Hyperventilation with a subsequent breath-hold has been successfully used as a non-pharmacological vasoactive stimulus to induce changes in myocardial oxygenation. The purpose of this pilot study was to assess if this maneuver is feasible in patients with multi-vessel coronary artery disease (CAD), and if it is effective at detecting coronary artery stenosis > 50% determined by quantitative coronary angiography (QCA).n = 24) or coronary artery bypass  revascularization procedure. The CMR exam involved standard function imaging, myocardial strain analysis, T2 mapping, native T1 mapping and oxygenation-sensitive CMR (OS-CMR) imaging. During OS-CMR, participants performed a paced hyperventilation for 60s followed by a breath-hold to induce a vasoactive stimulus. Ten healthy subjects underwent the CMR protocol as the control group.Twenty-six patients with coronary artery stenosis (QCA > 50% diameter stenosis) underwent a contrast-free cardiovascular magnetic resonance (CMR) exam in the time interval between their primary coronary angiography and a subsequent percutaneous coronary intervention  and apnea . The breath-hold maneuver unmasked regional oxygenation differences in territories subtended by a stenotic coronary artery in comparison to remote territory within the same patient .All CAD patients completed the breathing maneuvers with an average breath-hold duration of 48 ± 23 s following hyperventilation and without any complications or adverse effects. In comparison to healthy subjects, CAD patients had a significantly attenuated global myocardial oxygenation response to both hyperventilation  contains supplementary material, which is available to authorized users. In developed countries, more than 40% of deaths are due to cardiovascular diseases, in particular coronary artery disease (CAD) . As a reOxygenation-sensitive (OS)-CMR has been introduced to directly assess myocardial oxygenation , 4. ThisIn combination with pharmacological vasodilators, OS-CMR has been successfully used to detect myocardial oxygenation abnormalities in CAD –11. ReceThe study was comprised of data from participants enrolled in a single-centre study at the University Hospital Bern, Switzerland . Twenty-six patients who had undergone a primary angiography visit were included in this analysis along with 10 young and healthy control subjects. All subjects provided informed consent prior to study enrolment.Patients were eligible to participate in the CADOS study if there was at least one untreated vascular territory with a > 50% diameter stenosis (%DS) in quantitative coronary angiography (QCA) after primary diagnostic angiography or primary percutaneous coronary intervention (PCI), and if the CMR scan could be performed prior to the secondary revascularization procedure of a secondary PCI or a scheduled coronary artery bypass graft (CABG) surgery. A further inclusion criterion was that there was an unaffected territory of least two segments according to the American Heart Association 17-segment model with presumed normal perfusion according to the angiography, to serve as intra-subject control tissue. All participants were required to be older than 18 years, capable of providing written consent, to not be pregnant or have any CMR contraindications . Patients with acute myocardial infarction within 4 weeks prior to the CMR exam, with pre-existent coronary bypass grafts, or with severe pulmonary disease were also excluded.Healthy participants were recruited by public notification, and were required to be under the age of 35 years, non-smokers for the last six months, free of any medication that would affect the cardiac or circulatory system, and with a medical history free of cardiac or pulmonary disorders, or disorders known to affect the microvasculature.QCA was performed from the angiography images obtained in the primary angiography/PCI clinical visit. The %DS of all coronary arteries ≥1.5 mm was determined by a trained cardiologist independent from the CMR analysis . To allow a comparison between the angiography and CMR results, this reader then coded each American Heart Association segment as either 1: remote, perfused by a healthy coronary artery; 2: affected by a significant stenosis (%DS > 50%); 3: reperfused with a stent; or 4: undetermined or possibly mixed perfusion territory.Prior to the CMR exam Fig. , particiAll images were obtained at an end-expiratory breath-hold. Cine images for ventricular function analysis were obtained covering the ventricles with 7 to 10 short-axis slices using an electrocardiogram gated bSSFP sequence . T1 maps, T2 maps, and OS-CMR images were obtained in 2 short-axis slices, basal and mid-ventricular. Coloured pixel-wise parametric T2 and native T1 maps were obtained for tissue characterisation. The 5(3)3-modified Look-Locker sequence was used for T1 mapping, . T2 maps were generated after acquiring three single-shot gradient echo images . OS-CMR was imaged using a triggered balanced steady-state free precession sequence  .42  by an experienced reader. Standard function parameters were calculated including left-ventricular (LV) ejection fraction (EF), cardiac index (CI), and body surface area indexed end-diastolic (EDVI), end-systolic (ESVI) volumes and myocardial mass. Using feature-tracking software, circumferential strain was calculated for the left ventricle from the cine images, excluding slices that included the outflow tract and mitral valve planes. For strain analysis, OS-CMR, T1 and T2 mapping, data were reported as a global value, and also as segmental values, based on the automatic segmentation according to American Heart Association definitions. After un-blinding, these segmental CMR results were grouped based on the QCA categorization. Relative OS signal intensity (SI) changes were reported as %-change from baseline for the hyperventilation analysis. For the breath-hold analysis, %-change was calculated for each measurement in relation to the first image acquired after hyperventilation , and were masked onto the original OS cine.The CMR images were re-coded to blind the CMR reader to the identity of the participant, group allocation and angiography results. All CMR images were analyzed quantitatively after manual tracing of epicardial and endocardial contours using cvip < 0.05.Continuous data is reported as mean ± standard deviation (SD), while categorical data is reported as frequency and percentage. Ventricular function measurements and global myocardial values were compared between the two groups using independent Student’s t-test. Correlation was assessed using Pearson’s correlation coefficient. Non-parametric equivalents were used if appropriate. Regional analysis was performed using a repeated measures univariate linear model. Additional post-hoc analysis compared myocardium subtended to a stenosed or reperfused vessel to remote myocardium, using Bonferroni correction for multiple comparisons. For assessing inter-observer reliability, the OS response of both hyperventilation and the breath-hold of ten random participants were read by a second reader and an intra-class correlation coefficient (ICC) was determined based on single measures using a two-way mixed model assessing absolute agreement for global oxygenation changes. Furthermore, intra-observer reliability was available for eight participants that were recoded and analyzed with at least six months between readings, assessed with a one-way random ICC test. Tests were performed with GraphPad Prism  and SPSS . Results were considered statistically significant at a two-tailed 2. CAD patients were significantly older, with chronic medication, with the indication for PCI referral shown in Table n = 3). Twenty-three patients (88%) had a PCI procedure performed on one vessel during the initial visit; three patients had diagnostic angiography only and were subsequently scheduled for subsequent PCI (n = 1) or a CABG surgery (n = 2).Healthy participants  had a mean age of 27 ± 4 years and a body mass index of 23.9 ± 2.3 kg/mCompared to healthy subjects, CAD patients had lower LVEF, stroke volume and cardiac index Table . Global n = 3, CAD: n = 4), temporary headache , dizziness , and dry mouth . All side effects dissipated within 60s of recommencing normal breathing. The majority reported no adverse effects at all .All participants successfully completed the hyperventilation component of the breathing maneuver and performed breath-holds adequately. The mean duration of the breath-hold was 75 ± 23 s in the control group and 48 ± 23 s in the patient group; two patients resumed breathing within 20s. Reported adverse effects during the breathing maneuvers were: tingling in the extremities  and intra-observer  analysis demonstrated excellent reliability.Global oxygenation effects: Healthy subjects responded to hyperventilation with a global SI reduction (− 9.6 ± 6.8%), while CAD patients showed a lesser reduction .Regional oxygenation heterogeneity in CAD: There was no significant difference of the response to hyperventilation between remote (− 3.0 ± 7.1%), post-stenotic (− 2.7 ± 7.9%) or reperfused (− 2.5 ± 6.3%) segments.p = 0.011) and reperfused territories , which showed a weaker response than remote territories (+ 3.8 ± 5.3%). Interestingly, in 5 (21%) of 24 patients with breath-holds of more than 30s, there was a global deoxygenation response during apnea, i.e. a SI decrease in all territories r = 0.405, p = 0.049). From all the CMR data, no measurements were associated with the degree of stenosis defined by QCA. Similarly, most measurements were not associated with the days between the first PCI, except for the OS response to hyperventilation in reperfused segments .In CAD patients a poorer oxygenation response to the breath-hold was associated with a younger age  [OS-CMR could be used as a part of a comprehensive CMR exam, including data on volumetry and function (cine images), as well as tissue characteristics (T1 and T2 maps). Along with strain analysis, native mapping sequences are now suggested as alternatives to contrast imaging for scar tissue , 27. Thi/1.73m2) .In the present study, the severity of coronary artery stenosis was estimated by QCA measurements, rather than FFR, which is the current gold standard. Hemodynamic assessments such as FFR are not commonly performed at this site and were thus not available for the study. Another study using OS-CMR with adenosine as the vasodilator had shown a correlation to the degree of stenosis assessed by QCA, albeit weaker than with FFR . AdditioIt is important to note that in this study we did not perform contrast enhanced imaging to assess scar. In the reperfused territories we often observed a thin myocardium in the infarcted area with poor circumferential strain suggesting scar , yet theDuring the study design, we chose to recruit younger participants in good general health since they were most likely to have minimal microvascular or other cardiovascular dysfunction, The oxygenation response of these young healthy subjects was similar to our previous publication, which recruited an older healthy population . We recoOur results indicate that a combined maneuver of hyperventilation and subsequent breath-holding is a feasible method to elicit a coronary vasomotor response in CAD patients associated with minimal side effects. In conjunction with OS-CMR, the breathing maneuvers can unmask oxygenation deficits in myocardium subtended to stenotic coronary arteries.Additional file 2:Explanation of the video file. 