Acoustic cardiography is a hybrid technique that couples heart sounds recording with ECG providing insights into electrical-mechanical activity of the heart in an unsupervised, non-invasive and inexpensive manner. During myocardial ischemia hemodynamic abnormalities appear in the first minutes and we hypothesize a putative diagnostic role of acoustic cardiography for prompt detection of cardiac dysfunction for future patient management improvement.r2 = 0.9583, p < 0.0001), PV diastolic filling time vs. AC perfusion time ]. Indexes of systolic and diastolic impairment correlated with quantifiable features of heart sounds [Tau vs. fourth heart sound Display Value  cardiac output vs. third heart sound Display Value (r2 = 0.0791 p = 0.0023)]. Additionally, acoustic cardiography diastolic time , perfusion time  and third heart sound Display Value  emerged as possible indicators of coronary occlusion. Finally, these three parameters, when joined with heart rate into a composite joint-index, represent the best model in our experience for ischemia detection .Ten female Swiss large white pigs underwent permanent distal coronary occlusion as a model of acute myocardial ischemia. Acoustic cardiography analyses were performed prior, during and after coronary occlusion. Pressure-volume analysis was conducted in parallel as an invasive method of hemodynamic assessment for comparison. Similar systolic and diastolic intervals obtained with the two techniques were significantly correlated [Q to min dP/dt vs. Q to second heart sound (In the rapidly evolving setting of acute myocardial ischemia, acoustic cardiography provided meaningful insights of mechanical dysfunction in a prompt and non-invasive manner. These findings should propel interest in resurrecting this technique for future translational studies as well as reconsidering its reintroduction in the clinical setting. Cardiac auscultation has been a pivotal part of patients’ examination since the stethoscope invention in 1816 by the French physician René Laennec. Despite technical refinements, knowledge advancements and limited costs, auscultation has lost momentum over time in favor of less operator-dependent techniques. In fact, findings obtained from acoustic examination can be affected by operator’s expertise, limited sensitivity of the human ear and lack of reproducibility.Nevertheless, by coupling heart sound recordings together with ECG tracings, investigators can acquire important insights regarding the electrical-mechanical activity of the heart in an unsupervised, non-invasive and inexpensive manner. Such a hybrid technique, acoustic cardiography (AC) , has beeIn the specific setting of acute coronary syndrome, AC might play a role in patient management by detecting cardiac dysfunction  in a proThe animal housing and experimental protocols were approved by the Cantonal Veterinary Department, Zurich, Switzerland, under license no. ZH 219/2016, and were in accordance with Swiss Animal Protection Law. Housing and experimental procedures also conformed to the European Directive 2010/63/EU of the European Parliament and of the Council on the Protection of Animals used for scientific purposes and to the Guide for the Care and Use of Laboratory Animals .2) of 0.5, tidal volume of 6–8 mL/kg, a frequency of 20 breaths per min, and a positive end-expiratory pressure (PEEP) of 5 cm H2O. Anesthesia was maintained with 0.6–1% isoflurane and deepened in accordance with the study protocol with a continuous infusion of propofol (2–5 mg/kg/h) .Ten female Swiss large white pigs (50 ± 2 kg) were included in this study. All animals were pre-medicated with an intramuscular injection of 15 mg/kg BW Ketamine , 2 mg/kg BW Azaperone  and 0.5 mg/kg BW Atropine sulfate 0.1%. All animals were intubated and ventilated with an inspired oxygen fraction , Italy]. Both AC and PV assessment were simultaneously conducted in supine position before, during and after coronary occlusion. Echocardiography was performed with a Philips IE 33 machine  and its 3D-transesophageal probe. All data were stored digitally and evaluated by one person (MZ). After optimal placement of the transesophageal probe in a four chamber view, the probe was not moved throughout the study. Firstly, a 3D dataset for volume and ejection fraction analysis was registered. Secondly, transmitral flow was aquired with Pulsed Wave (PW) Doppler  and tissue velocities of medial mitral anulus with PW-Doppler  after optimization to a most perpendicular view as possible. E/A and E/E’ ratios were obtained by dividing Evmax by Avmax and Eamax, respectively.Acoustic cardiography was performed with AUDICOR  allowing simultaneous dual acquisition of heart sounds and ECG signals. The sensor was placed approximately between V2 and V4 lead location. Raw data were recorded and transferred to Inovise Medical Inc., and subsequently analyzed by the computerized algorithm for the measurement of ECG, heart sounds and systolic and diastolic interval times.The following parameters were conceived and employed for our study. Intensities and persistence of heart sounds S1 , S2 , S3 , and S4 (diastolic sound of stiffness) were recorded and a derivative parameter called Display Value (DV) was generated. The AUDICOR automated heart sound algorithm is a hidden Markov model with inputs derived from a 6-level stationary wavelet transformation of the acoustic signal and from select fiducial times of the simultaneous ECG signal. The output includes a segmentation of the acoustic signal into individual heart sounds, as well as measurements derived from that segmentation. The S3 and S4 DV parameters are a combination of intensity and persistence of the acoustic signal within the segments appropriate in timing for those heart sounds. S3 and S4 DV is expressed on a 0 to 10 scale where if the DV is =5.0 a third or fourth heart sound is considered present. STIs were as follows: the Q-S1 interval is the time from the onset of the Q-wave on the ECG to the mitral valve closure (peak of the first heart sound or S1), also known as electromechanical activation time (EMAT). Left ventricular systolic time (LVST) is defined between (S1) and aortic valve closure (peak “aortic component” of the second heart sound or S2). Electromechanical systolic time (AC EMST) is defined by the time-window between the Q-wave onset and the aortic valve closure (S2). Concerning DTIs, the following parameters were employed: diastolic time (DT) as the time between aortic valve closure (S2) and the next mitral valve closure (S1), perfusion time (PT) as the interval between S2 and the next Q-wave onset.Simultaneous pressure-volume (PV) measurements were performed with a conductance catheter . The conductance method calculates continuous volume tracings by measuring parallel electric conductance between adjacent electrodes. Correct positioning was verified by fluoroscopy and by inspecting segmental signals. Volume calibration was obtained by transoesophageal 3D echocardiography and/or by injection of NaCl hypertonic boluses. Data analysis was performed with dedicated data acquisition and analysis software . Along with real-time pressure, volumes, and a series of normally employed derivative parameters regarding myocardial contractility  additional intervals were conceived for our comparison. STIs were defined as follows: one interval starting from the onset of the Q wave until max dP/dt (Q to max dP/dt) also known as Pre-Ejection Period (PEP), and a longer one lasting until min dP/dt (Q to min dP/dt) (PV EMST). Additionally, the time window between maximal and minimal dP/dt values was also calculated. A DTI called diastolic filling time (DFT) was defined as the interval between dP/dt min and diastole’s end according to the Conduct NT manual.As shown in p-value obtained from paired t-test and Wilcoxon signed rank test were reported in two distinct heatmaps. Significant parameter changes at specific timepoints are indicated with an asterisk symbol in order to increase readability.Heatmaps were generated by comparing a constant baseline timepoint after the animal was fully instrumented and before engaging the coronary arteries with a pre-ischemic timepoint and every minute upon complete balloon inflation for 5 min as reported in In order to identify parameters that could be of diagnostic usefullness in detecting ischemic insult, we employed areas under the receiver operating characteristic (ROC) curve (AUC) for each single AC parameter during our experiment and allocated timepoints into two groups (ischemic and non-ischemic) based on the status of coronary patency. Data obtained prior to coronary engagement were considered as non-ischemic; on the other hand, data gathered after complete coronary occlusion were allocated into the ischemic group. With the intention of identifying a superior parameter in terms of predictive power we tested different models containing various combinations of the four significant single parameters. AUC was assessed for each model and the first three outperforming the single most significant one were reported. For this specific analysis, data obtained within the interval of coronary engagement and occlusion (pre-ischemia) were not employed in order to reduce a heterogenous confounding factor.t-test and Wilcoxon signed rank test, respectively. Areas under the receiver operating characteristic (ROC) curve (AUC) were used to quantify the predictive accuracy of AC parameters for coronary occlusion detection. Using logistic regression, the four most significant AC parameters were modeled for ischemic detection improvement.Continuous variables were intially tested (Shapiro-Wilk) for normal distribution. Data are presented as mean ± standard deviation or median (IQR) when appropriate. Parametric and non-parametric tests for paired comparisons between two datasets included paired p-value < 0.05 was considered significant. Statistical analyses were performed on GraphPad Prism 8  and STATA14 .A two-tailed The data that support the findings of this study are available from the authors.p < 0.001, Left Ventricular End-Systolic Pressure (LVESP) from 73.8 to 64.9 mmHg, p < 0.001, Left Ventricular End-Systolic Volume (LVESV) from 45.6 mL at baseline to 56.6 mL after balloon occlusion, p = 0.005]. Upon experiment termination, venous blood was drawn for Troponin-T assessment in all animals and a median value of 48.5 ng/mL (41.25–211.5) was detected. Taken together these alterations prove the reliability of our working animal model and subsequently of our dataset.During our 5 min study time-window, 3 out of 10 animals suffered from ventricular arrhythmias which required prompt defibrillation and therefore seven pigs completed the protocol. In all three cases, resuscitation maneuvers were successful and subsequent echocardiographic assessment was performed in all ten animals. Recordings were of good quality in the entire cohort. Coronary occlusion was effective in inducing significant morpho-functional alterations consistent with myocardial ischemic damage as shown in r2 = 0.9995, p < 0.0001). As for STIs, an overall positive correlation between parameters was found. For instance, the correlation between Electromechanical activation time (EMAT or QS1) and Q to max dP/dt , nevertheless longer STIs such as left ventricular systolic time (LVST) was better correlated with its PV associated parameter (max to min dP/dt)   (ax dP/dt  was sign 0.0001) . This wa 0.0001) .r2 =0.9689, p < 0.0001)   ( 0.0001)  as well  0.0001) .r2 = 0.0791, p = 0.0023) which was not valid for Audicor S4 DV . As for diastolic function assessment, Tau weakly correlated with Audicor S3 DV , however, a more significant correlation was found with Audicor S4 DV .or S4 DV   (up to −12.1%), stroke work (SW) (up to −22.7%), min dP/dt (up to −18.5%), max dP/dt/end diastolic volume (up to −9.7%), left ventricular end systolic pressure (LVESP) (up to −15.1%), left ventricular end systolic volume (LVESV) (up to +19.0%), pre-recruitable stroke work (PRSW) (up to−23.7%), Q to max dP/dt (up to −10.2%). Of note, SW, min