 (33%) on day 3. These patients were classified as having abnormal diastolic function in 94 and 89% with the 2016 guidelines on day 1 and day 3, respectively, compared with 50 and 28% using the 2009 guidelines. The 2016 guidelines had less patients with indeterminate diastolic function on days 1 and 3 (11 and 6%) compared to the 2009 guidelines (50 and 72%). Normal systolic function was identified in 44 patients on day 1 and 37 on day 3. In this group, abnormal diastolic function was present in 45 and 54% on days 1 and 3 according to the 2016 ASE/EACVI guidelines, compared with 9 and 16% using the 2009 guidelines, respectively. In those with normal systolic function, the 2016 guidelines had less indeterminate patients with 30 and 16% on days 1 and 3, respectively, compared to 84 and 76% in the 2009 guidelines.The 2016 ASE/EACVI diastolic function guidelines identify a significantly higher incidence of dysfunction in patients with severe sepsis and septic shock compared to the previous 2009 guidelines. Although the new guidelines seem to be an improvement, issues remain with the application of guidelines using traditional measures of diastolic dysfunction in this cohort.The online version of this article (10.1186/s13613-017-0342-x) contains supplementary material, which is available to authorized users. Systolic and diastolic dysfunction occur frequently in severe sepsis and septic shock . Whilst We sought to compare the 2009 ASE and the recent 2016 ASE/EACVI algorithms for diagnosing diastolic dysfunction in a population with severe sepsis and septic shock to assess and compare their ability to detect and differentiate grades of diastolic dysfunction. Our hypothesis was that there would be poor agreement in classifying patients with diastolic dysfunction between the 2009 and 2016 guidelines for diastolic dysfunction.9/L, respiratory rate > 20/min or PaCO2 < 32 mmHg) with additional evidence of organ dysfunction. Septic shock is defined as sepsis with refractory hypotension requiring vasoactive treatment [We conducted a prospective, observational cohort study at the Nepean Hospital Intensive Care Unit, Sydney, NSW, from September 2014 to February 2016. The study was approved by the Nepean Blue Mountains Local Health District Research Governance Office (14/35-LR/14/Nepean/70). As echocardiography is a standard procedure in critically ill patients in our unit, consent was waived. Inclusion criteria were: adult patients > 18 years) admitted to Nepean ICU with severe sepsis or septic shock based on the previous 2012 Surviving Sepsis guidelines that were current at the time of data collection. Severe sepsis was defined as having a documented or strong suspicion of infection, with at least 2 of 4 clinical signs of inflammation  when available were acquired, although the grading of diastolic dysfunction for these studies was not based on the 2016 ASE/EACI guidelines. SOFA scores were retrospectively calculated at the time of the echo studies. Current rates of noradrenaline infusion and total volume of noradrenaline infused were also recorded to the nearest hour.A baseline, comprehensive echocardiogram was performed by sonographers or S.O.  at the earliest opportunity following admission (day 1). Parameters measured were in accordance with current practice and included: LV size, LV ejection fraction, left atrial volume, mitral inflow velocity, septal and lateral annulus tissue Doppler, tricuspid regurgitation (TR) velocity and cardiac output. Ejection fraction and left atrial volume were measured with Simpson’s biplane technique. Measurements were averaged from 3 cardiac cycles if the patient was in sinus rhythm and 5 cardiac cycles in those with atrial fibrillation. Tissue Doppler measurements were taken from the modal velocity  rather than the peak of the waves, given the variable accuracy of peak tissue Doppler measurements in various machines . A repeaE and A waves due to tachycardia and Valsalva manoeuvres were not performed due to difficulty in performing in the critically ill. Pulmonary venous Doppler parameters were sought if available to aid in the diagnosis, but only to be used if the sample was adequate. The E:e′ was calculated based on an average of the medial and lateral e′ values. Left atrial volume was indexed for body surface area and considered increased if > 34 ml/m2. If height and weight data were not available, left atrial volume was considered increased if > 52 ml  and > 58 ml . For the 2016 guidelines, if patients had normal systolic function and no obvious structural abnormalities, they were first screened for diastolic dysfunction via a separate algorithm before subsequent grading, requiring at least 3 of the 4 prescribed parameters to be positive. Those with structural abnormalities, known ischaemic heart disease or abnormal systolic function, given that they will have impaired myocardial relaxation, proceeded directly to grading of diastolic dysfunction.Systolic dysfunction was defined as those with a calculated ejection fraction (EF) (using Simpson’s biplane method) < 52%. Diastolic dysfunction was classified according to both the 2009 ASE and 2016 ASE/EACVI guidelines  who were blinded to each other’s findings. Measurements taken were in keeping with recommendations from the ASE [Statistical analysis was performed with the software program JMP version 11 . Cohen’s kappa analysis was performed to assess the level of agreement of the 2009 and 2016 guidelines, with the null hypothesis accepted if kappa was greater than 0.7 (considered reasonable agreement) and rejected if kappa was less than 0.4 (considered poor agreement). Using a significance level of 0.05, a sample size of 44 was required to give 90% power of detecting a true difference [ the ASE  and