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Silent myocardial infarction (MI) is a prevalent finding in patients with type 2 diabetes and is associated with significant mortality and morbidity. Late gadolinium enhancement (LGE) by cardiovascular magnetic resonance (CMR) is the most validated technique for detection of silent MI, but is time-consuming, costly, and requires administration of intravenous contrast. We therefore planned to develop a simple and low-cost population screening tool to identify those at highest risk of silent MI validated against the CMR reference standard.A total of 100 asymptomatic patients with type 2 diabetes underwent electrocardiogram (ECG), echocardiography, biomarker assessment, and CMR at 3.0T including assessment of left ventricular ejection fraction and LGE. Global longitudinal strain from two- and four-chamber cines was measured using feature tracking.P = .05), had lower E/A ratio , lower GLS , and higher amino-terminal pro brain natriuretic peptide . A combined risk score derived from these four factors had an area under the receiver operating characteristic curve of 0.823 (0.734–0.892), P < .0001. A score of more than 3/5 had 82% sensitivity and 72% specificity for silent MI.A total of 17/100 patients with no history of cardiovascular disease had silent MI defined by LGE in an infarct pattern on CMR. Only four patients with silent MI had Q waves on ECG. Patients with silent MI were older (65 vs 60, Using measures that can be derived in an outpatient clinic setting, we have developed a novel screening tool for the detection of silent MI in type 2 diabetes. The screening tool had significantly superior diagnostic accuracy than current ECG criteria for the detection of silent MI in asymptomatic patients. The rate of silent MI in this cohort of patients with type 2 diabetes was 17%. A screening tool for its detection was created from clinical parameters including age, E/A ratio, GLS and NT-proBNP. Cardiovascular disease, primarily stroke and myocardial infarction (MI), account for the vast majority of mortality associated with type 2 diabetes , 2. SileCurrently, the most extensively validated method to assess for the presence and extent of silent MI is the late gadolinium enhancement (LGE) technique measured by cardiovascular magnetic resonance (CMR). Using this technique, it is possible to establish the location and distribution of scar tissue. The prevalence of silent MI according to the presence of LGE in symptomatic patients with type 2 diabetes is reported to be between 21 and 28% , 4. In tThere has been a decrease in the rate of acute MI in patients with type 2 diabetes over the past two decades . This reThe detection of patients with silent MI remains a challenge as the most accurate method relies on CMR, which has limited availability, is relatively time consuming, costly and requires administration of IV contrast, making it a less than ideal population screening tool. Several imaging and biomarker tests have been shown to be able to detect the presence and determine the extent of clinically recognized MI measured by LGE including Q waves on a 12-lead electrocardiogram (ECG) , ejectioIn this study, we aimed to assess the diagnostic accuracy of several commonly measured parameters in asymptomatic patients with type 2 diabetes to detect silent MI. We hypothesized that a risk score derived from a combination of these measurements could accurately predict the presence of silent MI on CMR.A total of 100 asymptomatic patients with type 2 diabetes were recruited from 30 primary care health centers in West Yorkshire, UK. The study was approved by the local ethical committee (13/YH/0098) and individuals were enrolled onto the study after informed consent. Exclusion criteria were known cardiovascular disease , kidney disease (estimated glomerular filtration rate < 30), uncontrolled hypertension (with latest BP >140/80 mm Hg ), treatmAll patients underwent an identical CMR study on a dedicated cardiovascular 3 Tesla Philips Achieva TX system (Philips) equipped with a 32-channel coil and MultiTransmit technology. Data were acquired during breath-holds at end-expiration.3, 50 cardiac phases repetition time/echo time 2.6/1.3 ms, flip angle 40°, field of view 300–420 mm). Cines planned to cover the entire left atrium short axis plane in end-systole were also acquired (as in LV stack but with a slice thickness of 5 mm).From scout CMR images, the left ventricular (LV) long and short axes were determined. Cine images covering the entire heart in the LV short axis plane and orthogonal long-axis planes were then acquired  imaging was carried out more than 6 minutes after contrast injection  using inversion recovery-prepared T1-weighted echo. The optimal inversion time to null signal from normal myocardium was determined using a Look-Locker approach. Typical parameters are repetition time/echo time 3.5/2.0 ms, flip angle 25°, acquired spatial resolution 1.54 × 1.76 × 10 mmCMR data were assessed quantitatively using commercially available software  blinded to clinical details. LV mass, ejection fraction, and left atrial volume were measured from short axis cine images.For feature tracking analysis, endocardial and epicardial LV contours were drawn on long axis four-chamber and two-chamber cines using a semiautomated process. Peak global longitudinal strain, systolic strain rate, and early and late diastolic strain rates were measured. Late diastolic strain rates were defined as peak rate during active atrial contraction.The presence of silent MI was identified by two physicians experienced (5 and 15 years) in CMR interpretation based upon typical subendocardial distribution of LGE present. The mass of LGE was quantified by the Otsu method .All patients underwent echocardiography  focused on Doppler measurements of mitral inflow and tissue Doppler imaging of the lateral and medial mitral annulus. E/A ratio (the inverse was used for the index), E′, A′, and S′ are measured on the machine using inbuilt software. Diastolic dysfunction was graded 0–3 by an accredited echocardiographer blinded to clinical details according to international guidelines . Twelve-Blood was drawn from each subject at the time of CMR and tested for HbA1c. Serum was stored at –70 C and tested in one batch for hs-cTnT typical coefficient of variability 4.4% at 13.7 ng/liter and 3.6% at 95.3 ng/liter, NT-proBNP typical coefficient of variability 2.9% at 91 ng/liter and 2.1% at 415 ng/liter  and hs-CRP . Fasting cholesterol values were recorded from review of electronic records.t test or Mann Whitney U test depending on normality. Categorical variables were expressed as N (%) and compared using Fisher exact test.Statistical analysis was performed using IBM SPSS Statistics 22.0 (IBM Corp.). Continuous variables were expressed as means ± standard deviation and compared using Receiver operating characteristic (ROC) analysis was used to determine the diagnostic accuracy of age, E/A ratio, GLS, and NT-proBNP for the detection of silent MI. These parameters were chosen because they were significantly different in those with silent MI and have biological validity. The diagnostic accuracy is expressed as area under the curve (AUC) and 95% confidence interval (CI). Optimal sensitivity and specificity were calculated using Youden index. Nested models were used to establish the best possible AUC from combining the variables associated with silent MI. AUCs were compared by using validated methods described by DeLong et al .Using the cutoffs derived from the Youden analysis of the ROC curves, each variable was given a binary classification (0 or 1). These four categorical variables were summed to calculate a silent MI risk score (range 0–4). The AUC of the silent MI risk score was compared to the best possible AUC from the individual parameters derived from the nested risk model.P < .05 two-sided was considered statistically significant.We estimated that for a screening tool to be clinically useful it would need sensitivity a of more than 80% and to be significantly superior to the current screening test of Q waves, which has a sensitivity of 28% . AssuminSeventeen of the 100 patients had evidence of silent MI defined as a subendocardial pattern of LGE identified by two experienced CMR reporters independently. P = .05), but there was no significant difference in any other patient characteristic or use of medication. There was no significant difference in any cardiac risk factors including 24-hour BP, fasting cholesterol, duration of diabetes, or smoking .Patients with silent MI were older than those without silent MI .The mean number of previous HbA1c measurements included in the analysis was 9.7 ± 5.7 per patient over 4.3 ± 2.7 years. There was no significant difference between mean, median, or highest HbA1c since diagnosis between those with and without silent MI . Other ECG abnormalities present in 19/100 patients were not associated with silent MI and included left axis deviation in five, right bundle branch block in five, LV hypertrophy by voltage criteria in four, left anterior hemiblock in three, T wave abnormalities in three, and trifascicular block in one.P = .03) in patients with silent MI. Grade of diastolic dysfunction was not significantly different between those with and without silent MI .Results of echocardiography are shown in 2, P = .01). There was no other difference in volumetric parameters. Of the longitudinal strain parameters measured by feature tracking, GLS –15.2 ± 3.7 vs –17.7 ± 3.1%, P = .004, peak systolic strain rate –93.8 ± 31.8 vs –111.2 ± 42%, P = .04, and early diastolic strain rate 64.1 ± 16.6 vs 84.0 ± 33.1%, P = .02, were all significantly lower in those with silent MI. There was no difference in late diastolic strain rate, P = .89.CMR results are shown in P < .0001), E/E′ , and hs-cTnT .Of the patient characteristics shown in P = .003). There was no difference in hs-CRP or hs-cTnT .NT-proBNP was significantly higher in those with silent MI , P < .0001, and the maximum possible sensitivity was 94% and specificity 71%. The nested model had higher diagnostic accuracy than Q waves, age, E/A ratio, and GLS alone . The improvement over NT-proBNP showed a trend (P = .07). The addition of Q waves did not significantly improve the AUC of the model.The area under the ROC curve for age, Q waves, E/A ratio, GLS, and NT-proBNP are shown in P < .0001, and better diagnostic accuracy than Q waves, age, or E/A ratio alone . The sensitivities and specificities for each possible silent MI risk score are shown in The combined four-variable silent MI risk score had an AUC of 0.823 (0.734–0.892), The prevalence of silent MI (17%) detected by LGE imaging in this low-risk asymptomatic population was high approaching one in five patients. We have found increasing age to be the only conventional risk factor associated with silent MI. We have identified several markers of silent MI that can be detected by cardiac imaging or blood test and have shown that these markers can be combined to develop a simple screening tool with good diagnostic accuracy.We have demonstrated that a simple risk score can predict the presence of silent MI in patients with type 2 DM as shown by LGE on CMR. The risk score is composed of age, E/A ratio below 0.79, GLS greater than –18.4%, and NT-proBNP above 29 ng/liter. These are all parameters that are often measured in a cardiology clinic or could easily be measured in a community-based screening. In the model, we derived GLS from feature tracking of CMR cine images; however, it is possible to measure GLS from standard echocardiography, which has been demonstrated to show good agreement with GLS measured from CMR .The decision about where to make the cutoff to recommend further investigation depends on whether sensitivity or specificity is the predominant clinical priority . If the All of the measured components within the score, impaired GLS , elevateThe imaging parameters associated with mass of silent MI were different from those included in the silent MI risk score and included LV ejection fraction, E/E′, and hs-cTnT. These parameters are all recognized to correlate with extent of infarction and prognosis after symptomatic MI , 10, 22;It was an unexpected finding that conventional risk factors including fasting cholesterol, 24-hour BP, smoking, and even previous glycemic control had no association with the likelihood of silent MI in our population, although this may reflect a relatively small sample size and appropriate use of primary prevention medication. However, it is unclear whether the pathological processes that lead to silent MI are identical to acute MI. The lack of association with conventional risk factors suggests that further research is needed to identify alternative risk factors specifically for silent MI.To our knowledge this is the first study to assess silent MI by LGE CMR in a truly asymptomatic diabetic population. Previous studies have demonstrated that in patients with diabetes, silent MI detected on CMR is associated with increased mortality and adverse cardiovascular events , 4. KwonDespite recommendations of aggressive risk factor modification in type 2 diabetes uptake remains variable  (with onThere several limitations to this work that should be acknowledged. First, we have excluded certain higher risk patients—for example, those on insulin or angiotensin-converting enzyme inhibitors—therefore, general applicability of the findings is uncertain. The silent MI risk model we propose would need to be validated in more varied populations to broaden its clinical use. Second, we have not performed coronary angiography to confirm that silent MI was caused by coronary disease; however, in an asymptomatic cohort, undertaking an invasive procedure would not be appropriate. Third, we have recruited a relatively low proportion of women; however, previous data suggest that the rate of silent MI tends to be equal or lower in women , 4. FinaThe rate of silent MI in this low-risk asymptomatic cohort of patients with type 2 diabetes was higher than expected. Several simple clinical parameters including age, E/A ratio, GLS, and NT-proBNP were associated with silent MI. By combining them, we were able to define a novel screening tool with superior diagnostic accuracy than current ECG criteria for the detection of silent MI, which can be used both clinically and for interventional studies.