dP/dt and ESP were significantly and constantly decreased compared to baseline reference at every timepoint during the 5 min observation window.On the other hand, AC identified the following parameters as significantly changed in comparison to baseline: diastolic time percentage (DT%) (up to −3.7%), left ventricular systolic time percentage (up to + 6.3%) and first heart sound intensity (up to −20.8%). Single dataset trends over our observation window for AC parameters are presented for clarity in p < 0.001), Diastolic Time , S3 DV , Perfusion Time . With the intention of identifying a more powerful joint-index that could outperform any of the above mentioned single parameters we employed models upon linear regression with different combinations of the four AC parameters shown in p < 0.001), HR + S3DV , HR + PT + S3DV .As anticipated, Cardiac auscultation has known a crescendo-decrescendo use trend in the medical community. Despite acknowledging the usefulness of information obtained by auscultatory examination, other diagnostic methods are usually preferred. Nevertheless the digitalization, in addition to the ECG coupling has propelled new interest in acoustics in light of the minimal invasiveness of such technique. Being already proven as an effective diagnostic and prognostic method, we envisioned a diagnostic role of AC in the setting of myocardial ischemia, a well-known condition characterized by mechanical dysfunction that could be detectable in the first minutes of coronary occlusion. In the past, different investigations have led to divergent results in light of heterogeneous infarct sizes, adrenergic tone, time of infarct onset and adopted methods of detection .In order to overcome a number of these biases, we employed a porcine model of AMI by occluding the coronary artery at similar levels of the coronary tree thus reducing confounding factors in a stable and rapidly evolving condition by dissecting the role of acoustic changes and derivative parameters in AMI.Contractile dysfunction can be detected by abnormalities in force generation, wall shortening, ejected blood volume and temporal relationships of contraction phases .As shown in the heatmaps in As extensively described by Lewis, STIs bear limited diagnostic significance in AMI compared to chronic conditions particularly if no pre-existing comorbidities are present, as in the case of our study . In the With regard to DTIs, our study provides evidence of significant correlations between PV and AC analysis in identifying overlapping intervals. Of note is the significant reduction observed in diastolic time (expressed as percentage within the entire cardiac cycle) upon coronary occlusion even with a non-invasive method, therefore configuring itself as a possible criterion for ischemic damage. Despite being significant for a single timepoint, statistical significance was reached with a relatively small sample as our cohort and more importantly this finding is not unexpected. In fact, clinical investigations conducted by Whether reported as unit of time or as a ratio, diastolic duration, appears as pivotal indicator of ischemic damage independently of the primary limiting factor: coronary lumen patency or vasodilator capacity in coronary artery disease or syndrome X patients, respectively.The prominent feature of AC is certainly the quantification of heart sound properties, particularly diastolic ones, which are of difficult interpretation even for experienced clinicians .p = 0.019, The S3 and S4 heart sounds are diastolic filling cardiac sounds generated for a series of pathological causes. They are validated as relatively specific and non-invasive indicators of heart failure  and founOn the other hand S4, is a better indicator of diastolic stiffness and our dataset confirms such axiom as S4 DV positively and significantly correlated with the isovolumic relaxation constant (Tau) . These fThe current study has a number of contemplated limitations: here we presented a pre-clinical study with a relatively small cohort composed of healthy animals under general anesthesia. Despite the abovementioned limitations, our experience sheds light on putative immediate mechanical alterations that would be otherwise unfeasible to replicate in a real-world clinical scenario and it might represent a reference point for future studies involving AC with more complex and heterogenous conditions.In conclusion, the present study provides novel and preliminary evidence of the usefulness, reliability and responsiveness of AC in detecting mechanical defects (particularly S3 heart sound and DTIs) appearing in the very first minutes during coronary occlusion. This responsive detection might have a possible application in peculiar patient subpopulations who would benefit from a chronic, non-invasive monitoring approach. Lastly, the digitalization of this hybrid technique will allow the quantification of acoustic parameters which could be of great diagnostic importance  in an unThe animal housing and experimental protocols were approved by the Cantonal Veterinary Department, Zurich, Switzerland, under license no. ZH 219/2016, and were in accordance with Swiss Animal Protection Law. Housing and experimental procedures also conformed to the European Directive 2010/63/EU of the European Parliament and of the Council on the Protection of Animals used for scientific purposes and to the Guide for the Care and Use of Laboratory Animals .NC, PB, AG, ER, PE, MZ, and FM conceived and designed the study. MaL, MS, SK, PA, PB, and MZ analyzed the data. MaL and PA performed the statistical analysis. MaL wrote the first draft of the manuscript. NC, MiL, PA, and MZ wrote the sections of the manuscript. All authors contributed to the manuscript revision, and read and approved the submitted version.PA and PB work for VisCardia, Inc., United States. The remaining 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.


N = 10) and patients with HF induced by (N = 22) or unrelated to (N = 25) doxorubicin therapy. The model predicts that HF in the absence of doxorubicin is characterized by a 2- to 3-fold stiffness increase, decreased tension (0–20%), and ventricular dilation (of order 10–30%). HF due to doxorubicin was similar but showed stronger bias toward reduced active contraction (10–30%) and less dilation (0–20%). We find that changes in active, passive, and anatomical properties all play a role in doxorubicin-induced cardiotoxicity phenotypes. Differences in parameter changes between patient groups are consistent with doxorubicin cardiotoxicity having a greater dependence on reduced cellular contraction and less anatomical remodeling than HF not caused by doxorubicin.Late-onset heart failure (HF) is a known side effect of doxorubicin chemotherapy. Typically, patients are diagnosed when already at an irreversible stage of HF, which allows few or no treatment options. Identifying the causes of compromised cardiac function in this patient group may improve early patient diagnosis and support treatment selection. To link doxorubicin-induced changes in cardiac cellular and tissue mechanical properties to overall cardiac function, we apply a multiscale biophysical biomechanics model of the heart to measure the plausibility of changes in model parameters representing the passive, active, or anatomical properties of the left ventricle for reproducing measured patient phenotypes. We create representative models of healthy controls ( Doxorubicin, a common chemotherapeutic drug, is a known cause of heart failure. The relative significance of its molecular, cellular, and tissue physiological effects in shaping the long-term condition remains unclear. Diagnosis and treatment options are hence severely limited, given the gap in understanding between symptoms and underlying causes. This study aims to bridge this gap through computational biomechanical modeling, linking left-ventricular mechanics with clinical measurements. By providing a framework for integrating and interpreting heart-failure clinical measurements (either associated with or independent of doxorubicin), we seek to identify underlying mechanisms specific to cardiotoxic heart failure. Ultimately, identifying these dominant mechanisms may help improve diagnosis, therapies, and at-risk patient identification in this challenging patient group.Doxorubicin is a common anthracycline chemotherapeutic drug with multitudinous irreversible cardiotoxic side effects that increase the risk of heart failure (HF) , 2, 3. TThe multifariousness of doxorubicin cardiotoxicity constitutes a major challenge for developing systematic treatment strategies. At the subcellular molecular level, doxorubicin facilitates the formation of free radicals and reactive oxygen species, thereby generating significant oxidative stress, particularly in mitochondria , 9. ThisThe aim of this study is to identify characteristic changes in cellular and material function, specific to this patient group, that could be used for developing early identification biomarkers or informing patient treatment. We propose to combine known physiology, inherent physical laws, and pressure, motion, and anatomical measurements within a single biophysical framework to generate plausible estimates of the dominant factors that give rise to cardiotoxic HF. We used computational simulations of the cardiac cycle to map principal clinical cardiac phenotypes routinely measured in HF patients , and the maximal ejection pressure (MEP)) onto underlying mechanistic properties. To reproduce the observed phenotype variations with maximal objectivity while acknowledging the scale of the complexity of the physiological system, our analysis considered three broad classes of cardiac features from a phenomenological perspective: the strength of active contraction, passive mechanical properties, and anatomical dimensions of the LV. Model parameters expressing these properties were constrained using LVEF, LVEDD, and MEP measurements, as well as measurements of the collagen volume fraction (CVF) performed on biopsies. Hence, by separately analyzing data from healthy and diseased patients, we sought to determine 1) what alterations to mechanistic properties of healthy hearts can most plausibly account for the development of the HF phenotypes and 2) whether such alterations differ in HF due to doxorubicin compared to HF resulting from other causes. Identifying the dominant or even the most likely factors responsible for cardiotoxicity-induced HF is an important first step in developing future studies for at-risk patient identification, early diagnosis, and treatment.All patients were recruited at the Academic Hospital Maastricht, Maastricht University Medical Centre in a study approved by the local ethics committee and adhering to the declaration of Helsinki. Three patient cohorts were considered:C) (N = 22) were doxorubicin-treated cancer patients with HF symptoms . The HF symptoms developed typically 1 year or more after the cessation of chemotherapy (average 6 ± 6 years). HF treatments involved a range of medications and dosage adapted to each patient according to their body mass  , N = 22 ody mass . Average0) (N = 25) were patients suffering from HF (same symptoms as for HFC) with no history of chemotherapy. Average age = 55 ± 14 years, BMI = 27 ± 5 kg/m2, gender 32% male, 68% female. HF treatments involved a range of medications and dosage adapted to each patient according to their body mass (Noncardiotoxic HF patients (HF0) , N = 25 ody mass .N = 10) were average age = 49 ± 10, BMI = 27 ± 4, gender = 80% male, 20% female.Healthy adults (HA) , N = 10 All the data reported in the manuscript were obtained when patients were admitted to the hospital and diagnosed with idiopathic HF . However, the cohorts were heterogeneous in the sense that some patients were already undergoing HF medical treatment while others were not. Unfortunately, this information was not available.The LV end-diastolic and end-systolic diameters , cavity wall thicknesses (interventricular septum (IVS) and LV posterior