as sSixty-eight patients were included in the study see Fig. . Six werp = 0.0002). On day 3, of the 55 patients studied, 22 patients (40%) were defined as having diastolic dysfunction, with 6 (11%) having indeterminate diastolic dysfunction according to the 2016 ASE/EACVI guidelines, compared to the 2009 guidelines where 11 (20%) were diagnosed to have diastolic dysfunction and 41 (75%) had indeterminate diastolic function. Again agreement was poor . The details of the abnormal parameters with respect to the 2009 and 2016 grading of diastolic dysfunction for days 1 and 3 are included  had diastolic dysfunction according to the 2016 ASE/EACVI guideline with a further 23% having indeterminate diastolic function, compared to the 2009 ASE guidelines where only 13 (21%) had confirmed diastolic dysfunction with 46 (74%) having indeterminate diastolic dysfunction. The degree of agreement between the two guidelines on day 1 was poor, with Kappa being 0.24 (p = 0.004) and 0.07 on day 3 (p = 0.34).Systolic dysfunction was identified in 18 patients (29%) on day 1 and 18 of 55 33%) on day 3 .There were 44 patients on day 1 with a normal ejection fraction. Using the 2016 ASE/EACVI guidelines, 11 (25%) patients had normal diastolic function, with 20 (45%) having diastolic dysfunction and 13 (30%) unable to be determined, whereas using the 2009 guidelines 7% were normal, 9% had diastolic dysfunction and 84% were indeterminate  on day 3.p = 0.005). Those with normal systolic function but abnormal diastolic dysfunction tended to be older compared with patients with normal diastolic function on both days. There was no significant difference in noradrenaline requirements, heart rates, SOFA scores, PEEP, or mechanical ventilation on either day 1  had normal diastolic function, 20 54%) had diastolic dysfunction and 6 (16%) were indeterminate according to the 2016 guidelines, compared to 8% normal, 16% with diastolic dysfunction and 76% indeterminate using the 2009 guidelines  more important [e′, have been validated in patients who are at rest and are not currently under stressed states, as may be seen in the critically ill [It is important for the critical care physician to be able to detect diastolic dysfunction in patients with severe sepsis and septic shock. Despite the relative improved diagnostic capabilities of the 2016 ASE/EACVI guidelines, significant challenges still remain. Firstly, each parameter used in the current guidelines is subject to several caveats. Examples of this include preload dependence , the effmportant ? FurtherMyocardial relaxation and diastolic function will be abnormal in the setting of systolic dysfunction. This is evident with only 6 and 11% of patients with abnormal systolic function on day 1 and day 3, respectively, having indeterminate diastolic dysfunction (per the 2016 guidelines). Issues may arise, however, when trying to assess the patient with normal systolic function, as noted by the increased proportion of patients with indeterminate diastolic dysfunction in this cohort. Despite the aforementioned limitations, it is the opinion of the authors that future research in this field could use the 2016 ASE/EACVI guidelines as a reference standard for the diagnosis and detection of diastolic dysfunction. By having a consistent framework for the definition of diastolic dysfunction, further research will be strengthened. Such research may revolve around the association with mortality , the impact of fluid balances, ventilation, beta blockade therapy and the comparative use of novel modalities for detecting diastolic dysfunction.Our study has several limitations. This is a single-centre study and although performed in a unit with an active echocardiographic service, it was not always possible to recruit suitable study patients. A significant proportion of patients with indeterminate diastolic dysfunction based on the 2016 guidelines on day 3 had missing data, which may have changed their grading. Further, a significant proportion of those with normal systolic function had increased myocardial wall thickness, indicating that they would likely have had diastolic dysfunction prior to their ICU presentation. Attempts to clarify pre-existing diastolic dysfunction by searching through patient’s history revealed limited documentation of pre-existing diastolic dysfunction. The authors have not performed a comparison of the two guidelines in ability to predict mortality as firstly, the sample size is too small and secondly the impetus was to focus on how diastolic dysfunction is defined in this cohort, something which is a significant limitation of previous research. Based on our findings, the 2016 ASE/EACVI guidelines could be used in further research to detect if diastolic dysfunction does affect prognosis in severe sepsis and septic shock.The 2016 ASE/EACVI guidelines on assessing diastolic function identify a significantly higher incidence of dysfunction in patients with severe sepsis and septic shock compared to the previous 2009 guidelines. Despite limitations, the 2016 ASE/EACVI recommendations appear to have an improved clinical applicability in septic patients relative to the 2009 ASE guidelines. Difficulties remain with recognition of impaired diastolic function in this cohort, particularly those with normal systolic function. Previously published prognostic studies based on diastolic dysfunction in septic patients need to be interpreted with the above findings in mind.Additional file 1. ASE 2009 Guidelines—number of patients with each abnormal parameter.Additional file 2. ASE/EACVI 2016 Guidelines—number of patients with each abnormal parameter.Additional file 3. Severity of systolic dysfunction for patients with abnormal systolic function on day 1 and day 3.