The model of the heart was coupled to lumped-parameter circulatory systems to simulate realistic ventricular loading conditions. Finally, the impact of ventricular assistance was investigated by incorporating a pump with pressure-flow characteristics of an LVAD (HeartMate II™ operating between 8 and 12 k RPM) in parallel to the left ventricle. This allowed us to investigate the mechanical impact of acute left ventricular assistance at multiple operating-speeds on right ventricular mechanics and septal wall motion. Our findings show that left ventricular assistance reduces myofiber stress in the left ventricle and, to a lesser extent, right ventricle free wall, while increasing leftward septal-shift with increased operating-speeds. These effects were achieved with secondary, potentially negative effects on the interventricular septum which showed that support from LVADs, introduces unnatural bending of the septum and with it, increased localized stress regions. Left ventricular assistance unloads the left ventricle significantly and shifts the right ventricular pressure-volume-loop toward larger volumes and higher pressures; a consequence of left-to-right ventricular interactions and a leftward septal shift. The methods and results described in the present study are a meaningful advancement of computational efforts to investigate heart-failure therapies in silico and illustrate the potential of computational models to aid understanding of complex mechanical and hemodynamic effects of new therapies.Predictive computation models offer the potential to uncover the mechanisms of treatments whose actions cannot be easily determined by experimental or imaging techniques. This is particularly relevant for investigating left ventricular mechanical assistance, a therapy for end-stage heart failure, which is increasingly used as more than just a bridge-to-transplant therapy. The high incidence of right ventricular failure following left ventricular assistance reflects an undesired consequence of treatment, which has been hypothesized to be related to the mechanical interdependence between the two ventricles. To investigate the implication of this interdependence specifically in the setting of left ventricular assistance device (LVAD) support, we introduce a patient-specific finite-element model of dilated chronic heart failure. The model geometry and material parameters were calibrated using patient-specific clinical data, producing a mechanical surrogate of the failing  In view of the growing number and dismal prognosis of patients with end-stage heart failure, interest in emerging mechanical therapies such as left ventricular assistance devices (LVADs) has intensified. LVADs are used as a bridge to transplant, bridge to decision, destination therapy and, increasingly, as a bridge to recovery. The latter is fueled by the nearly ubiquitous demonstration that left ventricular (LV) unloading provided by LVADs causes reverse remodeling and, in a small percentage of patients, induces myocardial recovery to the point where devices can be explanted  data sets were obtained as part of the Aliskiren Study in Post-MI Patients to Reduce Remodeling (ASPIRE) trial  were imported and processed in Simpleware ScanIP . Geometrically detailed segmentations of the LV and RV were created relying on a combination of well-established techniques, including region growing, level-set thresholding, and morphological smoothing  was fixed in the longitudinal direction. Furthermore, the nodes on the endocardial annulus were constrained by coupling the average translation and rotation of the nodes to a fixed point in space located at the annulus center. This prevents rigid body rotation while allowing the annulus relative motion to inflate and contract during the cardiac cycle.The passive material response of the cardiac tissue uses an anisotropic hyperelastic formulation proposed by Holzapfel and Ogden  is defined through eight material parameters F is the deformation gradient, J is the determinant of the deformation gradient, J = det(F) and where The expression of these strain invariants can now be defined as:f0 and s0 are orthogonal vectors in the fiber and sheet direction in the reference configuration. Equation (2) is defined through J and a penalty term D, which is a multiple of the bulk modulus (D = 2/K). For deformation that perfectly preserves volume, J = 1.Where This passive material model, Equations (1–2), ensures that the material exhibits the well-documented exponential and anisotropic response to strain TF. We consider an active contractile stress in the fiber direction, resulting in a total Cauchy stress in the fiber direction,  by combining this with to the passive stress state in this direction (σpf):We consider the total Cauchy stress to be an additive contribution of passive and active components. The passive Cauchy stress, ns ∈ , such that the total Cauchy stress in the sheet direction is:Biaxial investigations on actively contracting rabbit myocardium revealed significant stress development in the cross-fiber direction that could not be completely attributed to myofiber dispersion or deformation effects  of 254 ml and an end-systolic volume (ESV) of 224 ml. End-diastolic pressure (EDP) and end-systolic pressure (ESP) were assumed to be 23 and 86 mmHg, respectively. These classify the patient with a severely dilated LV (>200 ml), elevated EDP  and exponential  terms were subject to uniform scaling by parameters A and B, a scalar and an exponential multiplier, respectively. These values were found by minimizing the error between the in silico diastolic PV course resulting from loading the LV of the FE model to the analytical Klotz curve . Material parameters were calibrated using ABAQUS as the forward solver, and an in-house PYTHON script containing the sequential least squares programming (SLSQP) optimization algorithm . Calibrated material parameters are presented in Table Once passive parameters were found, the active parameter TThe FE model of the heart was coupled to lumped models of the pulmonary and systemic circulatory systems used in our previous study  between the inflow and outflow cavities to which the pump connects. Experimental datasets specifying flow rates for a range of dP between 0 and 200 mmHg at discrete intervals of 2 mmHg were incorporated in the simulated flow profile for each operating speed. Flow rates were interpolated and extrapolated linearly between discrete values to account for a continuous flow-rate description for any dP the model may encounter. This is illustrated in Figure SD) unless otherwise stated. The differences between results were evaluated using analysis of variance (ANOVA) with differences considered statistically significant with p < 0.05. Time points in the cardiac cycle, such as end diastole, were defined for the untreated case and compared to the time points in simulations with LVAD support. End diastole and end systole, for each ventricle, were identified from the pressure-volume curves as the points immediately preceding isovolumetric contraction and relaxation respectively.For this study, cardiac function was simulated for a patient with chronic heart failure. LVAD therapy was introduced by simulating the effect of a HeartMate II operating at speeds ranging from 8–12 k RPM in 1 k RPM increments. Pressure and volume measurements of the ventricular chambers were recorded and compared to quantify ventricular loading and output performance. Myofiber stress was recorded and quantified for each simulation and compared to analyze the efficacy of treatment in the LV and potential harm of treatment to the septal wall and RV. Stress data in this study are expressed as mean ± standard of deviation , as shown in Table These functional changes are also captured in pressure-volume loops of each chamber, as shown in Figure The interventricular septum is in constant motion throughout the cardiac cycle. We tracked the midpoint motion at the base of the septal wall and quantified the leftward shift of this point in reference to the line through the anterior and posterior LV-septal-RV junctions. This measure of septal shift is positive when the septal wall bulges into the LV cavity, zero when the septal wall forms a straight line and negative when the wall bulges into the RV cavity. A time course of this measure over two heartbeats, shown in Figure SD are presented in Table p < 0.001). The improvements to RV mean myofiber stress were less substantial, with both end diastole and end systole myofiber stress in the RV remaining relatively unaffected.The volumetric-averaged myofiber stress  was calculated at end diastole and end systole, and the mean ± Myofiber stress distributions and overall geometry are presented in Figure A quantitative analysis of myofiber stress distribution in a segmented region of the vulnerable septal wall is presented in Figure We describe a geometrically and physically realistic model of an end-stage failing heart with representative systolic and diastolic myocardial material properties coupled to lumped parameter Windkessel-like models of the pulmonary and systemic circulations. This permitted study of heart mechanics and dynamics under realistic loading conditions i.e., pre-load and afterload of each ventricle. Finally, we simulated the effects of LVAD support by using experimentally recorded pressure-flow characteristics of a commonly used device. The present model represents a significant improvement over our prior modeling efforts  before computational models contribute to clinical decision making. We intend to address this in our future work. Finally, as noted, we studied only one combination of myocardial properties, RV and LV and vascular properties. Every patient is unique and conclusions arrived at are not generalizable.We described results of an FEA model based on the anatomy of an end-stage failing heart coupled to systemic and pulmonary vascular systems and an LVAD. We demonstrated the anatomic and hemodynamic impact of increasing LVAD speed on global pump function, regional stress distributions, and septal position. Realistic results were obtained in terms of ventricular deformation and PV loops. We demonstrated the expected findings that RV systolic and diastolic properties are affected by LVAD-induced unloading of the LV, resulting in RV dysfunction at high LVAD operating speeds. Having established the foundation of this model, we are poised to address the important question of whether and under what conditions, septal shift, and reduced LV pressure generation are important mechanisms of the development of RV failure following LVAD implantation. The specific conditions studied in the present model demonstrate that septal shifting alone is not sufficient to induce RV failure. Simulations spanning a wide range of conditions are required to fully address this important question.in vivo. Such an approach has the potential for predicting hemodynamics, such as the degree of unloading achievable, and the risk of developing right heart failure following LVAD implantation. Advances in patient-specific modeling in other fields of cardiology are already having an impact on clinical practice and it is anticipated that new applications will emerge, especially in the field of heart failure. The methods and results described in the present study have potential to meaningfully advance such efforts.Beyond this, the methods are generalizable in the sense that patient-specific geometries and vascular properties can be incorporated into the model, with the ultimate purpose of gaining insights into LVAD effects Patient cardiac MR data was obtained as part of the Aliskiren Study in Post-MI Patients to Reduce Remodeling (ASPIRE) trial. The study protocol was written by members of the executive committee of the trial and was approved by the ethics committees at each participating site. Individual patients provided written informed consent in accordance with the Declaration of Helsinki and anonymized data were sent to a core laboratory for analysis.KS, TF, DB, and JG were involved in the conception and design of study. KS created the computational models. Acquisition of various data critical to model creation was performed by SS and DB. The analysis and interpretation of modeling results was performed by all authors. KS wrote the first draft of the manuscript. DB and JG wrote sections of the manuscript. All authors contributed to manuscript revision, read and approved the submitted version.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.