wall (LVPW)), and LVEF were measured by standard transthoracic echocardiogram according to the American Society of Echocardiography guidelines using commercially available ultrasound systems with phased-array transducers Sonos 5500 or iE33 .C: n = 8, HF0: n = 8) to measure collagen content. Samples were dyed with Sirius red, and the CVF was calculated as the fraction of dyed regions in the thin tissue slices. Biopsies were extracted with no specific orientation and therefore provided no directional information with respect to the muscle fibers.Endomyocardial biopsy samples were taken as part of the clinical treatment for a selection of HF patients . The wall thickness was fixed at 10 mm, and the innermost  semiellipsoid was 60 mm long. Meshes with different endocardial radii  were constructed to simulate LV dilation. Muscle-fiber orientations within the tissue were defined by imposing a rule-based configuration, with elevation angles varying linearly across the wall, from −60°  to +80°   , 22.FiguLV contraction in the real heart is initiated by periodically releasing intracellular calcium to generate tension. This cardiac cycle was simulated within the computational framework described by Land et al. , 24, usib). Tissue contraction is modeled using a set of ordinary differential equations describing the activation of force generation by myosin cross-bridges and actin filaments. Maximal tension is characterized by the tension-scaling parameter Tref. The phenomenological representation of the physiological behavior includes length and velocity dependences observed in muscle (c1 (see The simulation is driven by a periodic (1 Hz) intracellular calcium stimulus, derived from human-cell measurements , appliedn muscle , 26, 27. .Partial differential equations describing the mechanical force balance were solved subject to tissue incompressibility . Spatialel model b.pa, the isovolumic constraint is removed, representing the opening of the aortic valve, and the Windkessel model governs blood ejection from the LV until the volume-flow direction is reversed . Fixing the LV volume again in this state, isovolumetric relaxation is initiated, terminating when the LV pressure attains a preset diastolic pressure (0.2 kPa = 1.5 mmHg). Diastolic filling is then reactivated as the mitral valve reopens. The process is repeated until the model converges to a steady-state limit cycle, typically after three contractions (when the LV end-diastolic volume (LVEDV) varies by no more than 0.5% between successive cycles). The mesh-node coordinates and LV volume and pressure are recorded as functions of time over the limit cycle. A representative pressure-volume loop is plotted in c.The cardiac cycle was simulated as previously described, implementing the basic steps of the cardiac cycle , 24. In ped for all simulations and amalgamated it with the mechanical stiffness c1 into a phenomenological scaling parameter: c1 ∼ c1/ped. The systolic properties represented by LVEF and LVESD additionally require a consideration of the active tension magnitude, scaled phenomenologically by the model parameter Tref. Because MEP was the same in all cohorts, the aortic pressure pa was assumed constant. We therefore defined the model parameter space as comprising the reference (unstrained) LV endocardial diameter 2 × rendo and treating Tref and c1 as phenomenological parameters that cumulate the entire ensemble of cellular-level mechanisms defining active and passive mechanics.The simulation setup was guided by the clinical results summarized in rendo = 22.3 mm to represent cohort HA but allowed rendo to vary to accommodate LV dilation in HF. MEP and minimal aortic pressure (MinAP) values are similarly homogeneous across cohorts, and the aortic pressure was therefore set to a constant pa = 15 kPa (112 mmHg). A constant wall thickness w = 10 mm, consistent with the echo measurements, was also adopted in all the simulations.We constructed a mesh of fixed basal radius Tref  around 120 kPa . Passivrils  or with neither .The analysis workflow is illustrated in Q ∈  to quantify the degree of agreement between a simulated and a measured phenotype for a given cohort, taking into account the variability of that phenotype within the cohort, as illustrated in b1. For a given value of x of a generic phenotype, we define 1 is the number of measurements that are more distant than x from the distribution mean 2 is the total number of measurements that are on the same side of x, as indicated. Thus, Q = 1 corresponds to a simulation for which x coincides with Q = 0 signifies that the simulation lies outside the measurement range (no consistency). An overall consistency metric Qtot ∈ , covering all the phenotypes, is then computed by multiplying the particular Q values:We define a metric b2 map the functions Qtot obtained separately for HA (green) and HFC (red), assuming rendo = 22.3 mm for both cohorts , reflecting the aptitude of LVEF as an indicator of HF. This effect is accompanied by a significant increase in LVESD (p ≤ 0.003) for both HF cohorts, also consistent with impaired ejection. In contrast, MEP, MinAP, IVS, and LVPW differ much less significantly between the cohorts (p > 0.1). However, LVEDD is increased in HF by a factor of order 10%, albeit less significantly for HFC (p = 0.06) than for HF0 (p = 0.01). None of the phenotypes, including LVEF, LVEDD, and LVESD, show any significant difference when comparing HFC with HF0 directly (p(HFC → HF0) > 0.3).Phenotypes are compared in C and HF0 in terms of LVESD and LVEDD. pgrad) assessed in the last column of pgrad > 0.4). However, LVEDD, LVESD, and MinAP all display significant differences (p < 0.0005), which supports the exploration of the simulation parameter space defined by c1, Tref, and rendo  and HF0 (8.4%) cohorts differ by factors of 4.0 and 3.2, respectively, relative to the mean healthy CVF (2.6%).CVF was measured in endocardial biopsies taken from a subset of HFa and b; . Healthye.Variations in cardiac collagen content have been shown to correlate with passive mechanical stiffness , 40, 41.c1, the vertical axes increasing Tref, and successive images denote LV dilation with increasing rendo. We interpret each distribution as a measure of the plausibility that a given combination of changes in c1, Tref, and rendo reproduces the development of the HF phenotypes, starting from the healthy configuration, either in the presence (a1–a6) or absence (b1–b6) of doxorubicin exposure.The main results of this work are shown in presence , a1–a6 o absence , b1–b6 oC and HF0 both display a correlation between Tref varies inversely with an increase in c1, with the balance depending on the extent of LV dilation, as indicated by the shift in the distribution along an upward diagonal with increasing rendo. We observe a stronger dilation in the case of the HF0 transition  axes of a and b. We estimated the expected change in c1 by assuming a proportionality with the change in CVF mCVF, as suggested by the literature reviewed in e. An effective distribution of mCVF was calculated by cross-correlating the healthy and failing-heart CVF distributions shown in PCVF (c and d) characterize the distributions of ratios mCVF that describe the difference in CVF between the cohorts. For the cases of both HFC and HF0, PCVF covers an order of magnitude, with the bulk of the distribution being in the range mCVF < 4, suggestive of a stiffness increase up to threefold and a Tref decrease ranging from ∼0 to 20%. The HFC case, however, is more strongly weighted toward lower values (mCVF < 2), suggesting a stronger bias toward decreased Tref (by ∼10–30%).To further constrain the computed distributions to the patient data, we related the biopsy CVF measurements to the stiffness . The coc1) and active properties (Tref). To assess the extent to which the effective reduction in Tref can be accounted for purely as a result of the CVF change, we assumed the simplest scenario, namely an inverse correlation between CVF and the volume fraction of the contracting myocardium, i.e., muscle volume fraction (MVF) = 1 − CVF; and secondly, a linear scaling of the contractile strength with MVF. We hence estimated the decrease in active tension associated with a given increase in c1 using the formula derived in the Appendix. The dashed lines in c3 represent the expected effective decrease in Tref arising solely from an increase in collagen . The regions of the map located above these dashed lines thus represent regimes where the decrease in Tref can be explained in terms of reduced MVF rather than through a reduction of muscular contraction. In all the cases considered, this region covered no more than 9% of the total integral. This supports the hypothesis that the extent of decrease in Tref required to account for HF cannot be fully explained by a simple decrease in muscle density. Consequently, a greater contribution to the decrease in Tref must have other causes, e.g., sarcomere density or alignment.The results of Owing to the natural heterogeneity of patient cohorts and the limited scope of available measurements, our simulations are inevitably approximations of the physiological system. To assess the significance of some potential confounding factors, we performed the following additional simulations.C and HF0 cohorts being more biased toward females (breast cancer patients). Among various gender dependences reported in the cardiac system (1/3) in all dimensions to represent “female” meshes. Simulations were repeated and analyzed as previously, using these smaller meshes for mapping the HFC and HF0 data. The results  or more circumferential (−10°) relative to the baseline fiber configuration. The effect on the simulated phenotypes was generally minimal. In particular, the maximal change in LVEF was ∼3%   . Thus, aactility .By identifying classes of mechanisms that most likely account for HF phenotypes and by accommodating for the natural variety within cohorts, our approach sought to discern trends that would escape notice in experiments focusing on individual cases or specific mechanisms. Ultimately, this may provide a framework for contextualizing known results and guiding more focused and detailed clinical investigation. Within this perspective, our results suggest a greater emphasis on the deterioration of active contractile function following from doxorubicin chemotherapy than in more general cases of HF.Like all patient modeling studies, this study has limitations. HF is a heterogeneous disease, and we recruited limited patient numbers. Chemotherapy patients typically receive a range of simultaneous medications rather than being limited to doxorubicin see . In addiSeveral authors have reported that a portion of the generated stress is exerted transversely relative to the mean local fiber orientation , 63. Thic1, makes no explicit reference to collagen or titin, known determinants of cardiac tissue stiffness (Tref can in principle result from a range of different possible perturbations at the sarcomere level (A further limitation of the approach is its inability to assign functional changes to specific molecular mechanisms, which are instead encapsulated into phenomenological representations of broad classes of phenomena. For example, passive stiffness, quantified by tiffness , 65, 66.re level , 60, 67.We have created the first biomechanical models, to our knowledge, to study long-term doxorubicin-induced cardiotoxicity. This provides a physiologically and physically constrained framework for integrating and interpreting clinical data in terms of underlying mechanisms. We have used these models to provide bounds on the anatomical, tissue, and cellular mechanisms that explain the organ-scale clinical phenotypes within this challenging patient group.A.L. performed the simulations and analysis and wrote the article. S.L. wrote the code for the computational model. J.M., A.R., S.H., and P.S. provided the clinical data. J.K. directed the HeCaToS project that comprised this study. S.A.N. supervised the study and wrote the article.