Both plasma FGF21 (log rank p < 0.0001) and NT-pro-BNP levels (log rank p = 0.0057) showed good predictive power to the 1-year adverse cardiac events. This finding suggested FGF21 could be involved in the pathophysiology of diastolic heart failure.Fibroblast growth factor 21 (FGF21), a polypeptide ligand promoted glucose homeostasis and lipids metabolism, was recently reported to attenuate cardiac hypertrophy. The aim of this study was to investigate the impact of FGF21 in diastolic heart failure. Subjects admitted for coronary angiogram were screened for heart failure, and those with left ventricular (LV) ejection fraction < 45% were excluded. Diastolic dysfunction was defined as functional abnormalities that exist during LV relaxation and filling by echocardiographic criteria. Plasma levels of FGF21 and N-terminal Pro-Brain Natriuretic Peptide (NT-pro-BNP) were determined. All patients were followed up for 1 year, or till the occurrence of heart failure readmission or death. Totally 95 patients with diastolic dysfunction and 143 controls were enrolled. Circulating FGF21 level was correlated with echocardiographic parameters of diastolic function and LV end-diastolic pressure (LVEDP). In multivariate logistic analysis, FGF21 was significantly associated with diastolic dysfunction, either identified by echocardiographic criteria (odds ratio: 2.97,  Heart failure is a severe clinical syndrome involving dysregulation between the autonomic, neuroendocrine and immune systems, which continues to be a major health problem worldwide. Heart failure has classically been considered to be a clinical syndrome associated with impaired left ventricular (LV) systolic function. There is growing recognition that among patients with clinical symptoms associated with heart failure, approximately half the patients have preserved LV systolic function, known as heart failure with preserved LV ejection fraction (HFpEF) or diastolic heart failurest member of the FGF family, is discovered as a new type of cytokine that regulates glucose and lipid metabolism10Fibroblast growth factors (FGFs) are secreted proteins with diverse metabolic functions, and act as autocrine, paracrineA total of 95 diastolic heart failure patients and 143 controls were enrolled for analysis. As shown in p < 0.001). Scatter plots of the correlation between FGF21, NT-pro-BNP, E/e′ ratio, LVEDP, and LVMI are presented in Both FGF21 and NT-pro-BNP levels presented significant positive correlation with hypertension, diabetes, severity of heart failure, coronary artery disease (CAD), peripheral artery disease, LA dimension, LVMI, E/e′ ratio, and LVEDP; negatively associated with hemoglobin level, estimated glomerular filtration rate (eGFR), and central diastolic blood pressure (DBP) . Moreovep = 0.011) showed better association with LVEDP than log NT-pro-BNP (p = 0.082).We further performed linear regression analysis to clarify the association between various parameters, FGF21, NT-pro-BNP and E/e′ ratio, and LVEDP . In univp = 0.012) or confirmed with the LVEDP level . Similar results were also noted when grouping subjects according to their FGF21 level in the logistic regression analysis . When diastolic dysfunction was diagnosed by echocardiography as well as the cardiac-catheterization results (p = 0.957). Taking LVEDP into consideration, the predictive power of FGF21 was non-inferior to NT-pro-BNP in assessment of diastolic dysfunction.The receiver operating characteristic (ROC) curves of FGF21 and NT-pro-BNP in predicting diastolic dysfunction were presented in  results , the difp = 0.0031) and 1-year heart failure readmission events (log rank p < 0.0001) between subjects grouped by FGF21 value  were identified after following up for 1 year, including 12 cases of death (5.04%). The average follow-up time was 10.72 ± 3.17 months. Patients were divided into two equal groups according to their circulating FGF21 or NT-pro-BNP concentrations. The Kaplan–Meier analysis demonstrated a significant difference in 1-year mortality  signaling pathway3et al. found a significant elevation of pro-inflammatory markers and reduction of fatty acid oxidation in the cardiomyocytes of FGF21-KO mice, which could be reversed by providing FGF21 supplyet al. found that mice treated with FGF21 had fewer cardiomyocyte apoptosis, higher capillary density in the infarcted border zone, and better LV systolic function after MI eventet al. showed that the deletion of FGF21 would promote lipid uptake and accumulation in cardiomyocytes, ultimately leading to adverse cardiac remodeling in the diabetic micein vivo and in vitro studies, clinical evidence supporting FGF21’s effect on cardiac remodeling remains limited, especially in the population of HFpEF.Several possible rationales could explain the association between FGF21 and diastolic dysfunction. In condition of HFpEF, myocardiocytes may secret FGF21 to protect the heart from adverse cardiac remodeling and leads to a modest rise of serum FGF21 level. FGF21 could directly act on cardiomyocytes to suppress the inflammatory pathway and attenuate cardiac hypertrophyet al. conducted a cross-sectional study, which enrolled 6 patients of dilated cardiomyopathy waiting for transplantation and 10 health donorsRecent clinical studies had reported the correlation between serum FGF21 and cardiovascular disease, such as hypertensionThere were several limitations in our study. First of all, it was a retrospective study with relatively small case numbers, which limited the generalization of its findings. Enrolled patients with HFpEF were significantly older, which might imply higher levels of serum FGF21 according to the previous studyIn conclusion, this study showed that circulating FGF21 is associated with diastolic dysfunction and 1-year adverse events in patients with diastolic heart failure. These findings suggest that FGF21 may be involved in the pathophysiology of myocardial remodeling and could be a potential therapeutic target in the treatment of heart failure.From February 2010 to December 2014, 515 subjects who had stable CAD admitted for elective coronary angiogram at Taipei Veterans General Hospital were screened. Pre-procedure laboratory exam and cardiac catheterization were performed for each patient. Patients older than 18 years of age and with either one symptoms of heart failure mentioned by the Framingham criteriaet al.3−LVDd3] + 0.6. The LV mass index (LVMI) was calculated as the ratio of LV mass to the body surface area (BSA). LV hypertrophy was defined as LVMI greater than 118 g/m2 in men, or greater than 108 g/m2 in womenEchocardiography was performed by trained sonographers using IE33 . LV end-diastolic dimension (LVDd), interventricular septal thickness (IVST) and posterior wall thickness (PWT) were assessed in the parasternal long axis view at end diastole; whereas LA dimension was measured at end systole. We calculated the LV mass by the formula proposed by Devereux Patients were diagnosed to have diastolic dysfunction when either of the following echocardiographic criteria were met:35Blood samples were obtained after overnight fasting for more than 8 hours. The blood cell count, serum creatinine, sodium, glucose, albumin, lipid profiles, and C-reactive protein were measured by routine laboratory methods. Estimated glomerular filtration rate (eGFR) was calculated by the Modification of Diet in Renal Disease equation for Japanese subjectsThe coronary angiograms were interpreted by two experienced interventional cardiologists. Each coronary lesion with a diameter narrowing of more than 50% were considered to be significant stenosis. The central systolic blood pressure (SBP) and central diastolic blood pressure (DBP) were measured at the aortic root level by a 6-French pigtail catheter balanced to the atmospheric pressure. Pulse pressure was defined as the difference between SBP and DBP. The pigtail catheter was also placed into mid-LV cavity to measure the LV end-diastolic pressure (LVEDP) at the onset of the QRS complex. An elevated LV filling pressure was defined as LVEDP > 16 mmHget al.p-value < 0.05 was considered to indicate statistical significance.Clinical, laboratory, and echocardiographic data were presented as mean ± standard deviation for numeric variables, and as counts (percentage) for categorical variables. Patients were grouped according to the presence of diastolic dysfunction. Comparisons between two groups were performed by using Student’s t-test for continuous variables, and using Fisher’s exact test for categorical variables. A Spearman rank correlation test was used to assess the correlation between FGF21 and categorical variables, and a Pearson correlation test was used to assess the correlation between continuous variables. Univariate analysis was performed for FGF21, age, gender, MVD, and clinical chemistries with significant difference between groups. To access the independent effect of FGF21, variables with statistical significance in the univariate analysis were further entered into the multivariate model. The area under the ROC curve (AUC) was used as a measure of the predictive accuracy of FGF21 and NT-pro-BNP. The statistical significance of pairwise comparison between 2 AUCs was tested with the method of DeLong How to cite this article: Chou, R.-H. et al. Circulating Fibroblast Growth Factor 21 is Associated with Diastolic Dysfunction in Heart Failure Patients with Preserved Ejection Fraction. Sci. Rep.6, 33953; doi: 10.1038/srep33953 (2016).