Clinically, patients with chronic heart failure arising from different etiologies receive the same treatment. However, the prognoses of these patients differ. The purpose of this study was to elucidate whether the pathogenesis of heart failure arising from different etiologies differs.Heart failure-related dataset GSE1145 was obtained from the Gene Expression Omnibus database. Differentially expressed genes were identified using R. A protein-protein interaction network of the differentially expressed genes was constructed using Search Tool for the Retrieval of Interacting Genes. The modules in each network were analyzed by Molecular Complex Detection of Cytoscape. The Database for Annotation, Visualization and Integrated Discovery was used to obtain the functions of the modules.Samples contained in GSE1145 were myocardial tissues from patients with dilated cardiomyopathy, familial cardiomyopathy, hypertrophic cardiomyopathy, ischemic cardiomyopathy, and post-partum cardiomyopathy. The differentially expressed genes, modules, and functions of the modules associated with different etiologies varied. Abnormal formation of extracellular matrix was overlapping among five etiologies. The change in cytoskeleton organization was specifically detected in dilated cardiomyopathy. The activation of the Wnt receptor signaling pathway was limited to hypertrophic cardiomyopathy. The change in nucleosome and chromatin assembly was associated with only familial cardiomyopathy. Germ cell migration and disrupted cellular calcium ion homeostasis were solely detected in ischemic cardiomyopathy. The change in the metabolic process of glucose and triglyceride was detected in only post-partum cardiomyopathy.These results indicate that the pathogenesis of heart failure arising from different etiologies varies, which may provide molecular evidence supporting etiology-based treatment for heart failure patients. Patients with heart failure suffer from a high mortality and a poor prognosis. Worldwide, the mortality of patients within 5 years of chronic heart failure is greater than 50% Currently, patients with chronic heart failure arising from different etiologies are given the same treatment in clinical practice, and the differences in etiology are ignored The purpose of this study was thus to elucidate whether the pathogeneses of various types of heart failure arising from different etiologies is different. The pathogenesis of diseases is usually not determined by a single gene but by the interactions among multiple genes forming a pathogenetic network, which is characterized by determining changes in the gene expression profile GSE1145 was downloaded from the Gene Expression Omnibus (GEO) database. The samples contained in GSE1145 were myocardial tissues from patients with heart failure arising from five different etiologies, including 12 samples arising from dilated cardiomyopathy (DCM), 5 from familial cardiomyopathy (FCM), 5 from hypertrophic cardiomyopathy (HCM), 20 from ischemic cardiomyopathy (ISCM), and 4 from post-partum cardiomyopathy (PPCM), as well as 11 normal controls. The myocardial samples of heart failure were collected from patients undergoing cardiac transplantation whose failure arose from the different etiologies mentioned above. The normal control myocardial samples were collected from normal organ donors whose hearts could not be used for transplants. The platform used was GPL570 [HG-U133_Plus_2] Affymetrix Human Genome U133 Plus 2.0 Array, which contains a total of 54,675 probes. These probes correspond to 20,283 genes. When multiple probes corresponded to one gene, the variance of the expression levels of the probes was averaged as the expression value of the gene.The raw data from the original CEL files were preprocessed and transformed into expression values by Affy, an R package. Then, the expression values were normalized using the robust multiarray averaging (RMA) algorithm, and the missing data were filled in using the k-Nearest Neighbor (KNN) algorithm p-value <0.05, and the fold change values ≥2 Limma, a package of R, was applied to identify the DEGs between each etiology and the normal controls http://string-db.org/), a database containing both direct  and indirect  associations of protein interactions, was used to predict the interactions between the identified DEGs and to construct the protein-protein interaction (PPI) network Search Tool for the Retrieval of Interacting Genes , a plugin of Cytoscape, was used to identify the modules in each network. The parameters of MCODE were as follows: the degrees of each node in a module were no less than 2, and subgraphs of each node were greater than 2 https://david.ncifcrf.gov/) was applied to perform the functional enrichment analysis for the modules associated with the different etiologies P<0.05 was set as the cut-off.The Database for Annotation, Visualization and Integrated Discovery  are the main substrate for the normal heart to produce ATP. Approximately 60%-90% of ATP is derived from the aerobic oxidation of FFAs. Upon the development of heart failure, the substrate utilization changes. The aerobic oxidation of FFAs diminishes, and the uptake of glucose increases. The metabolic pattern also changes from the aerobic oxidation of FFAs to anaerobic glycolysis The major strength of this study was that based on the microarray dataset, we showed different pathogeneses of heart failure arising from different etiologies and found the similarities and differences in the DEGs among the different types of heart failure. However, because there are only 4 or 5 samples for FCM, HCM and PPCM, our results of these three groups may have been due to chance and must be confirmed by increasing the sample size.Our results indicate that the pathogenesis of heart failure arising from different etiologies not only shares similarities but also exhibits differences, which may provide molecular evidence supporting the concept that etiology-based treatment is required for patients with heart failure.Ma A, Yang G and Wang T participated in the design of the study. Yang G and Lu J carried out the study. Yang G and Chen S analyzed the data. Yang G and Wang T drafted the manuscript.


We have previously identified that right ventricular systolic dysfunction (RVSD), present in one third of patients with non-ischaemic dilated cardiomyopathy (DCM), is an independent predictor of all cause mortality and cardiac transplantation. CMR provides a robust and reliable way of quantifying RVSD.The natural history of RVSD in DCM has not been formally evaluated. We sought to evaluate whether baseline left ventricular systolic function is predictive of the development of RVSD and whether progression of right-sided ventricular impairment is linked to progression of left-sided ventricular impairment.130 DCM patients  underwent 2 cardiovascular magnetic resonance (CMR) studies, with a median interval of 2.7 years between studies (IQR 1.4-4.7 years). CMR was performed on a 1.5T Siemens scanner.DCM was diagnosed on conventional criteria (increased LV end diastolic volume indexed to body surface area and reduced left ventricular ejection fraction (LVEF) compared with reference ranges normalised for age and gender; absence of significant underlying coronary artery disease). RVSD was defined as right ventricular ejection fraction (RVEF) <45%.Data are presented as mean ± standard deviation. Correlation between interval change in RVEF and LVEF was assessed with Pearson's correlation test. ANCOVA was performed to identify independent predictors Table  of the fMean baseline LVEF was 42% (± 12%) and RVEF 53% (± 16%). Thirty-two patients (25%) had RVSD at baseline, and 22 at follow up (17%). Mean follow up LVEF was 47% (± 13%) and RVEF 54% (± 14%).When controlling for baseline RVEF, baseline LVEF was not predictive of follow up RVEF . When controlling for potential confounders, baseline LVEF remained non significant in predicting follow up RVEF.The interval change in RVEF was strongly correlated with the interval change in LVEF between CMR studies . Controlling for baseline RVEF, the interval change in LVEF between studies was strongly predictive of follow up RVEF. For every 10% increase in LVEF between studies, the follow up RVEF would be 4.3% higher . This remained highly significant even when adjusting for potential confounders(listed in Table These data show no evidence that progression of RVSD in DCM is dependent on baseline left ventricular systolic function.However, adverse or reverse remodelling of RV function mirrors the change in LV function.This suggests therefore that patients with significant LV impairment but normal RV function at baseline may not necessarily develop RVSD. However if LV function improves or deteriorates then RV function is likely to follow a similar course.