Cardiomyopathy is a group of disorders in which the heart muscle is structurally and functionally abnormal in the absence of other diseases that could cause observed myocardial abnormality. The most common cardiomyopathies are hypertrophic and dilated cardiomyopathy. Rare types are arrhythmogenic right ventricular, restrictive, Takotsubo and left ventricular non-compaction cardiomyopathies. This review of cardiomyopathies in pregnancy shows that peripartum cardiomyopathy is the most common cardiomyopathy in pregnancy. Peripartum cardiomyopathy develops most frequently in the month before or after partum, whereas dilated cardiomyopathy often is known already or develops in the second trimester. Mortality in peripartum cardiomyopathy varies from <2% to 50%. Few reports on dilated cardiomyopathy and pregnancy exist, with only a limited number of patients. Ventricular arrhythmias, heart failure, stroke and death are found in 39%–60% of high-risk patients. However, patients with modest left ventricular dysfunction and good functional class tolerated pregnancy well. Previous studies on >700 pregnancies in 500 women with hypertrophic cardiomyopathy showed that prognosis was generally good, even though three deaths were reported in high-risk patients. Complications include different types of supraventricular and ventricular arrhythmias, heart failure and ischaemic stroke. Recent studies on 200 pregnancies in 100 women with arrhythmogenic right ventricular cardiomyopathy have reported symptoms, including heart failure in 18%–33% of pregnancies. Ventricular tachycardia was found in 0%–33% of patients and syncope in one patient. Information on rare cardiomyopathies is sparse and only presented in case reports. Close monitoring by multidisciplinary teams in referral centres that counsel patients before conception and follow them throughout gestation is recommended. Mothers are estimated to have any type of cardiovascular disease in 1%–4% of all pregnancies. This is the most common non-obstetric cause of maternal death.Cardiomyopathy is defined as a ‘myocardial disorder in which the heart muscle is structurally and functionally abnormal, in the absence of coronary artery disease, hypertension, valvular disease and congenital heart disease sufficient to cause the observed myocardial abnormality’Cardiomyopathies in pregnancy are generally not well described because they are relatively rare diseases. However, during the last decade, case series, case reports and a small number of controlled studies on cardiomyopathy in pregnancy have been published. In this review, different types of cardiomyopathies and pregnancy are described.In the adult population, HCM and DCM have an estimated prevalence of 0.2%–0.4%. The estimated prevalence of ARVC is 0.02%–0.05% and restrictive cardiomyopathy is even more uncommon. HCM and ARVC predominantly have a genetic cause, while DCM and RCM have mixed causes.The Kaiser Permanente Health system, which is the USA’s largest non-profit health plan including 9.9 million members, provided data that identified pregnant women with heart failure from 2003 to 2014.The Registry Of Pregnancy And Cardiac disease (ROPAC) study, which was a voluntary registry for pregnancy and heart disease managed by the European Society of Cardiology Heart Survey Programme, included 1321 women with cardiac disease from 2007 to 2011. Of these, 89 patients had cardiomyopathy, 32 had DCM, 25 had PPCM, 27 had HCM and 5 had other cardiomyopathies.In normal pregnancy, cardiac output increases by 30%–50% through increased stroke volume during the first two trimesters. During the second part of pregnancy, cardiac output increases through an increase in heart rate of 10–15 beats/min (secondary to increased sympathetic tone); however, this increased rate does normally not reach >90 beats/min. The increase in plasma volume during pregnancy is larger than the increase in red blood cells, which leads to physiological anaemia. Systemic vascular resistance decreases at the end of the second trimester and then increases towards the end of pregnancy. The heart undergoes concentric remodelling and/or a mild eccentric hypertrophy.There have been few reports of pregnant patients with DCM because the literature recommends against pregnancy if the ejection fraction is <30%. Idiopathic DCM accounts for approximately 50% of all cases and 35% are inherited.Either the diagnosis of DCM is already known or overt heart failure can develop secondary to asymptomatic left ventricular dysfunction and haemodynamic changes during pregnancy. Even if DCM is diagnosed before conception, symptoms can appear acutely or insidiously. Many symptoms of heart failure are compatible with those related to pregnancy; therefore, diagnosis of cardiomyopathy may be delayed.Biomarkers, such as brain natriuretic peptide/N-terminal probrain natriuretic peptide, support a diagnosis of heart failure. Echocardiography shows the current status of the heart. Because gadolinium contrast crosses the placenta, late gadolinium MRI should be avoided during pregnancy.Because of increased haemodynamic load and cessation of heart failure medication, adverse cardiac events in women with cardiac disease are more likely to appear towards the end of pregnancy. This is especially the case in higher New York Heart Association functional classes and in moderate to severe left ventricular dysfunction where adverse cardiac events are reported in 39% and 60% of pregnancies, respectively.A previous cardiac event is the most predictive risk factor for a subsequent major event.A commonly used definition of PPCM is symptoms of heart failure secondary to left ventricular systolic dysfunction with an ejection fraction <45% towards the end of pregnancy or in the months following delivery with no other cause of heart failure.The reported incidence of PPCM varies between 1:100 and 1:20 000 deliveries worldwide and between races within countries, with the highest incidence in African countries and the lowest in Scandinavia and Japan. An increasing trend of PPCM has been reported and is likely secondary to greater knowledge about and attention to this disease.Known predisposing factors of PPCM are multiparity, African ethnicity, malnutrition, increasing age and young age, pre-eclampsia and traditional risk factors for cardiovascular disease, such as diabetes and smoking.The most probable aetiology of PPCM is a multifactorial aetiology, including inflammation, angiogenic imbalance and genetic factors inducing apoptosis and vascular damage.The EURObservational Research Programme (EORP) has completed enrolment of 766 patients with PPCM worldwide. This registry provides information on risk factors, symptoms, clinical findings, investigations, treatment, repeated pregnancies and prognoses. Because PPCM is a diagnosis of exclusion, obtaining information about risk factors and other medical conditions is important, and typical signs of heart failure are most often present. In 411 patients with PPCM who were included in the EORP registry, 6.8% developed some type of thromboembolic event.In DCM, specific treatment against the aetiology may be possible. Moreover, disease management is common for most DCM subtypes and PPCM. Symptoms of DCM or PPCM can develop before and after parturition. Because these symptoms can be mild or life threatening, the patient’s general status must be assessed first.If the patient is pregnant, the first decision is whether she can complete pregnancy or if it must be interrupted. If pregnancy is continued, treatment must be adjusted while considering the fetus.Treatment for heart failure should follow the 2016 European Society of Cardiology Guidelines for the treatment of acute and chronic heart failure, as well as the 2017 ACC/AHA/HFSA Focused Update and the 2013 ACCF/AHA Guideline for the Management of Heart Failure.Bromocriptine blocks prolactin. In a small, randomised study, bromocriptine hastened recovery of the ejection fraction compared with conventional treatment.Careful discussion is necessary before installing an implantable cardioverter defibrillator because PPCM often improves. However, particularly initially, there is a high risk of malignant arrhythmia in PPCM. This is why a wearable cardioverter defibrillator is recommended in patients with an ejection fraction ≤35% for the first 3–6 months.Treatment is recommended for at least 12 months after recovery of both the left ventricular ejection fraction and dimensions.If a patient cannot be stabilised haemodynamically, urgent delivery by caesarean section is necessary. Vaginal delivery is preferred in haemodynamically stable patients.Strong risk factors for deterioration of left ventricular function and death are an ejection fraction <20%, right ventricular failure, mitral regurgitation, atrial fibrillation and/or hypotension.Information on subsequent pregnancies in patients with PPCM is limited, which has led to high variation in reports. Each patient should have the option to meet with a joint multidisciplinary team to discuss the risk of PPCM relapse. The rate of PPCM relapse is 14%–44% if the ejection fraction has recovered and 16%–56% if the ejection fraction has not normalised. Mortality in subsequent pregnancies in PPCM vary (0%–48%)%).Contraception must be discussed in all patients with DCM and PPCM, preferably before discharge. Progesterone-only devices or pills are recommended.Hypertrophy can be general or local and is often located in the left ventricular outflow tract, which may lead to outflow tract obstruction. The diagnosis of HCM is made with echocardiography.The increase in plasma volume during pregnancy may reduce the left ventricular outflow gradient. However, arrhythmia and hypovolaemia may cause an increase in the left ventricular outflow gradient in patients with obstruction of the outflow tract. Generally, women with HCM tolerate pregnancy well, even though symptoms, such as dyspnoea, heart failure, arrhythmia, angina, dizziness and syncope, occur in up to 48% of affected patients, especially in patients with symptoms before pregnancy .6 7 29 3Evaluation of risk factors and counselling before conception is important. During pregnancy, moderate risk to high-risk patients should be followed each trimester if they are in WHO class II and followed monthly or every second month if in WHO class III. This should be performed to detect symptoms and signs and to perform echocardiography, especially following a left ventricular outflow tract gradient and monitoring heart rhythm. If a patient is already receiving a beta-blocker, this should be continued, and if more symptoms appear in beta-blocker-naive patients, a beta-blocker should be started .23 VerapHypovolaemia secondary to blood loss and vasodilation is poorly tolerated. Addressing these issues and carefully choosing anaesthesia are important. Vaginal delivery with regional anaesthesia is preferred, but a plan for caesarean section, if necessary, should be prepared in high-risk patients. However, in the ROPAC study findings, only 5% of patients required emergency caesarean section.Left ventricular non-compaction is partially an inherited disease, which is characterised by hypertrabeculation with deep clefts in the myocardium and an increased risk of thromboembolic events.Restrictive cardiomyopathy, which is a partly acquired and partly inherited disease, may affect both ventricles. Restrictive cardiomyopathy is complicated by increased myocardial stiffness and reduced relaxation that result in reduced ventricular filling. An increase in plasma volume during pregnancy may lead to volume overload and left or right heart failure. A case report described a pregnant patient with restrictive cardiomyopathy who was symptomatic before pregnancy.ARVC is an inherited cardiomyopathy. Loss of cardiomyocytes is followed by fibrofatty replacement in the right ventricle that causes arrhythmia, as well as right heart failure. Occasionally, the left ventricle may also be involved. Increased plasma volume during pregnancy may provoke these complications. Recent studies that included approximately 200 pregnancies in 100 women with ARVC reported no mortality in relation to pregnancy .7 38–41 Most of the reported Takotsubo cardiomyopathy cases became symptomatic close to childbirth with caesarean delivery. One-third of these cases were found during caesarean section. All patients with Takotsubo cardiomyopathy recovered between 4 days and 3 months, as in non-pregnant patients with Takotsubo cardiomyopathy.The most common complications during pregnancy in cardiomyopathy are heart failure and arrhythmia. Currently, pregnant patients with cardiomyopathy who were previously discouraged can, in many  cases, proceed with help from a multidisciplinary team, even if there is an increased risk for complications, especially in DCM. Therefore, these parents require proper counselling before conception and must be aware of the risks.