The interest in measurements of magnetic resonance imaging relaxation times, T1, T2, T2*, with intention to characterize healthy and diseased lungs has increased recently. Animal studies play an important role in this context providing models for understanding and linking the measured relaxation time changes to the underlying physiology or disease. The aim of this work was to study how the measured transversal relaxation time (T2) in healthy lungs is affected by normal respiration in mouse.T2 of lung was measured in anaesthetized freely breathing mice. Image acquisition was performed on a 4.7 T, Bruker BioSpec with a multi spin-echo sequence (Car-Purcell-Meiboom-Gill) in both end-expiration and end-inspiration. The echo trains consisted of ten echoes of inter echo time 3.5 ms or 4.0 ms. The proton density, T2 and noise floor were fitted to the measured signals of the lung parenchyma with a Levenberg-Marquardt least-squares three-parameter fit.T2 in the lungs was longer (p<0.01) at end-expiration (9.7±0.7 ms) than at end-inspiration (9.0±0.8 ms) measured with inter-echo time 3.5 ms. The corresponding relative proton density (lung/muscle tissue) was higher (p<0.001) during end-expiration, (0.61±0.06) than during end-inspiration (0.48±0.05). The ratio of relative proton density at end-inspiration to that at end-expiration was 0.78±0.09. Similar results were found for inter-echo time 4.0 ms and there was no significant difference between the T2 values or proton densities acquired with different interecho times. The T2 value increased linearly (p< 0.001) with proton density.The measured T2 in-vivo is affected by diffusion across internal magnetic susceptibility gradients. In the lungs these gradients are modulated by respiration, as verified by calculations. In conclusion the measured T2 was found to be dependent on the size of the alveoli. Relaxation times T1 and T2/T2* may reflect structural changes of lung tissue caused by physiology, respiration, lung injury or clinical pulmonary disease . A few eThe relaxation time T2* in lungs has been proven to be sensitive to the structure and physiology of the lungs. It has been shown that in-vivo T2* of the lungs is related to the alveolar size in mouse , state oCompared to T1 and T2* less attention has been directed towards T2 relaxation time measurements of the lungs in recent years. However, there is an extensive literature from the 1990’s with particular emphasis on ex vivo studies in isolated lungs . In animRecently, interest in T2 measurements of the lung has been rekindled. T2 values of the lungs were used to differentiate between various regional patterns of interstitial lung disease  and a HaThe aim of this study was to measure in vivo T2 relaxation time in mouse at end-inspiration and end-expiration during normal breathing at 4.7 T.int is the intrinsic T2 without diffusion effects and T2diff is the effect of diffusion.Air and tissue have different susceptibility and the alveolar structure in the lung creates microscopic magnetic field gradients in the tissue. The diffusion of spins through these internal gradients affects the magnetization and as a result the measured T2 relaxation time decreases and be expressed as :1T2=1T2The expected effect of the internal magnetic field gradients on the measured T2 with a Carr-Purcell-Meiboom-Gill (CPMG) sequence can be estimated from :1T2=1T2 process .The study was approved by the Local Ethical Animal Review Board . Ten male CB57BL/6  were anaesthetized with isoflurane (~1–2%) inhalation in a 1:1 air oxygen mix. The animals were freely breathing during image acquisition. The animals were terminated immediately after the completion of the experiment by sodium pentobarbital and spine dislocation.The experiments were performed on a 4.7 T MR scanner  with a BGA12 gradient insert  and a manually tuned linear polarized transmit/receive coil (Ø = 35 mm).The mice were anaesthetized and positioned on a dedicated animal bed equipped with a fluid based heating system driven by a thermostat-controlled pump to maintain body temperature . Respiration was tracked by a small pressure sensitive pad on the abdomen connected to a computer controlled monitoring system .The imaging session started with a set of localizers, to ensure that the lungs of the mouse were approximately in the center of the magnet and the coil. Coronal, sagittal and transaxial spin-echo images of the lungs were acquired to outline the basic anatomy of the thorax and serve as localizers for the following imaging.2, matrix 96x96, bandwidth 100 kHz, and 6 averages were acquired. With the help of the localizer images, a coronal slice of 1.5 mm thickness was located centrally in the lungs, with both lung lobes depicted clearly. Two sets of images were acquired, one at end-inspiration and the other at end-expiration. All details of the sequence are given in All mice were scanned with a 2D multi spin echo sequence (CPMG) with inter echo time 3.5 ms and 10 echoes for the T2 measurement. The repetition time was 1000–1200 ms depending on breathing rate, FOV was 30x30 mmFor five of the mice the T2 measurement was repeated using an inter echo time of 4.0 ms keeping all other settings identical. These measurements were also carried out at end-inspiration and end-expiration.The image calculations and post processing of the images was performed with in-house software . T2-maps and relative proton density (PD) maps were calculated on a pixel-by-pixel basis. The parameters PD, T2 and noise floor (NF) were fitted to the signals from the multi spin echo images according to Eq , with a On the T2-maps of the thorax the lungs were segmented out with a seeding algorithm. All pixels with T2 values between 1 and 15 ms were assigned to lung tissue. The chosen T2 interval excluded major vessels and other tissue in the lung area from the ROI. A second ROI was manually drawn in muscle tissue. The PD values were read from the corresponding PD map with