Among immigrants of sub-Saharan origin, parasitic infection is the leading cause of eosinophilia, which is generally interpreted as a defense mechanism. A side effect of the inflammatory mediators released by eosinophils is damage to host organs, especially the heart. The main objectives of this study were to i) assess cardiac involvement in asymptomatic sub-Saharan immigrants with eosinophilia, ii) relate the presence of lesions with the degree of eosinophilia, and iii) study the relationship between cardiac involvement and the type of causative parasite.In total, the study included 50 black immigrants (37 patients and 13 controls) from sub-Saharan Africa. In all subjects, heart structure and function were evaluated in a blinded manner using Sonos 5500 echocardiographic equipment. The findings were classified and described according to established criteria. The diagnostic criteria for helminthosis were those reported in the literature. Serum eosinophil-derived neurotoxin levels were measured using enzyme-linked immunosorbent assay. A significant association was found between the presence of eosinophilia and structural alterations . However, the lack of an association between the degree of eosinophilia and heart valve disease and the absence of valve involvement in some patients with eosinophilia suggest the role of other factors in the appearance of endocardial lesions. There was also no association between the type of helminth and valve involvement.We, therefore, suggest that transthoracic echocardiography be performed in every sub-Saharan individual with eosinophilia in order to rule out early heart valve lesions. Endomyocardial fibrosis is characterized by fibrosis of the apical endocardium of the right ventricle, left ventricle, or both. Epidemiological studies of endomyocardial fibrosis indicate a predominance in tropical regions, with young people and men being affected predominantly. Little is known about the natural history and pathogenic factors of this condition. One of the most important factors is the presence of eosinophilia, which is mainly related to helminth infections. The aim of the study was to evaluate cardiac involvement in patients with absolute eosinophilia. We performed an echocardiographic study in asymptomatic sub-Saharan immigrants with eosinophilia and compared them with a group of control patients from the same region and of the same age. Our results suggest that eosinophilia associated with helminth infection (regardless of the causative microorganism) contributes to the asymptomatic phases of endomyocardial involvement. Treatment of these infections is simple, effective, and economical. Therefore, we suggest that all immigrant patients with eosinophilia undergo etiologic study and causal treatment as well as transthoracic echocardiography in order to rule out early damage. Eosinophilia is a common finding among immigrants, especially those of sub-Saharan origin. In this population, the main cause of eosinophilia is parasitic infection, specifically by helminths . There nA side effect of the inflammatory mediators released by eosinophils is lesions in host organs, with cardiac involvement being especially characteristic ,5. InjurTherefore, the objectives of this study were to i) evaluate cardiac involvement in asymptomatic sub-Saharan immigrants with eosinophilia; ii) relate the presence of lesions with the degree of eosinophilia; and iii) study the relationship between cardiac involvement and the type of causative parasite.This study was approved by the Ethics Committee of the Complejo Hospitalario Insular-Materno Infantil . Written informed consent was obtained from the participants in their local languages. The reasons for the collection and storage of blood samples and echocardiography were clearly described in the consent form.In total, 52 black immigrants from sub-Saharan Africa, namely West Africa, were included in the study. Their mean age was 25 years and the male/female ratio was 47/5. Two patients were excluded, owing to rheumatic mitral valve disease in one case and mitral valve prolapse associated with mild mitral valve insufficiency in the other. Therefore, the final study group consisted of 37 patients and 13 controls.The subjects, who met following inclusion criteria, were recruited consecutively during external consultations at the Unit of Infectious Diseases and Tropical Medicine: i) absence of clinical manifestations of heart disease, ii) presence of absolute eosinophilia (>450/μL), and iii) explicit consent to participate in the study. Eosinophilia was classified as mild (450–999/μL), moderate , or severe .The control group consisted of asymptomatic subjects from the same geographic region in whom the presence of eosinophilia and/or parasitosis were ruled out by means of the indicated tests, who provided consent to participate in the study. All parasitological studies  were performed in the same specialized laboratory using the investigation strategy suggested by Whetham for African patients, with some modifications .Strongyloides stercoralis (Baermann concentration test and agar culture method) [Wuchereria bancrofti antigens, with skin snips and the Mazzotti test used in selected cases.The direct parasitological tests used in this study were i) three examinations of stool samples for ova and parasites using the Kato-Katz and Ritchie techniques and specific tests for  method) , ii) micDirofilaria immitis worm (AWA Di) [Schistosoma bovis adult worm antigens (AWA Sb) [F. hepatica excretory/secretory antigens (E/S Fh) [Trichinella spiralis L1 worm antigens (L1 Ts) [(ortho-phenylenediamine plus H2O2) was added and the reaction was stopped with 3N H2SO4. The individual conditions of the assays and the sensitivity and specificity of the tests are described in our previous publication [The serological assays were performed using enzyme-linked immunosorbent assay (ELISA). Crude extracts of adult (AWA Di) , Schisto(AWA Sb) , F. hepa(E/S Fh) , and Tri L1 Ts)  were use Ts  wereIn order to assess the degree and type of cardiac involvement in the study and control group subjects, two-dimensional, M-mode, and Doppler evaluations were performed using the same echocardiographic equipment . The tracings were recorded for playback later on and blinded analysis by a single investigator.2+10 (in mm Hg) (where V represents the maximum velocity).The following determinations were made for each patient: i) The dimensions of the left and right ventricular chambers and the left atrium were measured using the M-mode technique in the parasternal long and short axis planes. ii) The morphological characteristics of the heart were analyzed using two-dimensional echocardiography (2D echo), with optimization of the image by adjusting the frequency and parameters of gain, compression, and image processing. Standard parasternal long and short axes as well as four- and two-chamber apical and subcostal planes were used. A high-resolution zoom magnification system was applied to specific areas, including the ventricular apical zones and valvular planes, for better visualization and quantification of possible alterations. iii) The left ventricular ejection fraction was analyzed using 2D echo, using the Simpson biplane technique. iv) The functional parameters of ventricular filling were analyzed using pulsed-wave Doppler ultrasound of transmitral and transtricuspid flow during mid-expiratory apnea, with calculation of the initial peak velocities (E in cm/s), slope deceleration (TD in milliseconds), speed atrial contraction (A in cm/s), and E/A ratio. If possible, the pulmonary venous flow  with calculation of the peak systolic (S in cm/s) and diastolic (D in cm/s) velocities and S/D ratio, and peak velocity (cm/s) and duration (in milliseconds) of the retrograde atrial wave (Ar) were measured. In all cases, measurements of a minimum of four consecutive heartbeats were analyzed. v) The presence of valve regurgitation was evaluated using color-coded Doppler ultrasound in the parasternal planes, long and short axes, and apical four and two chambers. vi) In cases with tricuspid insufficiency, the pulmonary systolic pressure was calculated using the Bernoulli equation: 4VThe findings were classified into two groups according to the following descriptions from the literature on cardiac involvement in the presence of eosinophilia ,18:Classic findings: Endocardial thickening, described as thickening of the wall, with refringent and additional echogenic layers in the endocardial zone; thrombus in the left ventricle, characterized by an echodense mass at the left cardiac apex, causing obliteration or limitation of the blood flow during filling; apical thrombus in the right ventricle, with the same characteristics as on the left side; affectation (thickening) of the mitral valve leaflets, especially the posterior leaflet, determined by thickness values greater than 3 mm; and tricuspid insufficiency, defined as the detection of signals of tricuspid valve insufficiency on color-coded Doppler with a semiquantitative assessment of its severityi) Non-classic findings: Left ventricular hypertrophy, defined according to the criteria described by Casale et al. [ii) e et al.  using meSerum EDN levels were measured by sandwich ELISA using a commercial kit  following the manufacturer instructions. The limit of detection of the technique is 0.62 ng/mL . The norQualitative variables were expressed as frequency distributions. Quantitative variables with normal distributions were expressed as the mean and standard deviation (SD). The associations between qualitative variables were analyzed using the chi-square or Fisher’s exact test, as appropriate. Normally distributed variables were compared using the Student’s t-test. Data distribution as compared with theoretical models was verified, and the assumption of the homogeneity of variance was tested in all cases. Analyses were performed using GraphPad InStat. Differences were considered significant if p values were less than 0.05.In the study group, the degree of eosinophilia was mild in 26 (70%), moderate in seven (22%), and severe in four (8%) patients. The etiological diagnosis was filariasis in 13 cases, schistosomiasis in eight cases, coexistence of filariasis and schistosomiasis in four cases, a geohelmintic disease in seven cases, and indeterminable in five people. The relationship between the degree of eosinophilia and the causal diagnosis is shown in All the subjects had an adequate echocardiographic image and were in sinus rhythm, with an average heart rate of 69 beats/minute (SD: 11). All subjects had normal blood pressure, with a mean value of 125/75 mm Hg. Tables The serum concentration of EDN was determined in 29 patients with eosinophilia, 28 of whom had high values (>66.6 ng/mL). However, there were no significant differences (p = 0.46) in the serum concentration of this protein between patients with valve involvement  and those without it . On the other hand, there was no statistically significant association between the number of eosinophils and serum levels of EDN (p = 0.18).Further, there was no statistical association between the degree of eosinophilia and the presence of valve involvement, or between the type of helminth responsible for eosinophilia and valve involvement, as shown in Endomyocardial fibrosis (EMF) is a syndrome characterized by fibrosis of the apical endocardium of the right ventricle, left ventricle, or both. The clinical manifestations are mainly related to the restriction of ventricular filling, which may trigger cardiac failure.Epidemiological studies of EMF indicate a predominance in tropical regions (15° around the equator), with young people  and men being affected predominantly. In this sense, our series is similar to that of patients with EMF in terms of age and sex, although our series included a greater number of people from West Africa. In some series, EMF data were available for up to 19.8% of the population studied by echocardiography, and only 22.7% of these had symptoms [The pathogenesis of EMF is not fully understood, although several types of factors have been identified. One of the most important factors is the presence of eosinophilia related to helminth infections or other causes  –25. The Therefore, the first objective of our study was to compare the echocardiographic findings of asymptomatic sub-Saharan immigrants from West Africa with eosinophilia with a group of controls from the same region and of equivalent age. Our results indicate that there is a significant association between the presence of eosinophilia and structural alterations, in the absence of evident clinical manifestations. Thus, mitral valve thickening suggests early involvement, independent of the racial characteristics and other factors controlled for in the study . There were significant differences in the structure of the leaflets of the mitral valve, with a significantly greater thickness in cases with eosinophilia. These data may have clinical relevance since the predominant involvement of the mitral valve in patients with EMF and eosinophilia has been demonstrated in other studies as well –33. On tAlthough eosinophilia plays an important role in the pathogenesis of EMF, there is no direct relationship between the two. Thus, in our series, we observed on the one hand that a significant percentage of patients with eosinophilia did not present any data suggesting cardiac involvement; on the other hand, there was no association between the degree of eosinophilia and cardiac valve involvement. One possible explanation for these findings is that not only is an increase in eosinophils required for the development of EMF but that these are also activated and release inflammatory mediators . HoweverTrichinella spp. infection [Toxocara spp. infection [Filarias is the most frequently described association [Schistosoma spp. infection, which is rarely indicated in the literature [In our series, the cause of eosinophilia was identified by direct or indirect techniques in 86% of cases. In all cases, it was a helminthic disease, mainly filariasis, schistosomiasis, or both. Cardiac involvement in helminths has three main patterns: i) myocarditis due to direct or indirect myocardial involvement in nfection ; ii) acunfection ,38, and ociation –41. Howeterature –44.These data suggest that eosinophilia related to helminth infection (regardless of the causative microorganism) contributes to the asymptomatic phases of endomyocardial lesions. The treatment of these infections is simple, effective, and cheap. Therefore, we suggest that an etiological study and causal treatment, as well as transthoracic echocardiography, be performed in all immigrant patients with eosinophilia in order to rule out early lesions.