Replacement fibrosis is irreversible and identified using late gadolinium enhancement on cardiac magnetic resonance, while diffuse fibrosis occurs earlier, is potentially reversible, and can be quantified with cardiac magnetic resonance T1 mapping techniques. There is a substantial body of observational data in this field, but there is now a need for randomized clinical trials of myocardial imaging in aortic stenosis to optimize patient management. This review will discuss the role that myocardial fibrosis plays in aortic stenosis, how it can be imaged, and how these approaches might be used to track myocardial health and improve the timing of aortic valve replacement.Aortic stenosis is characterized both by progressive valve narrowing and the left ventricular remodeling response that ensues. The only effective treatment is aortic valve replacement, which is usually recommended in patients with severe stenosis and evidence of left ventricular decompensation. At present, left ventricular decompensation is most frequently identified by the development of typical symptoms or a marked reduction in left ventricular ejection fraction <50%. However, there is growing interest in using the assessment of myocardial fibrosis as an earlier and more objective marker of left ventricular decompensation, particularly in asymptomatic patients, where guidelines currently rely on nonrandomized data and expert consensus. Myocardial fibrosis has major functional consequences, is the key pathological process driving left ventricular decompensation, and can be divided into 2 categories.   Aortic stenosis is one of the most common valvular diseases in the Western world Aortic stenosis progresses inexorably. Although the early stages are asymptomatic and associated with a good prognosis, advanced disease is associated with substantial morbidity and mortality Current guidelines recommend intervention in patients with severe aortic stenosis and evidence of left ventricular decompensation. Most commonly this is in the form of development of typical symptoms, but other markers include a reduction in ejection fraction <50%, an abnormal exercise tolerance test, or a rise in brain natriuretic peptide levels Consequently, there is extensive interest in identifying novel, objective markers of early left ventricular decompensation to optimize the timing of AVR and track myocardial health over time. The development of such markers requires improved understanding of the pathophysiology underling left ventricular decompensation in aortic stenosis. Histological studies have suggested that myocardial fibrosis and cell death are both important drivers of this process It is useful to consider aortic stenosis as a disease of both the valve and the myocardium Progressive valve narrowing causes pressure overload of the left ventricle and triggers a hypertrophic response that maintains wall stress and left ventricular performance for many years. Over time, this process decompensates and patients transition from hypertrophy to heart failure, leading to adverse clinical outcomes. This evolution is complex but is closely related to the development of myocardial fibrosis, myocyte injury, and cell death. Furthermore, there is adverse remodeling of the extracellular matrix, with degradation and disruption of the matrix structure Two distinct myocardial fibrosis patterns have been described. Reactive interstitial fibrosis is diffuse and follows increased myofibroblast activity and collagen deposition that begins even in the early stages of aortic stenosis. Importantly, this diffuse fibrosis is reversible and has been demonstrated to regress following AVR The degree of myocardial remodeling and fibrosis is closely related to hemodynamic markers of myocardial performance, such as end-diastolic pressure and ejection fraction Although myocardial biopsy and histological analysis are still considered the gold standard assessments of myocardial fibrosis, they have several important limitations precluding their routine clinical application. Myocardial biopsy is an invasive procedure that carries an attendant risk of complications CMR provides unparalleled soft tissue characterization and can be used to identify and measure both diffuse and replacement forms of fibrosis in a single scan without the use of ionizing radiation. When utilized together, the CMR techniques described in the following text offer the best available method of capturing the full spectrum of fibrotic changes within the left ventricular myocardium Gadolinium-based contrast agents (GBCAs) partition into areas of extracellular expansion . Interpretation of delayed imaging using GBCAs requires clear differences in signal intensity between healthy and diseased myocardium in a relatively discrete distribution. Consequently, late gadolinium enhancement (LGE) is an excellent marker of focal replacement fibrosis, but is insensitive for the detection of more diffuse interstitial fibrosis.LGE is now well established and widely used as a method for detecting replacement myocardial fibrosis in a broad range of cardiovascular conditions such as ischemic cardiomyopathy, nonischemic dilated cardiomyopathy, cardiac sarcoidosis, cardiac amyloidosis, myocarditis, and hypertrophic cardiomyopathy The poor prognosis associated with non-infarct LGE appears to persist long after AVR is performed, in keeping with the irreversible nature of replacement fibrosis. In the largest study to date, the British Society for Cardiovascular Magnetic Resonance Valve Consortium performed comprehensive CMR assessments in over 650 patients with severe aortic stenosis just prior to SAVR or TAVR NCT03094143) LGE is reliable, well-validated, and easily integrated into the standard workflow, with post-processing and qualitative analysis readily performed in <10 min in most cases. LGE is therefore ready for investigation as a tool for use in routine clinical practice. Indeed, the ongoing EVOLVED  trial .As fibrosis increases, native T1 is relatively uniform and reproducible when using the same sequence and scanner on the same patient, values are subject to a variety of factors such as patient age and sex, acquisition sequence, scanner field strength, and post-processing. In aortic stenosis, even within the same scanner and protocol, substantial overlap exists in T1 values across different severities of aortic stenosis and with healthy control subjects 1 holds major appeal as a marker of diffuse fibrosis that does not require contrast administration and is favored as a technique by various experts in the field, its specific role in aortic stenosis requires further research.Although native T1 mapping techniques therefore allow more specific interrogation of the extracellular space due to gadolinium’s shortening effects on T1 relaxation times. Unfortunately, standardization of post-contrast T1 mapping values is difficult due to variation in gadolinium kinetics between patients and even within the same individual on different days. Standardized normal values are again lacking, and consequently, post-contrast T1 mapping is not in widespread use.GBCAs do not cross cell membranes and therefore distribute throughout the extracellular space in the myocardium. Post-contrast T1 mapping values for blood pool and pre-contrast myocardial T1, thereby accounting for differences in blood concentrations of GBCAs. By incorporating the hematocrit, ECV% calculates the fraction of the myocardium comprised by the extracellular space according to the formula ECV% = (Δ[1/T1myo]/Δ[1/T1blood]) × (1 − hematocrit), where Δ(1/T1) is the difference in myocardial or blood T1 pre- and post-contrast The extracellular volume fraction (ECV%) corrects post-contrast myocardial T1 values on different scanners and sequences, making it appealing as a technique for multicenter research.Current scanning techniques assume a dynamic equilibrium between blood and myocardium ∼10 to 15 mins after a bolus injection of contrast A number of clinical studies have validated ECV% against histology in aortic stenosis and have demonstrated the association between ECV% and other markers of LV decompensation, including ECG changes of hypertrophy and strain and elevation in biomarkers such as troponin and N-terminal pro-brain natriuretic peptide 1 mapping parameters. Chin et al.2  could be used to differentiate healthy myocardium from diseased myocardium infiltrated by diffuse fibrosis, and in doing so, identify patients with early evidence of left ventricular decompensation and adverse long-term outcome Whereas ECV% provides a percentage estimate, the indexed extracellular volume (iECV) quantifies the total left ventricular extracellular myocardial volume indexed to body surface area by multiplying ECV% by the indexed left ventricular myocardial volume: iECV = ECV% × indexed left ventricular myocardial volume . FurtheriECV and ECV% have recently been used in combination to study changes in the composition of the intracellular and extracellular compartments before and after AVR. This has provided important insights into left ventricular remodeling and reverse remodeling after relief of loading conditions. Changes in iECV are not accounted for by changes in total left ventricular mass alone. Prior to AVR, iECV  and left ventricular mass appear to increase in a broadly balanced manner so that ECV% remains largely unchanged. Following AVR, left ventricular mass decreases. Cellular and extracellular mass regress, but cellular mass regresses more rapidly, thereby resulting in an apparently paradoxical increase in ECV% as the ratio of matrix to total mass is increased 1 mapping is an exciting and emerging research field in aortic stenosis research that provides the only method of identifying reversible diffuse myocardial fibrosis. It holds particular potential as a method to track myocardial health over time, with important clinical implications. Standardization of sequences and protocols have resulted in reproducible and powerful prognostic T1 mapping data in a variety of myocardial disease states 1 mapping in aortic stenosis is in a relatively early stage of development. Further work is required to establish validated thresholds to aid decision making, paving the way for future multicenter prognostic studies that are ultimately required. Of the T1 mapping parameters currently in use, we believe that ECV% and iECV currently provide the most complete understanding of cellular and extracellular remodeling in aortic stenosis, although native T1 provides important advantages, particularly with regard to ease of calculation and the avoidance of contrast administration.In summary, TAlternative imaging techniques to assess myocardial fibrosis in aortic stenosis are limited. Research into computed tomography (CT) assessments of myocardial fibrosis remains exploratory, with only limited data available that has largely focused on measuring ECV on CT scans performed after the administration of iodinated contrast agents . These tMyocardial fibrosis is well established as a hallmark pathological feature of left ventricular decompensation in patients with aortic stenosis; yet, it is not routinely assessed in clinical practice. In part, this has reflected the limitations of myocardial biopsy, many of which have now been overcome with advanced noninvasive imaging. The next step is to assess whether these imaging techniques will prove of clinical value in monitoring myocardial health, identifying left ventricular decompensation, and optimizing the timing of AVR.NCT03094143) LGE is the best validated of these approaches, is relatively simple to perform and analyze, and is supported by powerful prognostic data. Whether noninfarct LGE can be used to optimize the timing of valve intervention is currently being tested in the EVOLVED  trial (1 mapping is the only available imaging technique that is able to offer an assessment of diffuse fibrosis, and as such, it is crucial that ongoing research is conducted to provide standardization of sequences and protocols across sites and vendors to delineate clear cutoffs for health and disease in aortic stenosis. As T1 mapping research expands, this approach may offer clear advantages over LGE. For example, future investigation of antifibrotic therapies will require biomarkers to monitor myocardial health and treatment effects; T1 mapping will be indispensable in this regard.CMR assessments of diffuse fibrosis in aortic stenosis require further validation but offer the potential to identify the earlier stages of myocardial disease and track myocardial health with time. TFurther work to investigate the role of emerging CT techniques is also warranted, particularly as they may be more easily integrated into current clinical care pathways and workflows than CMR. There has also been early investigation of collagen- and elastin-specific CMR contrast agents, which may provide greater contrast to noise ratio compared with current GBCAs, but further advances in this field are awaited Myocardial fibrosis plays a key role in the pathophysiology of aortic stenosis. Modern imaging techniques now allow assessment of both replacement and diffuse interstitial fibrosis as well as their functional consequences. These techniques hold promise in tracking myocardial health in patients with aortic stenosis, aiding risk stratification and potentially optimizing the timing of aortic valve intervention, with ongoing trials currently testing the clinical efficacy of these approaches.