the coordinates taken from the T2 segmentation. The PD for the lung was normalized to the PD of muscle in each animal.If not stated otherwise, reported values are given as mean values plus/minus one standard deviation, and the statistical analysis was performed with a paired two-tail student’s t-test.One animal was excluded due to a technical problem with the triggering device. For the remaining nine mice it was possible to obtain images of the lungs during both end-inspiration and end-expiration from which T2-maps could be calculated. The T2 map and the corresponding PD-map of the lung obtained during end-inspiration are noticeably larger than the corresponding images obtained during end-expiration of the same mouse. The small change in measured T2 is not perceptible directly from the image, but the change in relative proton density is clearly depicted .The measured T2 in the lungs was longer at end-expiration than at end-inspiration. Using an inter echo time of 3.5 ms the T2 was 9.7±0.7 ms and 9.0±0.8 ms (p<0.01), for end-expiration and end-inspiration, respectively. With an inter echo time of 4.0 ms the T2 was 9.8±0.7 ms and 8.7±0.7 ms (p<0.01), for end-expiration and end-inspiration, respectively . There wThe relative proton density (lung/muscle tissue) was higher during end-expiration than during end-inspiration. With an inter echo time of 3.5 ms the PD was 0.61±0.06 and 0.48±0.05 (p<0.001), for end-expiration and end-inspiration, respectively. The ratio between PD at end-inspiration and end-expiration was 0.78±0.09. The PD results for inter echo time 4.0 were 0.57±0.05 and 0.43±0.05 (p<0.001), for end-expiration and end-inspiration, respectively. The PD ratio between end-inspiration and end-expiration was 0.76±0.05. The PD seems higher for the shorter inter echo time but the difference is not significant . The meaFor reference the T2 was calculated in muscle tissue. At inter echo time 3.5 ms the T2 was 31.2±2.6 and 31.7±1.5 ms, for end-inspiration and end-expiration, respectively. For inter echo time 4.0 ms the T2 was 31.1±1.3 and 32.3±1.5 ms, for end-inspiration and end-expiration, respectively. No differences were significant.In this study T2 relaxation time was measured in mouse lungs. To the best of our knowledge T2 measurements for different levels of respiration have not been reported in vivo for mouse lungs previously. We found a small but significant difference between the T2 relaxation time obtained from measured data in end-inspiration and end-expiration. In the mouse lungs the measured T2 was longer at end-expiration than end-inspiration. The animals were not mechanically ventilated and the change between end-inspiration and end-expiration represents the normal respiratory cycle. The effect on T2 was significantly smaller than the effect previously found on T2* .Changes in T2 for different states of inflation have been noted previously for isolated rat lungs, where the T2 increased by almost 100% going from collapsed to degassed lungs. However, the differences in T2 at intermediate inflation pressures were non-significant . Similar−8 m2/s representing the apparent diffusion coefficient in highly vascularized tissue [We assume that the effect of lung inflation on T2 can be attributed to water diffusion across the internal magnetic field gradients during the inter-echo time ,23. An id tissue . From Eqd tissue . The larThe ratio between PD at end-inspiration and end-expiration was 0.76–0.78. From the literature we have an end-expiration volume of 0.5 ml and tidal volume of 0.15 ml for mouse . These fdiff is linearly proportional to air volume fraction of the lung parenchyma. In this study there was a 30% increase of volume fraction from end-expiration to end-inspiration. As a result, one would expect a decrease of T2 by 1.5 ms. This is more than the measured result of 0.7 ms, but in the correct order of magnitude. Additionally, although the major change during inspiration is in alveolar enlargement, there is also a possibility that some degree of alveolar recruitment is involved.From the relative proton density (lung/muscle) obtained in this study the approximate alveoli volume fraction can be estimated. The measured proton densities for end-expiration and end-inspiration (0.61 and 0.48) correspond to a volume fraction of approximately 0.39 and 0.52. Volume fraction has been used in empirical models describing the transverse relaxation for heterogeneous media as systems composed of randomly distributed stationary magnetic spheres surrounded by proton spins undergoing unrestricted, isotropic diffusion motion . In thisThere are several other factors that may influence the measured T2 values of the lungs: molecular oxygen concentration in the alveoli, dissolved molecular oxygen concentration in blood, the oxy/deoxyhemoglobin levels in pulmonary venous and arterial blood, and oxygen concentration within tissue. However, these factors will only be of importance if they fluctuate with the respiratory cycle. Oxygen is exchanged between the alveolar air and the blood through diffusion, which occurs in response to concentration gradients. Under normal breathing conditions these gradients are more or less in steady state. In a study of freely breathing lambs a variation of 2% was found in the oxygen arterial pressure over the respiratory cycle . This vaAltogether, it can be concluded that the major cause for the change in T2 found in this study can be explained and attributed to the effect of water diffusion across the internal susceptibility gradients modulated by respiration. In conclusion, T2 was found to be dependent on the state of inflation, and thereby the size of the alveoli. To our knowledge, this is the first time the phenomenon is observed in vivo and for the normal breathing cycle. An imaging biomarker for alveolar remodeling could be used to follow progression or potentially regression of emphysema and COPD. This will be the subject for future studies.