These linear correlations remained significant even after stratificaion of the study subjects by age (<65 years vs ≥65 years) and genders (P < 0.05 for each). There were obvious differences in baPWV according to groups with normal LV diastolic function, intermediate profile and LV diastolic dysfunction in young (P = 0.010) and elderly (≥65 years) women (P < 0.001) and eldery men (P = 0.012) but not in elderly men (P = 0.270). There was a significant association of baPWV with septal e′ velocity  and E/e′  in elderly women even after controlling for multiple clinical covariates. This independent association was not seen in younger women and men (P > 0.05 for each). In conclusion, baPWV was independently associated with septal e′ velocity and E/e′ in elderly women but not in younger women or men. The results of this study provide additional evidence that increased arterial stiffness plays an important role in the development of heart failure with preserved ejection fraction as well as LV diastolic dysfunction in elderly women.Left ventricular (LV) diastolic dysfunction and subsequent overt heart failure are more prevalent in elderly women. Close interaction between arterial stiffness and LV morphology/function has been reported. The aim of this study was to investigate whether there is an age- and gender-dependent relationship between arterial stiffness and LV diastolic function. A total of 819 subjects  without structural heart disease (LV ejection fraction ≥50%) were retrospectively analyzed. All participants underwent transthoracic echocardiography and brachial-ankle pulse wave velocity (baPWV) measurement on the same day. The association of baPWV with septal e′ velocity and average E/e′ was assessed. In the total study subjects, baPWV was negatively correlated with septal e′ velocity ( Body of evidence from recent studies has shown the imporant role of arterial stiffness on left ventricular (LV) diastolic function.–10 Increased arterial stiffness may promote LV hypertrophy and reduce coronary perfusion, which seem to be related to LV diastolic dysfunction and heart failure with preserved ejection fraction (HFpEF).,11 Although it has been demonstrated that HFpEF is more prevalent in elederly women,,13 its underlying pathophysiology has not yet been fully understood. Recent studies have suggested that increased arterial stiffness is an important contributor to the development of heart failure.,14 It has been demonstrated that hemodynamics of the arterial system is different according to gender and age: greater arterial stiffness and higher vascular loading have been described in elderly woman, compared to young women and age-matched men.,17 However, age- and gender-related differences in the association between arterial stiffness and LV diastolic function are still conflicting. Additionaly, comprehensive analysis of the interplay between age and gender on this issue has been scarce. Therefore, this study was performed to investigate age and gender related differences in the association between LV diastolic function and arterial stiffness. Our hypothesis was that the association between arterial stiffness and LV diastolic funcion could be more pronounced in elderly women than in young women or men.Arterial stiffens with aging and arteriosclerosis of arterial walls.22.1 The Institutional Review Board of Boramae Medical Center  approved this study protocol. Informed consent was waived due to the routine nature of information collected and retrospective study design.This single center study was performed at Boramae Medical Center . We retrospectively reviewed a total of 925 subjects without overt cardiovascular disease undergoing brachial-ankle PWV (baPWV) measurement and transthoracic echocardiography (TTE) as their routine check-up between August 2013 and July 2014. In this study, baPWV measurement and TTE were perfomred on the same day. We excluded subejcts with the following conditions: history of coronary artery disease  (n = 35), nonsinus rhythm (n = 21), low ankle-brachial index (<0.9) (n = 12), low left eventricular systolic function (LV ejection fraction [EF] < 50%) (n = 12), regional wall motion abnoriality (n = 10), valvular stenosis or regurgitation more than mild degree (n = 9), and pericardial effusion (n = 7). Finally, 819 subjects were analyzed in this study. All study subjects were in medically stable conditions at the time of health check-up. Height and weight were measured, and body mass index (BMI) was calculated as a subject's weight in kilogram divided by the square of hieght in meters. Systolic and diastolic blood pressures and heart rate were measured on the right upper arm by a trained nurse using an oscillometric device. Information on underlying medical illness including hypertension, diabetes melliuts, and dyslipidemia was obtained by using a standarized questionnaire, and maintainance medications or laboraory test results were indentified. Hypertension was defined as history of hypertension, antihypertensive medications, or repeated measurements of systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg. Diabetes mellitus was defined as history of diabetes mellitus, antidiabetic medications, or fasting glucose ≥126 mg/dL at 2 or more measurements. Dyslipidemia was defined as history of dyslipidemia, lipid-lowering medication, or a pretesttotal cholesterol of ≥200 mg/dL or a low-density lipoprotein (LDL) cholesterol of ≥160 mg/dL. Information on smoking habits was also obtained, and subjects who smoked regularly during the previous 12 months were classified as smokers. All subjects underwent laboratory tests by sampling venous blood in the morning after overnight fasting. White blood cell count (WBC), hemoglobin, concentration and serum levels of fasting glucose, total cholesterol, LDL cholesterol, high-density lipoprotein (HDL) cholesterol, triglyceride, creatinine, and C-reactive protein were measured by an automated enzymatic procedure. Estimated glomerular filtration rate (eGFR) was calculated using the 4-component MDRD  equation incorporating age, race, sex, and serum creatinine level.2.2 Briefly, arterial pulse wave was measured on patients’ bilateral upper  and lower  extremities with gentle pressure using applanation tonometry, which simultaneously recorded blood pressures, electrocardiograms, and heart sounds in accordance with the manufacturer's recommendations. The baPWV values were calculated as distance between the brachial and posteriortibial arteries divided by time interval (velocity = distance/time) (cm/s). The distance between the brachialis and posterior tibial arteries was estimated on the basis of the height of the subject, and time interval between them was calculated by the time difference between waves in front of them. The average value between the left and right baPWV measurements was chosen for all analyses. All measurements were made by the same experienced operator blinded to all clinical data. The intraobserver coefficient of variation for baPWV was 5.1% in our laboratory.In this study, baPWV measurements were performed between 9:00 and 11:00 in the morning. Subjects were studied in the supine position after approximately 5 minutes of rest in an atemperature-controlled and quiet environment. Patients were allowed to take their regular medications, but, smoking, alcohol drinking, and caffein consumption were prohibited on the day of examination. The baPWV values were measured noninvasively using an automated waveformanalyzer .2.33 − LVIDd3]} + 0.6 g, and indexed for body surface area (= LV mass index [LVMI]). Simpson biplane method was employed in the calculation of LVEF. Early peak transmitral filling velocities during early diastole (E) was imaged at the tip of the mitral leaflets from the apical 4-chamber view. Color-coded tissue Doppler imaging (TDI) was applied to the apical 4-chamber view to determine peak early (e′) velocities at both septal and lateral annuli. The average value of septal and lateral e′ velocities was used for E/e′, which was calculated to estimate LV filling pressure. Peak velocity through tricuspid regurgitation was obtained in modified 4-chamber view. The left atrial volume (LAV) was calculated using the biplane method and indexed to the body surface area . Recent guidelines emphasize the important of role of septal e′ velocity and average E/e′ in assessing LV diastolic function in subjects with normal LVEF. Our study focused on these 2 TDI-derived diastolic indices. According to the guideline's recommendations, we considered LV diastolic function normal if none or one available parameter met cut-off values . LV diastolic dysfunction was considered intermediate in cases meeting 2 cut-off values. If more than 2 parameters met cut-off values, a diagnosis of LV diastolic dysfunction was made. The interobserver coefficients of variation for e′ and E/e′ were 6.8% and 7.0%, respectively, in our laboratory.TTE was performed by experienced cardiologists or cardiosonographers using a 2.5-MHz probe with commercially available ultrasound systems  according to the standardized protocol. M-mode images from the parasternal short-axis view were obtained to measure LV internal dimension during systole (LVIDs) and diastole (LVIDd), LV septal wall thickness during diastole (SWTd), and LV posterior wall thickness during diastole (PWTd). LV mass was calculated using the following formula: LV mass = 0.8 × {1.04 × [(LVIDd + PWTd + SWTd)2.4t test, and categorical variables were compared using the Chi-square test between the 2 groups. Pearson bivariate correlation analyses were used to investigate a linear association between baPWV and diastolic indices, and the linear correlations were demonstrated using scatter plots. Analysis of variance (ANOVA) was used in comparisons of mean baPWV values according to the LV diastolic function status . Multiple linear regression analyses were performed to investigate the independent association between baPWV and diastolic indices. Age, BMI, systolic blood pressure, heart rate, fasting glucose, total cholesterol, and eGFR were considered potential confounders and adjusted in multivariable models. A P-value of <0.05 was considered significant. All analyses were performed using SPSS 18.0 statistical package .Continuous variables are expressed as mean ± standard deviation, whereas categorical variables are presented as absolute values and their proportions. Continuous variables were compared using Student 33.1The clinical characteristics of the study subjects accroding to age (<65 years vs ≥65 years) and gender are shown in Table 3.2r = −0.266, P < 0.001), and positively correlated with E/e′   (Table P = 0.010) and elderly women (ANOVA P < 0.001) and eldery men (ANOVA P = 0.012) but not in elderly men (ANOVA P = 0.270)  and E/e′  even after controlling for multiple clinical corvariates. However, no statistical significance was observed in young women and men in the same multivariable analyses (P > 0.05 in for each model)  also showed significant correlations of cfPWV and central pulse pressure with lateral e′ velocity and E/e′. Borlaug et al performed noninvasive measurement using applanation tonometry in 58 participants, and showed that carotid augementation index and carotid characteristic impedence have an independent association with LV septal e′ velocity. Similarly, our results showed that arterial stiffness measured by baPWV was signficantly correlated with septal e′ velocity and E/e′ in univariate anslyses. When we performed multivariable analyses on the total subjects without stratification according to age and gender, there was an independent associaion between arterial stiffness and LV diastolic indicies (data not shown).Several prior studies have adressed the association between LV diastolic function and