Aortic stenosis (AS) is a progressive disease in which left ventricular (LV) diastolic dysfunction is common. However, the association between diastolic dysfunction and right ventricular (RV) loading conditions and function has not been investigated in asymptomatic AS patients.2 vs. 79 ± 15 ml/m2, p = 0.02) and end-systolic volume . An increase in mean RAP to ≥15 mmHg following exercise was not seen in patients with normal LV filling, compared to 4 patients (20%) with mild and 7 patients (63%) with moderate diastolic dysfunction (p = 0.003). PA pressure and PA elastance was increased in grade 2 diastolic dysfunction and correlated with RV volume and maximal oxygen consumption .A total of 41 patients underwent right heart catheterization and simultaneous echocardiography at rest and during maximal supine exercise, stratified according to resting diastolic function. Cardiac chamber size and morphology was assessed using cardiac magnetic resonance imaging (cMRI). RV stroke work index, pulmonary artery (PA) compliance, PA elastance, PA pulsatility index, and right atrial pressure (RAP) were calculated at rest and maximal exercise. Ten patients (24%) had normal LV filling pattern, 20 patients (49%) had grade 1, and 11 patients (27%) had grade 2 diastolic dysfunction. Compared to patients with normal diastolic filling pattern, patients with diastolic dysfunction had lower RV end-diastolic volume (66 ± 11 ml/mModerate diastolic dysfunction is associated with increased RV afterload (elastance), which is compensated at rest, but is associated with increased RAP and inversely related to maximal oxygen consumption during maximal exercise. Calcified aortic stenosis (AS) is a chronic, slowly progressing disorder where pressure overload can lead to heart failure symptoms warranting aortic valve replacement . HoweverThere are no previous studies that have assessed the association between LV diastolic dysfunction and RV physiology and morphology in a population with asymptomatic AS. Thus, it is not known whether LV diastolic dysfunction causes alterations in RV function, and whether this is due to ventricular interdependence or chronically elevated LV filling pressures causing afterload mismatch. The objective of this study was to investigate the association between LV diastolic function and RV morphology and function at rest and during exercise in asymptomatic patients with significant AS.2, aortic peak velocity > 3.5 m/s and LV ejection fraction > 50% were prospectively enrolled from January 2014 to January 2016.A total of 41 patients with significant AS defined as aortic valve area (AVA) < 1cmInitially, a total of 215 patients were screened. However, 174 patients were excluded due to s-creatinine > 200 μmol/l (n = 9), pacemaker dependency (n = 11), more than mild co-existing valve disease (n = 11), chronic atrial fibrillation (n = 16), inability to perform exercise testing (n = 25), LVEF < 50% (n = 8), and no consent (n = 94). Informed written consent was obtained at inclusion, and patients were carefully questioned to rule out any symptoms. Of the remaining 41 patients, 39 patients have been reported in a previous study [All patients underwent right heart catheterization at rest and during multistage symptom-limited exercise testing with simultaneous echocardiography. Cardiac magnetic resonance imaging (cMRI) and cardiopulmonary exercise testing were performed at different timepoints.The study was registered at the Danish Data Protection Agency and ClinicalTrials.gov (NCT02395107) and approved by the local ethics committee (S-20130067). All patients provided informed consent before enrollment.-1. The measurements were standardized to body surface area, as appropriate.Transthoracic echocardiography was performed and stored for later blinded analysis on a Vivid E9  ultrasound system. An average of 3 to 5 heartbeats was measured for Doppler recordings. Frame rate was kept at a minimum of 60 secMaximal aortic valve jet velocity was assessed in multiple apical views using continuous wave (CW) Doppler. Left ventricular outflow tract (LVOT) diameter was measured 5 mm below the aortic valve. AVA was calculated using the continuity equation.Left atrium (LA) endocardial border was traced in apical 4 and 2 chamber views, and LA volume was calculated using the biplane method of disks (modified Simpson's rule) and standardized to BSA .2 were considered to have normal diastolic function. Patients with E/A ratio <0.8 and e’ ≤ 7 cm/s were considered to have grade 1 diastolic dysfunction, and patients with EA-ratio 0.8 to 2, LA volume index ≥ 34 ml/m2, and e’ ≤ 7 cm/s were considered to have grade 2 diastolic dysfunction.Mitral inflow pattern was assessed with the pulsed-wave (PW) Doppler sample volume placed at the tips of the mitral valve leaflets during diastole. From mitral inflow, the peak early (E) and late (A) wave velocity, as well as mitral E-wave deceleration time were measured. Myocardial velocity was recorded using tissue Doppler imaging with a pulsed wave sample volume placed in the medial mitral annulus. From these recordings, tissue Doppler early diastolic (e’) velocity was measured at the septal mitral annulus. Diastolic function was graded based on: E/A ratio, e’, E/e’ ratio, and LA volume index . PatientcMRI was performed on a Philips Ingenia 1.5T scanner with Omega HP gradient system . Images were analyzed by an experienced examiner blinded to both the invasive and echocardiographic data on a dedicated work station with a Philips Intellispace software package (2.6.3.5 2013).Atrial and ventricular chamber volumes and LV mass were measured from a cine sequence with continuous short axis slices covering the atria and ventricles. LV mass was calculated at end-diastole as the inter-slice gap multiplied by the difference between epicardial and endocardial traced areas with a myocardial density of 1.05 g/ml . PapillaRight heart catheterization was done with a standard 7.5-F triple lumen Swan-Ganz catheter  advanced to the pulmonary artery. Patients underwent a multistage symptom-limited exercise test from rest until exhaustion with increments of 25 Watts every 3 minutes with the catheter in place. Exercise tests were done using an exercise bike  suitable for exercise echocardiographic studies with an electrical adjustable slope, and the patients were tested in a semi-supine position.Pulmonary artery wedge pressure (PAWP) was measured at end-expiration during rest and averaged for > 10 secs, whereas mean PAWP was measured during exercise. Blood pressure, heart rate, and arterial oxygen saturation were monitored continuously. Further, right atrial pressure (RAP), pulmonary artery pressure (PAP), and 3 consecutive measurements of cardiac output with <10% variability using thermodilution were recorded at each exercise level. Oxygen saturation and lactate concentration were measured in a mixed central venous blood sample before and immediately after termination of exercise.va = /stroke volume index) [RV stroke work index (RVSWi) was calculated using the formula: RVSWi = 0.0136*stroke volume index (SVi)*(mean PAP-RAP) . Pulmonae index) . CalculaThirty-one patients underwent a standard cardiopulmonary Bruce treadmill test to determine maximal oxygen consumption . RespiraData are presented as mean ± standard deviation or median (interquartile range) unless otherwise indicated. Between group differences for continuous variables with a Gaussian distribution were tested using ANOVA. For non-Gaussian distributed variables, a nonparametric rank-sum test was used. Fisher’s exact test was used to compare proportions of categorical variables. Linear bivariate analysis was assessed using Pearson’s correlation coefficient. Multiple regression analysis was used to evaluate associations between invasive hemodynamic calculations and oxygen consumption. A p-value of < 0.05 was used as the cutoff for statistical significance on a two-tailed test. STATA/SE 14.0  software was used for statistical analysis.va was significantly higher in patients with diastolic dysfunction compared to those with a normal diastolic filling pattern , which was driven by patients with grade 1 diastolic dysfunction (All 41 patients completed the exercise protocol and 1 patient did not complete cMRI due to claustrophobia. Patients were classified into 3 groups according to LV diastolic filling pattern: 10 patients (24%) had normal diastolic filling pattern, 20 patients (49%) had grade 1 diastolic dysfunction, and 11 patients (27%) had grade 2 diastolic dysfunction. Grade 3 diastolic dysfunction was not observed in this cohort. Patients with diastolic dysfunction were older compared to those with a normal filling pattern (p<0.001) . Furtherfunction . Althougfunction .2 vs. 79 ± 15 ml/m2, p = 0.02) and end-systolic volume  . No association between RV ejection fraction (RVEF) and diastolic function was observed (p = 0.55). In patients with diastolic dysfunction, no differences in LV size, mass, or LVEF were found  ). In addre found . On LGE,Diastolic dysfunction was associated with increased systolic and diastolic PAP, whereas no difference in CI was found at rest, and there was no difference in SVR at rest . Driven During supine exercise, patients achieved a median exercise load of 100 (81–119) Watts with no difference between grades of diastolic function (p = 0.87). Both RV and LV filling pressure increased significantly in all patients during exercise and PAWP increased above 30 mmHg after maximal exercise in 20 patients (49%). PAWP >30 mmHg was common in patients with grade 2 diastolic dysfunction  compared to those with normal diastolic function  (p = 0.03). An increase in mean RAP to ≥15 mmHg following exercise was not seen in patients with normal LV filling, compared to 4 patients (20%) with mild and 7 patients (63%) with moderate diastolic dysfunction (p = 0.003). However, RAP/PAWP was not different between groups. Further, systolic PAP was higher in patients with diastolic dysfunction after exercise.At maximal exercise, PA elastance was increased in patients with diastolic dysfunction and showed an inverse relation with RV size at rest  . No assoBoth PA elastance  and PA compliance  was associated with maximal oxygen consumption . After aThe present study confirms the following two findings: (1) abnormal LV diastolic function is a common finding in asymptomatic patients with significant AS; (2) right ventricular afterload is increased when diastolic dysfunction is moderate. The increase in RV afterload is compensated at rest but is associated with increased right atrial pressure and inversely related to oxygen consumption during exercise. Morphologically, RV remodeling in patients with diastolic dysfunction was characterized by smaller chamber size suggesting reduced RV compliance in these patients.AS is associated with excessive afterload during LV ejection. The classic LV response to normalize increased systolic wall stress on the myocardial sarcomere is myocardial hypertrophy, in which increased wall thickness counterbalances increased end-systolic pressure and end-systolic wall stress. Although initially an adaptive response, this will cause relaxation abnormalities and eventually lead to increased myocardial stiffness due to diffuse fibrosis causing LV diastolic dysfunction. We found that only one third of patients with asymptomatic significant AS had normal diastolic function. Previous studies have shown that the presence of diastolic dysfunction, especially when moderate or severe, was associated with severe symptoms and higher 1-year mortality than symptomatic AS . The sevA hallmark of diastolic dysfunction is an increase in LV filling pressure especially during exercise , 23, whiWe found RV size was lower in patients with diastolic dysfunction. Given that the physiology of LV diastolic dysfunction in AS shares many similarities with HFpEF, we speculate that the small RV cavity with