Fulminant myocarditis is a life-threatening disease, and myocardial damage expands the right ventricle as well as the left ventricle in some cases. There is a mortality rate of over 40% in patients with fulminant myocarditis who need mechanical circulatory support by peripheral venoarterial extracorporeal membrane oxygenation.We report a case of a 27-year-old Japanese woman who was successfully bridged to recovery by using a biventricular assist device. She was diagnosed with fulminant myocarditis, and peripheral venoarterial extracorporeal membrane oxygenation was established on the same day. Her left ventricular ejection fraction rapidly decreased from 40% to 5% in 3 days and weaning from venoarterial extracorporeal membrane oxygenation was deemed difficult. Therefore, we performed a ventricular assist device implantation on day 4. A left ventricular assist device was implanted first. However, adequate blood flow did not circulate to the left side of her heart because of right-sided heart failure. Thus, an additional implant of a right ventricular assist device was performed during the operation. Her left ventricular ejection fraction recovered to 50% on day 10. The biventricular assist device was successfully removed on day 14. She has not experienced worsening of biventricular function during her follow-ups for 4 years.Ventricular assist device therapy should be considered if there is no improvement in cardiac function in patients with fulminant myocarditis regardless of several days of support by venoarterial extracorporeal membrane oxygenation. A right ventricular assist device should always be implemented when necessary because biventricular involvement is not uncommon in fulminant myocarditis.The online version of this article (doi:10.1186/s13256-017-1466-1) contains supplementary material, which is available to authorized users. Fulminant myocarditis is often life-threatening because it may progress to cardiogenic shock. Peripheral venoarterial extracorporeal membrane oxygenation (VA-ECMO) is indicated for low output syndrome or life-threatening arrhythmia caused by fulminant myocarditis. A national survey in Japan showed that the mortality of patients with fulminant myocarditis who needed VA-ECMO was over 40% . VA-ECMOA 27-year-old previously healthy Japanese woman presented to a local hospital with chest discomfort and vomiting (day 1). She had no family history of cardiovascular disease, was a social drinker, and had never smoked. Her systolic blood pressure was 70 mmHg, a cardiac troponin T rapid test gave a positive result, and an electrocardiogram (ECG) showed an ST elevation in broad precordial leads. Transthoracic echocardiography showed edematous left ventricular myocardium and a left ventricular ejection fraction (LVEF) of 40% with diffuse hypokinetic wall motion. Myocarditis was suspected, and cardiac catheterization was performed after intubation and the insertion of an intra-aortic balloon pump (IABP). Coronary angiography revealed no coronary artery stenosis and left ventriculography showed diffuse hypokinesis . A right ventricular endomyocardial biopsy was performed at the same time. After catheterization, ventricular tachycardia suddenly appeared, her hemodynamics became unstable, and VA-ECMO was immediately employed (day 1). Regardless of ECMO support, her LVEF continued to decrease to 20% on day 2 and to 10% on day 3 . She was transferred to our hospital on day 3.Additional file 1: Movie 1. Left ventriculography on day 1 showed diffuse hypokinesis. (WMV 1201 kb)Additional file 2: Movie 2. Transthoracic echocardiography on day 3 showed that the patient's left ventricular ejection fraction decreased to 10%. (WMV 427 kb)2). The central venous pressure (CVP) was 15 mmHg regardless of right atrial venous drainage. Laboratory data on admission showed an aspartate aminotransferase (AST) level of 369 U/L, alanine aminotransferase (ALT) level of 212 U/L, serum total bilirubin (T-Bil) level of 1.0 mg/dL, creatine kinase (CK) level of 7537 U/L, creatine kinase-MB (CK-MB) level of 87 U/L, and serum creatinine level of 0.38 mg/dL. An ECG showed an atrioventricular junctional rhythm, a heart rate of 51 beats/minute, and ST elevation in broad precordial leads with low voltage , her pupils were 2 mm in diameter, and the bilateral light reflex was prompt. A physical examination revealed peripheral edema and coldness. Her mean blood pressure on admission to our hospital was 60 mmHg with the support of VA-ECMO, IABP, and intravenously administered noradrenaline (0.5 μg/kg per minute). The flow rate of ECMO was 2.8 L/minute The clinical course of our patient is shown in Fig. A histopathological examination of her myocardium obtained from the left ventricular apex during a VAD operation was consistent with lymphocytic myocarditis: inflammatory cell infiltration composed mainly of lymphocytes, myocardial damage, myocardial disarray, interstitial edema, degeneration of myocardial cells, and the appearance of a contraction band. There were a few eosinophils and neutrophils without evidence of giant cells . However, her LVEF improved to 40% on the third day after the VAD operation . Her LVEF improved to 50% on day 6 after the operation with a complete opening of the aortic valve in every beat .Additional file 4: Movie 4. Transthoracic echocardiography on day 7 revealed the patient's left ventricular ejection fraction improved to 40%. (WMV 115 kb)Additional file 5: Movie 5. Transthoracic echocardiography on day 10 revealed the patient's left ventricular ejection fraction improved to 50% with a complete opening of the aortic valve in every beat. (WMV 107 kb)The time course after the VAD implantation is shown in Fig. 2 without LVAD support. Her hemodynamics did not show significant changes for 30 minutes, and the LVAD was removed. Echocardiography 12 days after the BiVAD removal (day 26) showed a recovery of cardiac function: LVDd/Ds = 40/26 mm and LVEF = 64%. She was discharged on day 32. During follow-up, she did not have worsening biventricular function over 4 years.We performed a BiVAD removal operation on day 14 without a cardiopulmonary bypass. First, we switched off the RVAD after the redo median sternotomy. Intra-arterial blood pressure monitoring and a Swan-Ganz catheter revealed that her mean systemic blood pressure was 81 mmHg, mean right atrial pressure (RAP) was 11 mmHg, and the mean pulmonary artery pressure (PAP) was 19 mmHg