arterial stiffness in normal subjects. Cauwenberghs et al,11 All these fasctors are main contributors to LV diastolic impairment. A pararell increse in arterial stiffness and LV diastolic dysfunction is also a possible mechanism due to shared risk factors and common pathophysiology of the 2 conditions. Indeed, it has been suggested that patients with greater arterial stiffness are more likely to have increased LV stiffness,,25 and that these concurrent increases in ventricular and arterial stiffness with aging have been implicated in the pathogenesis of heart failure. The causal relationship between increased arterial stiffness and LV diastolic dysfunction was not observed in our cross-sectional analysis, which remains to be elucidated with further longitudinal studies.The exact pathophysiology underlying the association between LV diastolic function and arterial stiffness has not yet been completely elucidated. However, it has generally been accepted that increased arteiral stiffness influences the development of LV diastolic dysfunction, but not vice versa. Increased afterload by a stiff artery causes LV hypetrophy and a decrease in diastolic pressure associated with reduced coronary flow. found, in a study of 336 patients undergoing coronary angiography, that e′ velocity and LV filling pressure are significantly correlated with augmentation index and PWV, and that these correlations were independent of age and gender. Abhayaratna et al showed, in a study of 233 elderly subjects with normal LVEF, that brachial pulse pressure, central pulse pressure, and PWV progressively increase according to the severity of diastolic dysfunction in both men and women. Russo et al investigated 983 community subjets to assess gender difference, and showed that the stength of the association between arterial stiffness and LV diastolic function is similar betwen men and women even though higher arterial stiffness and more impaired LV diastolic function are observed in women. On the other hand, Shim et al showed, in a study of 158 age-matched subjects without structural heart disease, that LV diastolic function correlated significantly with the parameters representing arterial stiffness in women but not men. Similarly, Redfield et al investigated 2042 participants from the community, and showed tha advanced age and female gender are associated with increased arterial and LV diastolic stiffness. Our results support their studies demonstrating a pronounced association between baPWV and diastolic indices in eldelry women. Different study populations and measurements with different sensitivities for vascular stiffening might be, in part, responsible for different findings among studies.Gender-related differences in the association between arterial stiffness and LV diastolic dysfunction have been reported; however, results are still debatable. Weber et al and E/e′ has proved to be a useful surrogate measure of LV filling pressure compared to other diastolic indices. Recent guidelines also emphasize the importance and usefullness of these parameters for evaluating LV diastolic function, and recommend initial use of these parameters in the assessment of LV diastolic function especially in subjects with normal LVEF.There are many echocardiographic parameters used to assess LV diastolic function. Among them, TDI-derived parameters have deserved attention. During diastole, e′ velocity is closely related with LV relaxation, baPWV can be a useful target for the treatment of HFpEF as well as a tool to monitor patients with HFpEF.Our results may highlight the potential contribution of increased pulsatile load and LV-arterial coupling to LV diastolic dysfunciton in elderly women. Given that LV diastolic dysfunction is a main determinant of HFpEF, it can also be postulated that increased arterial stiffness is an important risk factor developing HFpEF in elderly women. In addition, arterial stiffness may be a good monitoring tool to assess LV diastolic dysfunction. More importantly, improving arterial stiffness may be a good therapeutic target for delays in the progression of LV diastolic dysfunction or for the prevention of overt clinical heart failure syndrome, espeically in elderly women. Furthermore, from a practical view point, considering that baPWV is a simple and reliable measure of arterial stiffness,Our study results should be interpreted in the context of its potential limitations. First, the cross-sectional study design could not confer the causal relationship between LV diastolic function and arterial stiffness, and how gender modifies the relationship was not elucidated. Further longitudinal studies and mechnism analyses are warranted. Secondly, the impact of medications on the association between arterial stiffness and LV diastolic function was not assessed. Thirdly, the indices of arterial stiffness and LV diastolic function were all noninvasive measures. Invasive parameters, more reliable indicators, may have been valuable in our study. Finally, our study population consisted of Korean adults without documented cardiovascular disese with normal LVEF: thus, direct application of our results to other groups of people may be diffucult.In the present study, baPWV was independently associated with septal e′ velocity and E/e′ in elderly women with normal LVEF but not in young women or men. Our results provide additional evidence that increased arterial stiffness plays an important role in the development of HFpEF as well as LV diastolic dysfunction in elderly women. Further studies are needed to confirm our findings.


Feature tracking in cine cardiac magnetic resonance (CMR) is a quantitative technique to assess heart structure and function. We investigated 4-dimensional (4D) dynamics and morphology of the mitral annulus (MA) using a novel tracking system based on radially rotational long-axis cine CMR series. A total of 30 normal controls and patients with mitral regurgitation were enrolled. The spatiotemporal changes of the MA were characterized by an in-house developed program. Dynamic and morphological parameters extracted from all 18 radial slices were used as references and were compared with those from subsequently generated sub-datasets with different degrees of sparsity. An excellent agreement was found among all datasets including routine 2-, 3- and 4-chamber views for MA dynamics such as peak systolic velocity (Sm) and mitral annular plane systolic excursion (MAPSE). MA morphology for size and shape was addressed adequately by as few as 6 radial slices, but poorly by only three routine views. Patients with regurgitation showed significantly reduced mitral dynamics and mild annular deformation, which was consistent between three routine views and 18 reference slices. In conclusion, feature tracking cine CMR provided a comprehensive and distinctive profile for 4D MA dynamics and morphology, which may help in studying different cardiac diseases. Hence, reliable quantification of MA deformation throughout the cardiac cycle is highly important. Tissue Doppler imaging (TDI), an echocardiographic technique based on the Doppler principle, has been widely adopted to measure the velocity of myocardial motion in clinical practice. A number of TDI-derived parameters, including peak velocity during systole (Sm), early diastole (Em), and late diastole (Am) have been shown to be potentially important prognosticators for various cardiovascular diseases2. In common with other Doppler modes, however, TDI is limited by angle dependency3 and influenced by translational motion and tethering4. Cardiac magnetic resonance (CMR) offers superior soft-tissue contrast and spatial resolution compared to echocardiography, potentially allowing improved quantification of MA deformation5. Most of the prior CMR studies were based on three routinely acquired long-axis cine imaging slices for MA motion tracking, with only six points for reconstruction of the 3-dimensional (3D) MA geometry6. Whether this is sufficient to constitute a good representation has hitherto not been studied. The obligatory minimum number of points or slices for satisfactory depiction of MA dynamics and morphology is not known.Atrioventricular valves separate the atria and ventricles. The mitral annulus (MA) forms the perimeter of the left-sided atrioventricular valves. Its dynamic characteristics mirror left ventricular (LV) contraction, relaxation and filling, providing a window into structural and functional information for assessing LV systolic and diastolic functionThe primary aims of this paper were: (1) to quantify the 4-dimensional (4D) dynamic and morphological characteristics of the MA using feature tracking in a series of equally spaced radially rotational long-axis cine CMR, based on which a reference set of clinically relevant parameters including peak systolic and diastolic velocities, displacement, 3D area, perimeter, diameter and height can be derived; (2) to systematically investigate the impact of different numbers of imaging slices on quantification accuracy by comparing results from sub-datasets with less equally spaced radial slices to the reference dataset; and (3) to study the difference in MA dynamics and morphology between normal controls and patients with mitral regurgitation.A total of 30 human subjects including 16 normal controls (mean age 54 ± 13 years) free from any objective evidence of cardiovascular or other diseases and 14 patients with mitral regurgitation (50 ± 18 years) were consecutively enrolled in this prospective study. The demographics and clinical characteristics of these two age- and gender-matched groups are given in Table A total of 18 long-axis slices were obtained from cine CMR covering the mitral valve orifice with 10° angular equidistance in a radially rotational manner Fig. . FeatureIn addition to the results obtained based on all 18 radial slices as reference, the same quantitative parameters were also generated from multiple sub-datasets with different degrees of sparsity consisting of less equally spaced radial slices. These included 9 slices (every other slice), 6 slices (every third slice), and 3 slices  for all subjects, to investigate the influence from the numbers of imaging slices. The average angular separations were about 67°, 52°, and 61° between 2- and 3-chamber views, between 3- and 4-chamber views, and between 4- and 2-chamber views, respectively, to best approximate the clinically conventional views.By tracking the MA motion trajectory in the spatiotemporal dimension along the annular region for all cardiac phases, four dynamic parameters were obtained. These included peak systolic velocity (Sm), peak early diastolic velocity (Em), peak late diastolic velocity during atrial contraction (Am) and mitral annular plane systolic excursion (MAPSE). They corresponded to the maximal peaks in the velocity curves throughout the cardiac cycle and the maximal values in the displacement curves, respectively Fig. .Figure 2r = 0.987, 0.994, 0.991, 0.994 for Sm, Em, Am and MAPSE, respectively, all p < 0.0001, Fig. Temporal MA dynamics agreed very well throughout the cardiac cycle for all sub-datasets, including the local maxima for Sm, Em, Am, and MAPSE Fig. . In partThe geometry of a nonplanar, saddle-shaped MA was reconstructed based on feature tracking and spatial transformation of the imaging coordinates. A typical example is shown in Fig. r = 0.985, 0.958, 0.955, 0.968, 0.814 for 3D area, perimeter, AP diameter, IC diameter and height, respectively, all p < 0.0001) and small limits of agreement. However, unlike dynamics, the MA morphology derived from three clinical routine long-axis views exhibited poorer correlation with larger deviation compared to those from the 18 reference slices. A complete comparison can be found in