reduced compliance possibly signifies a distinct phenotype among asymptomatic AS patients.At rest, the RV preload in terms of RAP was normal irrespective of LV diastolic function. However, during exercise, the RV preload increased considerably in patients with moderate diastolic dysfunction. In about 2/3 of the patients with diastolic dysfunction, RAP increased to 15mmHg or more while no increase was observed in patients with normal diastolic function. It is likely that patients with moderate diastolic dysfunction were not able to accommodate the increased venous return during exercise due to the increase in RAP.Although RV preload, elastance, and compliance were affected, no signs of RV systolic dysfunction  was observed. Thus, the observed changes in central hemodynamics were not associated with overt RV failure. There was a trend towards accentuated RV systolic function in patients with moderate diastolic dysfunction, which is in agreement with the study by Rain and colleagues where RV diastolic dysfunction was associated with an increase in RV contractility .Grading of diastolic function is widely done using Doppler echocardiography, but grading systems have changed considerably over the last decade. In addition, the different grading systems have several inherit limitations and are not interchangeable. Since the patient population included in the present analysis was selected based on the ability to perform supine exercise test and excluded patients with atrial fibrillation and other cardiopulmonary disorders, likely resulted in the selection of a relatively healthy AS population. Further, the present study is not applicable for patients with symptomatic AS and more advanced co-morbidity as it included completion of maximal exercise testing, which according to guideline recommendations excludes symptomatic patients. Even though, there were no cases with significant anemia, the presence of patients with comorbidities including diabetes (N = 5) and coronary artery disease (N = 3) may have biased the results. Further, no systematic assessment of asymptomatic coronary artery disease was done using coronary angiography; thus the number of patients with significant coronary stenosis is unknown. Notably, all patients underwent maximal exercise testing without significant angina or development of new regional wall motion abnormalities on 2D echocardiography. Exercise was done in a semi-supine position, which is known to increase preload conditions compared with upright exercise. Since all patients performed exercise testing in a semi-supine position, it is unlikely to be the primary determinant of between-group differences but may have increased RAP in some patients. It would have been preferable to include T1 mapping measurements of diffuse myocardial fibrosis but was not performed due to non-availability at our institution during the study, and we were only able to complete assessment of focal fibrosis. The lack of association between focal fibrosis and diastolic function may be due to the small sample size; therefore the risk of type 2 error exists.The present study demonstrates that abnormal LV diastolic function is a common finding in asymptomatic significant AS, and when diastolic dysfunction is moderate, right ventricular afterload is increased. The increase in RV afterload is compensated at rest with no signs of right heart failure but is associated with increased right atrial pressure and inversely related to oxygen consumption during exercise. Morphologically, RV remodeling in patients with diastolic dysfunction was characterized by smaller chamber size suggesting reduced RV compliance.


There are significant relationships between LV filling and IRF patterns. IRF patterns may provide an index for evaluation of LV diastolic function.The purpose of this study was to investigate the relationship between isovolumic relaxation flow (IRF) patterns in left ventricle (LV) and mitral inflow patterns. Color Doppler loops were acquired for vector flow mapping in apical long-axis view in 57 patients with coronary artery disease, 31 patients with dilated cardiomyopathy, and 58 healthy controls. IRF patterns were classified into three categories: pattern A, apically directed flow; pattern B, bidirectional flow with small scattered vortices; and pattern C, a large vortex. All normals and patients with normal LV filling (n = 10) showed pattern A. Patients with impaired relaxation consisted of 31 (66%) patients having pattern A, 11 (23%) having pattern B, and 5 (11%) having pattern C. Patients with pseudonormal filling included 4 (31%) patients having pattern A, 7 (54%) having pattern B, and 2 (15%) having pattern C. In patients with restrictive filling, 14 (78%) showed pattern C, 4 (22%) showed pattern B, and no patient showed pattern A. IRF patterns were associated with LV filling patterns (χ IRF has been found in patients with coronary artery disease (CAD)6, hypertension7, hypertrophic cardiomyopathy8, and right ventricular pacing10, and in normal subjects12. It can occur in conditions associated with a wide range of LV dysfunction, as well as normal to hyperdynamic LV function. IRF can be identified by different Doppler techniques, such as the color M-mode Doppler13, pulsed wave Doppler12, continuous wave Doppler5, and two-dimensional color Doppler flow imaging echocardiographies2.Left ventricular (LV) isovolumic relaxation (IVR) period starts with closure of the aortic valve and continues until the mitral valve opens, during which the LV pressure rapidly drops below left atrial pressure and then initiates LV early filling. The time constant of LV isovolumic pressure decay (tau) has been accepted as a gold standard of LV relaxation performance. IVR is an important determinant of early transmitral pressure gradient that in turn determines transmitral Doppler filling patterns. The IVR period is not a period of hemodynamic stasis. Normally, regional pressure gradient exists in the LV chamber during IVR, which generates suction and contributes to the occurrence of intraventricular isovolumic relaxation flow (IRF)14. In VFM, the flow velocity vectors are obtained through mathematical calculations that convert a two-dimensional distribution of measured velocity (in the beam direction) and inferred velocity (perpendicular to the beam direction) into a plane of vortical and nonvortical laminar flow vectors16. VFM is suitable for assessment of the local flow dynamics, especially the vortex flow in the LV chamber. In our previous study14, IRF patterns were divided into three types: pattern A, an apically directed flow; pattern B, a bidirectional flow with small scattered vortices; and pattern C, a large vortex persisting throughout the entire IVR period. However, it is not clear how the IRF patterns correspond to the LV diastolic filling patterns. We therefore sought to investigate the relationship between the IRF patterns and mitral inflow patterns using VFM in the present study. In order to evaluate various patterns of IRF and mitral inflow, normal subjects and patients with CAD or dilated cardiomyopathy who had a wide range of LV function ranging from normal systolic and diastolic performance to mild-to-moderate dysfunction and to overt heart failure were included in the present study.We have investigated IRF by using vector flow mapping (VFM) in our previous studyWe screened 110 patients who were diagnosed with CAD or dilated cardiomyopathy in our hospital. Exclusion criteria included inadequate echocardiographic visualization, arrhythmia, tachycardia, any type of valvular heart disease, congenital heart disease, hypertrophic or restrictive cardiomyopathies, myocarditis, pericarditis, or an unstable clinical or hemodynamic profile. CAD was defined as a diameter stenosis of >50% in one or more main coronary arteries as determined by selective coronary angiography. Of these patients, four had significant valvular regurgitation, four had valvular stenosis, three had arrhythmia, two had pericardial effusion, two had significant valvular regurgitation and arrhythmia, two had inadequate echocardiographic visualization, and one had pericardial effusion and significant valvular regurgitation. Four patients were also excluded due to the fusion of the mitral E and A waves. Thus the final study population consisted of 57 patients with CAD  and 31 patients with dilated cardiomyopathy, including 57 men and 31 women with a mean age of 58 ± 10 years (range 31–80 years). All patients were in sinus rhythm during echocardiographic examination.Fifty-eight age- and sex-matched healthy volunteers  with no previous history of cardiovascular disease served as a control group.18. Mitral inflow patterns included normal, impaired LV relaxation, pseudonormal LV filling, and restrictive LV filling. Transmitral E and A velocities were obtained in pulsed wave Doppler mode from the apical 4-chamber view. Also, Doppler tissue imaging was used to determine systolic and diastolic mitral annular velocities  at the septal side of mitral annulus from this view. The IVR period was determined by simultaneous phonocardiograms and two-dimensional color Doppler flow imaging recordings, which was identified as the period between the end of systolic outflow  and the start of transmitral inflow . LV ejection fraction (EF) was obtained using the biplane Simpson’s rule.Studies were performed with an Alpha 10 ultrasound system . Mitral inflow patterns were identified, and basic echocardiographic data and wall motion score index were acquired according to the American Society of Echocardiography criteriaColor Doppler flow images of the standard apical long-axis view in 3 consecutive cardiac cycles were acquired. Sector size and depth were optimized for a highest possible frame rate. Also, the low-velocity filter and Doppler velocity range were adjusted to allow detecting low-velocity Doppler signals without generating aliasing and avoiding ghosting artifacts during the IVR period. In this study, the Doppler velocity range was 25–66 cm/sec and the frame rates varied from 43 to 110 frames/sec (mean 71 ± 14 frames/sec).The color Doppler data were analyzed using VFM workstation  by off-line analysis. The frame-by-frame analysis of the intraventricular flow structure during the IVR period was performed. A vortex was represented as a series of concentric rings in the vortex map.16. The basic concept of VFM is that non-turbulent blood flows can be deconstructed into a single non-vortical laminar flow and several vortical laminar flows. The processing algorithm of VFM technology consists of four steps. First, the color Doppler data are decomposed into non-vortical laminar flow and vortex flow components. Second, in the vortex flow component, under the assumption that the flow velocity components perpendicular to the scanning plane are zero, the tangential velocities are calculated by using an algorithm that employs the stream function of hydrodynamics. Third, in the non-vortical laminar flow component, the directions of flow vectors are determined by using flow function19. The tangential velocities are derived from the directions of flow vectors and the non-vortical laminar flow component of the color Doppler data. Finally, the flow velocity vector is obtained by composing the vectors from the two components. The principles of VFM and detailed algorithms have been reported in other studies16.VFM can only deal with laminar flows and cannot be applied to turbulent flows20. The velocity components perpendicular to apical long-axis view might be minimal and negligible21. Apical long-axis view is quite acceptable for the analysis of the intraventricular vortex in most situations22.In VFM, two-dimensional assumptions are used to develop an intraventricular flow vector distribution and the through-plane flow is assumed to be minor or non-existent. The color Doppler data were obtained from apical long-axis