without RVAD support. A close observation showed no significant changes for 10 minutes. Thus we removed the RVAD. Second, we performed a LVAD-off test. The mean systemic blood pressure was 69 mmHg, mean RAP was 8 mmHg, mean PAP was 20 mmHg, mean pulmonary artery wedge pressure (PAWP) was 14 mmHg, and cardiac index (CI) was 3.1 L/minute/met al. studied 147 patients considered to have myocarditis according to endomyocardial biopsy results and reported that 10.2% (15/147) of the patients had fulminant myocarditis and 89.8% (132/147) had acute myocarditis [et al. studied echocardiographic findings in fulminant and acute myocarditis and reported that patients with fulminant myocarditis exhibit a substantial improvement in ventricular function at 6 months compared with those with acute myocarditis [Patients with fulminant myocarditis have a clinical course that is distinct from patients with acute (nonfulminant) myocarditis . McCarthd 89.8% 12/147 hadAlthough patients with fulminant myocarditis are critically ill at presentation, long-term survival is excellent . WhereasAlthough the results of the VA-ECMO have been excellent in selected patients , continuBiventricular involvement is not uncommon in fulminant myocarditis. Over 70% of right-sided heart involvement has previously been reported in patients with fulminant myocarditis . TherefoFor treatment of myocarditis with VA-ECMO, the possibility of initiation of VADs should be considered. RVAD implantation is indicated in cases accompanied with severe right ventricular dysfunction. RVAD should be added when necessary because biventricular involvement is not uncommon in fulminant myocarditis.


Tissue Doppler imaging (TDI) is a new echocardiographic imaging technique that is believed to be superior to older conventional techniques in assessing abnormalities of cardiac function in many conditions affecting the heart. There are very limited data regarding the role of TDI in evaluating patients with mitral valve prolapse (MVP). Current study evaluates diastolic function in patients with MVP by this method.From November 2009 to April 2011, one hundred and ten adults matched for age and sex and without structural heart disease were studied in two groups, with and without MVP, at Madani Heart Center, Tabriz, Iran. TDI was performed at the basal-lateral wall and S, E, E’, A, and A’ velocities, as well as the E/A and E’/A’ ratios were measured. Mitral annular systolic velocity and early diastolic (E’) velocities were measured lateral corner of mitral valve in apical 4-chamber view.Patients with MVP had higher left atrium volume  and deceleration time . Diastolic dysfunction, although seemed more prevalent in MVP group (14.54%) than normal subjects (5.45%), the difference was not statistically significant between groups (P = 0.11).Left atrial volume and deceleration time of mitral valve inflow was significantly higher in MVP which could be indicative of early stages of diastolic dysfunction in patients with MVP. However, larger follow-up studies are required to evaluate clinical significance of our findings in these patients. Mitral valve prolapse (MVP) is defined echocardiographically as single or bileaflet prolapse of 2 mm or more, beyond the long-axis annular plane, with or without leaflet thickening , 2. The Mitral valve prolapse is a fairly heterogeneous disease according to its natural course. Populational studies show that more than half of patients with MPV are asymptomatic and usually show a benign course of the disease. Their overall morbidity and mortality is similar to the general population. However, in the remaining portion of cases, MVP may be associated with severe cardiovascular complications such as progressive mitral regurgitation, arrhythmias, heart failure, and increased risk of infective endocarditis. Finally, 7.8% of the patients with MVP require mitral valve surgery .Historically, physical examination and transthoracic echocardiography (TTE) have been the diagnostic reference standards for MVP. However, physical findings such as the classic mid-to-late systolic click with a high-pitched late systolic murmur have low specificity, and TTE occasionally does not yield sufficient information for a diagnosis , 6.Tissue Doppler imaging (TDI) is a newer echocardiographic imaging technique that is believed to be superior to older conventional techniques in assessing abnormalities of cardiac function in many conditions affecting the heart . Today bThere are very limited data regarding the role of TDI in evaluating patients with MVP . The aimThe study was carried out at Madani Heart Center, Tabriz/Iran, from November 2009 to April 2011. A total of 110 adult subjects, aged 18 years and older, were studied in two groups. The first group consisted of 55 consecutive patients with newly diagnosed MVP, who met the inclusion and exclusion criteria. The second group consisted of 55 apparently normal controls with no known valvular disease, which were referred because of palpitation. Both groups were matched for age  and sex .Patients with associated cardiac disorders  and patients with systemic hypertension, significant mitral regurgitation, and atrial fibrillation were excluded from the study. Those receiving beta blockers and other drugs with influence on left ventricle diastolic function were also excluded.All patients gave written informed consents and the study was approved by our local Ethics Committee.Mitral valve prolapse (MVP) is an abnormal movement of one or both mitral valve leaflets  into the left atrium during systole. The diagnosis of MVP was made by physical examination (mid-to-late systolic click and a systolic murmur at auscultation) and echocardiography. The echocardiographic diagnosis of mitral valve prolapse was based on the parasternal long-axis view. Mitral valve prolapse was defined as systolic displacement (> 2 mm) of one or both mitral leaflets into the LA, below the plane of the mitral annulus .All echocardiographic studies were performed by one experiences echocardiographist. To define inter observer variability, echocardiograms of 15 patients with MVP and 15 control normal subjects were reviewed by another expert that reported the same findings.Echocardiographic studies were performed Vivid 7 Dimension .Myocardial velocities were measured on-line using a standard pulse wave Doppler technique. Color-coded images were acquired during a breath hold over two consecutive cardiac