Supplementary Table Significant agreement was found among MA morphological measurements from 18, 9 and 6 radial slices, as shown in the 45° line scatter and Bland Altman plots , Em , Am , and MAPSE . Data from three clinical routine slices, i.e. 2-, 3-, and 4-chamber views, showed the same results, in agreement to the reference. Meanwhile, 3 out of 6 morphological parameters increased significantly in patients, which included 3D area at ED , perimeter at ED  and with temporal averaging , as well as the ratio of AP to IC diameter at ED . The patient group had also increased MA perimeter at ES  and AP diameter at ED  although the difference did not reach statistical significance. Similar results were also observed with 6 radial slices.A comprehensive comparison of MA dynamics and morphology between normal controls and patients is presented in Tables All CMR feature tracking-derived parameters had excellent intra- and inter-observer reproducibility Table , with hiThis is the first work to demonstrate the feasibility, reproducibility, and systematic investigation of using a feature tracking system for imaging and modeling 4D MA deformation in combination of a series of radially rotational long-axis cine CMR data with varying numbers of slices. MA dynamics and morphology were measured and extensively studied in both normal controls and patients with mitral regurgitation.In Figs 7. Previous attempts to assess the MA dynamics and geometry include using 2D or 3D echocardiography and computed tomography (CT)13. These approaches suffer from either limited spatial resolution and coverage15 or ionizing radiation9. With CMR evolving into a versatile, non-invasive imaging tool with excellent contrast resolution for tissue characterization, its use in automatically tracking MA motion in consecutive time frames and quantifying both dynamic and morphological changes has recently become a core component in advanced cardiac function analysis17. However, most of the prior studies are based on three routinely obtained long-axis cine data for MA motion tracking, and only six points for reconstructing the 3D MA6. Whether this is sufficient to constitute the ground truth has not been fully investigated. In addition, the obligatory minimal number of points for satisfactory depiction of MA dynamics and morphology had hitherto not been ascertained.MA motion serves as an important clinical indicator of regional as well as global LV function18. In the current application, the features within the template containing the insertion area of the mitral valve leaflets were rendered with sufficient precision to support feature matching. The majority of templates in the CMR images did not undergo highly complex deformation between adjacent time frames, granting NCC as an appropriate approach with high computational efficiency to match the template within a search region. The developed program provides a semi-automatic approach for fast localization of the MA points in each cardiac CMR slice throughout the cycle with mask selection in the initial frame as the only user input. Thereafter, the algorithm automatically executes the adaptive feature tracking for all the subsequent frames. In less than 0.3% of the total frames (120 out of 43200) in this study the target feature was not correctly tracked automatically due to temporal blurring, which necessitated manual correction. The positions of the tracked points were visually judged by expert cardiologists.Our method involves a feature tracking algorithm with normalized cross correlation (NCC) as the similarity measureThe impacts of different mask sizes and positions were tested in a small cohort. No significant differences were found regarding the mask sizes . For instance, a 4-slice variation with 8 equally distributed points would not have been possible, which had been shown to be effective enough for characterization of the MA dynamics and geometry in an animal studySecond, the fact that the conventional 2-, 3-, and 4-chamber views from clinical scans are prescribed not based on a simple angulation but rather on specific landmarks may be different from the setup in the present study. They may share a common point at the apex, but anatomical variations imply that they may not necessarily be co-axial or share another common point. Therefore, an additional analysis has been performed to investigate the MA dynamic measurements using the clinically conventional 2-, 3-, and 4-chamber views. As can be seen in Supplementary Table Third, the number of cardiac phases above 30 is typically used in 2D CMR cine for functional assessment. A lower number may not be sufficient to resolve cardiac motions, particularly at rapid systole. It is, therefore, reasonable to employ CMR feature tracking based on the standard acquisition technique, such as 40 phases per cardiac cycle that was used in the present study. An additional analysis performed based on 20 cardiac phases (downsampled from 40 phases) showed lower MA velocity and displacement (negative bias) than those based on 40 phases  represents a potentially researchable and laudable goal in the future for evaluation of right ventricular (RV) function, as assessment by conventional 2D echocardiography remains limited due to its asymmetric, pyramidal shapeNormal controls without known cardiovascular disease or other major co-morbidities, and patients with known mitral regurgitation were prospectively enrolled from two centres. The severity of mitral regurgitation was evaluated following 2003 AHA guideline using Doppler echocardiography. Patients with vena contracta width ≥0.7 cm, large central mitral regurgitation jet , and enlarged left ventricle were diagnosed as severe mitral regurgitation. Those with vena contracta width <0.3 cm, small central jet , normal left ventricular size were interpreted as mild mitral regurgitation. Meanwhile, patients with mitral regurgitation jet area in between 20–40% of left atrial area were categorized as having moderate mitral regurgitation. All subjects underwent a CMR scan. The protocol was approved by the SingHealth Centralised Institutional Review Board and the institutional review board of Shanghai Renji Hospital. Informed consent was obtained from all participants. All experiments and methods for this study were performed in accordance with relevant guidelines and regulations.32. Typical imaging parameters were as follows: FOV 300 × 300 mm2, slice thickness 8 mm, matrix size 200 × 147, acquired pixel size 1.5 × 2.0 × 8.0 mm3, interpolated to 1.04 × 1.04 × 8.00 mm3, repetition time TR 3.0 ms, echo time TE 1.5 ms, water-fat shift 0.3 pixel, 40 cardiac phases, retrospective ECG gating, partial Fourier factor 0.875, SENSE factor 2, scan time for breathhold approximately 7 seconds.All subjects were imaged on a 3.0 T scanner  with a maximal 28-channel body  coil, using a standard CMR protocol including multi-slice multi-direction survey images, followed by balanced fast field echo (bFFE) cine sequences in 5 short-axis slices parallel to the mitral valve ring covering the left ventricle from base to apex. Based on those, a series of 18 radially rotational slices were acquired at 10° angular equidistance in the LV long axis, extending from the apex to the centre of the mitral valve orifice  while computing the normalized cross correlation (NCC) at each location. Given a w × h mask t and the search region x, the matching by correlation is conducted by computing the NCC at the location x and t, respectively. The point with the highest correlation coefficient in the resulting correlation image  within a larger image . Figure age Fig.  indicateage Fig. . This sa33, which is ready for clinical usage. In this software tool, we used the Insight Segmentation and Registration Toolkit (ITK) for image processing part of the MA tracking, the Visualization Toolkit (VTK) for interaction and visualization of the processed images, and Qt for graphical user interface.The tracking method in this study was enhanced with some latest development of an integrated software tool35. The whole process is shown in Fig. The MA located at the junction of the left atrium and ventricle was tracked for all 18 radially rotational long-axis slices and subsequently reconstructed in 3D over the entire cardiac cycle. This was performed semi-automatically using an in-house developed program at National Heart Centre SingaporeTo characterize MA dynamics, two annular points in each of the 18 acquired radial slices were tracked as a function of cardiac time. As described above, MA tracking was semi-automatic with mask selection in the initial frame of each radial slices as the only user input. Figure Sm: peak systolic velocityEm: peak early diastolic velocityAm: peak late diastolic velocity during atrial contractionMAPSE: mitral annular plane systolic excursionFollowing the MA tracking in all 18 radial slices Fig. , four cl36. The following spatiotemporal morphological measurements were calculated based on MA reconstruction for all successive frames throughout the cardiac cycle  diameter: distance between mid-points of the anterior and posterior walls.Inter-commissural (IC) diameter: distance between mid-points of the anterolateral and posteromedial walls.Ratio of AP to IC diameters.The 2D coordinates of MA motion trajectories obtained in each of the 18 CMR slices were transformed into a 3D coordinate system. A spline curve interpolation was performed to reconstruct the 3D MA geometry, using a fully automated smoothing procedure based on a penalized least squares methodcle Fig. :3D areaTo investigate inter-observer reproducibility, two observers performed independent analyses in a total of 10 cases  for all MA parameters. In addition, one observer repeated the measurements of the same data in one week to assess the intra-observer reproducibility.r correlation, the Bland Altman graphical approach and intra-class correlation coefficient (ICC). All data analyses were performed using SAS  and SPSS . A P-value of <0.05 was considered statistically significant.Data were summarized in mean ± SD. Comparisons of demographics and quantitative measures between the normal and patient groups were done using the Mann-Whitney U test. Agreement was assessed using Pearson’s P-values for multiple testing. The family-wise error rate is the probability that one or more null hypothesis among a ‘family’ of k hypotheses is falsely rejected. Rather than reporting adjusted P-values, we propose that the reader adjust the significance level at which a given hypothesis test in the ‘family’ of hypothesis tests is rejected. Multiple approaches exist with the Bonferroni and the Bonferroni-Holm being the most familiar. Both are applicable to independent and dependent tests and are straightforward in their application when control of a ‘family-wise’ error rate is desired. The Bonferroni adjusted significance level is simply obtained by dividing the nominal alpha by the number of tests in the ‘family’. The Bonferroni-Holm is a step-wise procedure with greater power for rejecting false null hypotheses. Given these straightforward approaches for adjusting significance levels for multiple comparisons (as well as other more sophisticated methods), and in large measure owing to the certainty of disagreement among readers as to what constitutes a ‘family’, we have opted to report uncorrected P-values.We have not adjusted All data generated or analyzed during this study are included in this published article (and its Supplementary Information files).Supplementary informationSupplementary Video S1 - MA tracking in all slices for a normal controlSupplementary Video S2 - MA tracking in all slices for a patient with regurgitationSupplementary Video S3 - reconstructed MA motion with varying numbers of radial slices