view in the present study. This plane includes both LV inflow and outflow axes, and normal intraventricular flow should be plane symmetry with respect to this planeTwenty-five subjects were randomly selected to determine the reproducibility of the detection of IRF patterns. Color flow Doppler cine loops were acquired by two independent observers (interobserver variability) and twice by the same observer (intraobserver variability), 10 minutes apart. VFM analysis was performed by the two independent observers and by the same observer on two distinct occasions. The two independent observers were blinded to all clinical and other echocardiographic measurements data, and without knowledge of each other’s readings.Continuous data are expressed as the mean ± SD unless otherwise indicated. All statistical analyses were conducted utilizing SPSS 11.5 software . One-way analysis of variance, followed by post hoc tests  if the analysis of variance resulted in significance, was performed for comparisons among the different groups. Differences in proportions were compared by the chi-square test. A P value < 0.05 was considered statistically significant.This study was supported by the grant from the Medical Scientific Research Project of Dalian (No. 1712063). Mitral inflow patterns were identified and basic echocardiographic data were acquired according to the American Society of Echocardiography criteria. The ethical committee of PLA 967th hospital approved the study, and all subjects gave written informed consent.14.On average, 5 ± 1 frames (ranging from 4 to 10 frames) of two-dimensional color Doppler flow images were acquired during the IVR period in this study. IRF was demonstrated in all subjects. IRF patterns in the LV chamber were classified into three categories as reported in our previous studyThe intraventricular flow is entirely or predominantly directed toward the apex throughout the IVR period, and red-encoded flow is widely distributed in all parts of the LV cavity. In the streamline map of VFM, IRF is organized along parallel streamlines heading towards the apex Fig. , top rowApically directed or basally directed flows can be found in different parts of the LV chamber, and the direction of the intraventricular flow can be changed during different phases of the IVR period. In the streamline map, the flow streamlines show not only apically or basally directed flows, but also rotational flow structures in the LV cavity Fig. , top rowThe streamline map shows that the blood flow within the whole LV chamber keeps a rotational motion during the IVR period. The flow in the posterior part of LV cavity is directed toward the apex and the flow in the anterior part is directed toward the base Fig. , top rowAll 58 normal subjects demonstrated IRF as pattern A. Of these normals, 45 showed parallel streamlines towards the apex throughout the whole IVR period and no vortex could be found in the LV chamber. The remaining 13 normal subjects had very few small transient vortices in one or more image frames. Among all normals, 34 showed an E/A ratio >1 and 24 showed an E/A ratio <1. The clinical and echocardiographic variables of normals are shown in Table Of all 88 patients, 45 patients showed pattern A, 22 patients pattern B, and 21 patients pattern C. In terms of transmitral filling patterns, 10 patients had normal LV filling pattern, 47 patients had impaired relaxation pattern, 13 patients had pseudonormal filling pattern, and 18 patients had restrictive filling pattern.2 = 52.026, P < 0.001; Fig. Patients with normal LV filling pattern all demonstrated IRF as pattern A. Patients with impaired relaxation pattern consisted of 31 (66%) patients having pattern A, 11 (23%) patients having pattern B, and 5 (11%) patients having pattern C. Patients with pseudonormal filling pattern included 4 (31%) patients having pattern A, 7 (54%) patients having pattern B, and 2 (15%) patients having pattern C. In patients with restrictive filling pattern, 14 (78%) showed pattern C, 4 (22%) showed pattern B, and no patient showed pattern A. The IRF patterns were associated with the LV filling patterns  and septal E/e′ ratio was <15 (10.5 ± 3.3). Patients with pattern B showed mean E/A ratio >1 (1.13 ± 0.78) and E/e′ ratio ≈15 (14.7 ± 7.6), and patients with pattern C showed mean E/A ratio >2 (2.11 ± 1.42) and E/e′ratio >15 (23.0 ± 9.3). E/e′ ratio was significantly higher in patients with pattern C than in patients with patterns A and B (both P < 0.05). Comparisons of clinical and echocardiographic variables between normals and patients are shown in Table A good reproducibility was demonstrated for the detection of IRF patterns by using VFM. IRF was identified as pattern A in 12 subjects, pattern B in 5 subjects, and pattern C in 6 subjects on two distinct occasions by the same observer. The intraobserver agreement rate for detection of IRF patterns was 92%. IRF was identified as pattern A in 13 subjects, pattern B in 4 subjects, and pattern C in 6 subjects by the two independent observers. The interobserver agreement rate was also 92%.In the present study, significant relationships were observed between the LV filling patterns and the IRF patterns. All normals, patients with normal LV filling pattern, and most of patients with impaired LV relaxation demonstrated IRF as pattern A. More than half of patients with pseudonormal filling pattern demonstrated IRF as pattern B. Most of patients with restrictive LV filling demonstrated IRF as pattern C.12, and a bidirectional or basally directed flow occurring in the impaired LV during the IVR period14. An intraventricular pressure gradient between the LV base and apex during the IVR period is now considered to be responsible for the genesis of IRF4. LV activation-inactivation, contraction, relaxation, recoil from systolic deformation, and nonuniformity are associated with the intraventricular flow pattern during the IVR period. IRF velocity is related to the LV systolic and early diastolic performance5. A faster IRF velocity may deliver good LV systolic performance to LV early diastolic filling3. In normal subjects, the duration and velocity of IRF get longer and higher with aging12. LV apical asynergy and global LV dysfunction can lead to an absence of IRF2. A low IRF velocity or disappearance of IRF is a manifestation of deterioration of LV systolic performance6. In myocardial ischemia and infarction, the reversal of IRF can be caused by wall motion abnormality1. Also, the LV activation sequence is an important determinant of the IRF direction10.IRF has been described as an apically directed flow occurring in the normal LV13, two-dimensional color flow2, pulsed wave12, and continuous wave5 Doppler echocardiographies have been used to visualize and evaluate the characteristics of IRF. However, most of these studies investigated only one-dimensional velocity information along the M-mode or Doppler cursor, and the two-dimensional hemodynamic status during IVR was seldom analyzed.The color M-mode28. In our previous study14, VFM was used for visualizing IRF in a plane corresponding to the apical long-axis view. IRF patterns were divided into three types and associated with LV function. Further, we investigated the relationship between the IRF patterns and LV diastolic filling patterns in the present study.VFM is a novel echocardiographic technology and enables visualization of the intraventricular flow structures in a two-dimensional scanning plane4. Normally, the pressure gradient generates suction and contributes to the occurrence of apically directed IRF4. Although the rate of relaxation is reduced in patients with impaired LV relaxation, the ability to decrease LV pressure should be preserved to some extent and intraventricular pressure gradient would be generated during the IVR period. Accordingly, in these subjects, IRF was the non-vortical laminar flow directed from base to apex  than in normals. Also, LV performance and size were moderately abnormal. The occurrence of some small scattered but sustained vortices in the LV chamber during IVR should correspond to the moderate LV diastolic dysfunction.The vast majority of patients with restrictive LV filling demonstrated IRF as pattern C. In these patients, a large vortex occupied almost all the LV chamber during the IVR period Fig. . The glo23. Likewise, in the present study, patients with pattern C had severe LV dilation and dysfunction. They showed significantly higher E/A ratio (>2) and E/e′ ratio (>15). The markedly depressed LV relaxation and elastic recoil severely reduced the ability of the ventricle to generate a diastolic intraventricular pressure gradient. LV diastolic suction performance during IVR was partly or entirely lost, the large vortex could not be dissipated, and it persisted throughout the IVR period. The appearance of the large sustained vortex during IVR should be a manifestation of severe LV diastolic dysfunction.Our previous studies have demonstrated that a large intraventricular vortex persists throughout the whole LV ejection phase and continues into the IVR period in patients with severely depressed LV function and enlarged LV chamberet al.25 reported that the LV late diastolic vortices struck the ventricular surfaces of the mitral leaflets and contributed to valve coaptation. Similarly, the vortex flow during IVR could cause a pushing force on the ventricular leaflet surfaces and hinder the opening of mitral valve. This might lead to a shortening of LV filling time to some extent.In addition, the large sustained vortex not only can depress the LV diastolic suction performance but also might delay mitral valve opening during early diastole. Sherrid 25, isovolumic contraction24, ejection23, and isovolumic relaxation14 in evaluating the cardiac function. Intraventricular blood flow patterns have been found to be correlated with cardiac disorders, such as ischemia29, cardiomyopathy26, aortic regurgitation30, and congenital heart disease31. VFM also provides a promising method to quantify dissipative energy loss in LV28 and left atrium32. In addition, the insights into LV vortex flow from use of VFM can have additional and potentially incremental value over the conventional methods to assess local flow dynamics, such as the cause of systolic anterior motion of the mitral valve in obstructive hypertrophic cardiomyopathy26 and the mechanism of mitral coaptation in normal subjects25.VFM is based on the two-dimensional color Doppler echocardiography, and it can be thus easily used for clinical applications as a part of the routine echocardiography. VFM is suitable for quantification and assessment of intraventricular vortex flow during LV filling21. Color Doppler loops were acquired for VFM in apical long-axis view in the present study, and the velocity components perpendicular to this view should be minimal and negligible22. Additional experiments can be performed in the future to evaluate to what extent the detection of the flow pattern is dependent on the view selection. In addition, optimal Doppler velocity range and instrument settings were adjusted to obtain optimized visualization of IRF and avoid ghosting artifacts.VFM has several limitations that should be noted: (1) neglecting through-plane flow in the third dimension; (2) underestimation of low velocity flow; and (3) the need for manual de-aliasing. The flow in a plane corresponding to a long-axis view should have no flow component vertical to this planeThere are significant relationships between the LV filling patterns and the IRF patterns. Pattern A of IRF should correspond to normal or mild diastolic dysfunction, pattern B should correspond to moderate diastolic dysfunction, and pattern C should correspond to severe diastolic dysfunction. The IRF patterns assessed by using VFM may provide an index for identification of LV filling patterns and evaluation of diastolic function.Dataset 1