cycles using low velocity, high-intensity myocardial signals at high frame rate (0.150 MHz). TDI of the mitral annulus was obtained from the apical 4-chamber view. A 1.5 mm sample volume was placed sequentially at the lateral and medial mitral annulus. All Doppler signals were recorded with a chart recorder set at 100 mm/s. The average of 3 end-expiratory cycles was used. Pulmonary venous flow was obtained using the right upper pulmonary vein in the apical four-chamber view. The measurements obtained were S-wave (systolic forward flow), D-wave (diastolic forward flow) and A-wave . Analysis was performed for Mitral inflow measurements included peak early (E) and peak late (A) flow velocities, the E/A ratio, the systolic (S’) and the early (E’) and late diastolic velocity (A’), the systolic filling fraction (S/D) and the deceleration time of early mitral flow velocity (DT) . These variables were analyzed individually, as the average of the medial and lateral annulus, and as the maximum of the medial and lateral annulus.LA volume was measured from standard apical 2- and 4-chamber views at end-systole. The left atrial volume was calculated using the formulae : LV voluWhere A1 is left atrial area in the apical four-chamber view, A2 is left atrial area in the apical two-chamber view, and L is orthogonal  left atrial dimension in the apical four chamber view.Comprehensive Doppler and two-dimensional features including E/A ratio, LA volume, DT, E/E’ ratio and A were used to assess LV diastolic function. Three grades of diastolic dysfunction have been defined. Grade I  is referred to as relaxation abnormality. Grade II  is called pseudo-normalization. Grade III is referred to decrease in relaxation time decreases and restrictive filling (E/A ≥ 2 and DT < 160 ms) .-value of 0.05 or less was considered significant. All calculations were done with SPSS for Windows .Continuous data with normal distribution are given as mean ± standard deviation, otherwise as median. Mean differences for continuous variables between groups were examined by the independent Student t-test. Chi-square test or Fisher exact test if applicable) was used for categorical variables. A PComplaints of patients in MVP group were palpitation (36.4%), chest pain (25.5%), and anxiety (3.6%). The rest were referred with the combination of above mentioned complaints. Auscultatory findings in these patients were increased S1 (16.4%), systolic click (14.5%) and systolic murmur (3.6%). Most patients (45.5%) had increased S1 sound and systolic clicks together, and 7.3% had a combination of these findings. However, 12.7% had normal cardiac auscultation.2; P < 0.001) and deceleration time .Comparison of TDI measurements between the two groups  revealedDiastolic dysfunction, although seemed more prevalent in MVP group (14.54%) than normal subjects (5.45%), the difference was not statistically significant between groups (P = 0.11). Diastolic dysfunction was mild (grade 1) in 5 cases and moderate (grade 2) in 3 cases of MVP group. All three cases in normal group had mild diastolic dysfunction.TDI findings in our study showed that left atrial volume and deceleration time were significantly higher in patients with MVP. There was also a nonsignificant trend towards larger left ventricle diameter in these patients.Scampordanis et al  for the In our study, mean deceleration time was significantly higher in the MVP group which is indicative of impaired diastolic relaxation in these patients. On the other hand, left atrial volume was also higher in this group, which once more is in favor of the probability of diastolic dysfunction. Nishimura et al  have alsWe did not find these differences between our study groups. In Zampoulakis’s study, patients with MVP were older than the control group . Our stuIn conclusion, among parameters studied, left atrial volume and deceleration time were significantly higher in patients with MVP, which could be indicative of early stages of diastolic dysfunction in these patients. However, larger follow-up studies are required to evaluate clinical significance of our findings in these patients.


Patent ductus arteriosus (PDA) is the third most common congenital abnormality in which the arterial duct, which normally closes spontaneously after birth within 24–48 h in full-term infants, remains permanently open. Breathlessness is very common in elderly patients and can be caused by several comorbidities, mostly cardiac and pulmonary diseases. PDA as a cause of heart failure in this patient population is very rare and diagnosis depends on high clinical awareness. Here we present a case diagnosed with multimodality imaging including 3‑dimensional (3D) transthoracic and transesophageal echocardiography and 3D-volume rendering technique (VRT) computed tomography. A patent ductus arteriosus (PDA) is the third most common congenital abnormality in which the arterial duct, which normally closes spontaneously after birth within 24–48 h in full-term infants, remains permanently open . BreathlAn 84-year-old female was referred for cardiac catheterization for evaluation of a suspected significant coronary artery disease and mitral valve regurgitation. The patient complained of worsening of dyspnea symptoms during exercise, New York Heart Association (NYHA) class II–III for several months without angina. The resting electrocardiogram (ECG) showed atrial fibrillation with a heart rate of 90/min . The N‑terminal pro B‑type natriuretic peptide (NT-proBNP) level was moderately elevated (2274 ng/l) with normal renal and thyroid function and borderline anemia (hemoglobin 116 g/l). Transthoracic and transesophageal 3D echocardiography  could be heard at presentation to our department. At this young age the patient was asymptomatic but over the subsequent decades the substantial left to right shunt led to left ventricular dysfunction and severe pulmonary arterial hypertension.It is very rare to diagnose a PDA in an octogenarian and the diagnosis requires a high clinical awareness as this congenital heart disease is uncommon in this patient population. The oldest published case was 91 years old  and patiPublished data on the management of PDA in octogenarians is very limited , 6. The Fig. 1: Resting electrocardiogram at first presentationSupplemental video 1: Three-dimensional echocardiography of patent ductus arteriosusSupplemental video 2: 3D-VRT computed tomography of patent ductus arteriosus