Mitral Stenosis and Mitral Regurgitation. The model mimics an adult cardiovascular system, comprising a four-chambered heart with systemic, pulmonic circulation. The simulation of the model output comprises regulated pressure, volume, and flow for each heart chamber, valve dynamics, and Photoplethysmogram signal for normal physiological as well as pathological conditions due to mitral valve disorders. The generated physiological parameters are in agreement with published data. Additionally, we have related the simulated left atrium and ventricle dimensions, with the enlargement and hypertrophy in the cardiac chambers of patients with mitral valve disorders, using their Electrocardiogram available in Physionet PTBI dataset. The model also helps to create ‘what if’ scenarios and relevant analysis to study the effect in different hemodynamic parameters for stress or exercise like conditions.Valvular heart diseases are a prevalent cause of cardiovascular morbidity and mortality worldwide, affecting a wide spectrum of the population. In-silico modeling of the cardiovascular system has recently gained recognition as a useful tool in cardiovascular research and clinical applications. Here, we present an in-silico cardiac computational model to analyze the effect and severity of valvular disease on general hemodynamic parameters. We propose a multimodal and multiscale cardiovascular model to simulate and understand the progression of valvular disease associated with the mitral valve. The developed model integrates cardiac electrophysiology with hemodynamic modeling, thus giving a broader and holistic understanding of the effect of disease progression on various parameters like ejection fraction, cardiac output, blood pressure, etc., to assess the severity of mitral valve disorders, naming  Cardiovascular diseases (CVD) account for a massive rate of mortality all over the world. Recent statistics from World Health Organization (WHO) reported nearly 17.9 million death due to cardiovascular disease along with the economic burden of billions of dollars spent every year on screening, diagnosis, and related health-care-associated to CVD . The agiOut of the valvular disease associated with the left ventricle, dysfunction of the mitral valve remains a leading medical problem worldwide . This vaRecently, cardiovascular research has shown significant involvement in simulating cardiac behavior through in-silico models . PoweredIn this paper, we present a closed-loop, real-time, lumped parameter cardiovascular simulation model, which contains the dynamics of four cardiac chambers, heart valves, and lumped pulmonic and systemic circulation. It is a reduced order model, where the pulsatile behavior of the heart chambers is triggered and modulated through cardiac electrophysiology. The forward electrophysiology pipeline (EP) has been implemented to generate a single lead electrocardiograph (ECG) signal from a cardiac source model. Hemodynamics is governed through time-varying compliance as derived from the EP model. A schematic workflow of the developed prototype is shown in Cardiac dynamics incorporate both active and passive filling phases resulting in more realistic changes of pressures with ventricular dilatation. Valve dynamics and precise adjustment of valvular properties allow realistic simulation of both stenotic and insufficient valves. The hemodynamics is coupled with central nervous system through sympathetic and parasympathetic control via baroreflex auto-regulation mechanism. The integrated EP-hemodynamics approach takes into account the cellular to organ level manifestation of cardiac dynamics, thus making the model multimodal and multiscale. Such prototype model can be used to simulate the cardiac dynamics for healthy physical condition as well as mitral valve disorders, namely ‘stenosis’ and ‘regurgitation’ with varying severity. The model is used to simulate the pressure-volume (PV) dynamics of the left ventricle and atrium. This in turn provides the information on the stroke volume, variations in aortic and pulmonary pressure and indications of hypertrophy/enlargement in cardiac chambers. Additionally, as part of modeling the systemic circulation, variations in the peripheral blood volume pulse are used to simulate the Photoplethysmogram (PPG) signals . Such PPWe demonstrate that the proposed model generates cardiac parameters, for both normal and pathophysiological cases, which are consistent with earlier published clinical and experimental data. Additionally, the model has been tested using a limited set of measured ECGs of patients with mitral valve disorders. In such a scenario, the measured ECG serves as an input to the model to generate hemodynamic parameters. A subset of these parameters namely, the dimensions of the left cardiac chambers are validated with the left ventricular hypertrophy and left atrial enlargement score, obtained from such clinical data.The rest of the paper is organized as follows. Section 2 comprises the methodology, which includes the layout of the cardiovascular hemodynamic model containing the four-chambered heart, followed by the EP model to generate ECG signal from a cardiac source model and subsequently deriving the chamber and valve dynamics, and PPG synthesis for a healthy adult. In section 3, we simulate the mitral valve stenosis and regurgitation of varying severity followed by section 4, where we present the simulation results for healthy, mitral stenosis and regurgitation condition and a hypertrophy or enlargement analysis based on real ECG data. In section 5, we discuss the capability of ‘what if’ simulation through a simulated stress condition and report its effect on mild mitral valve disorders followed by a brief discussion on the capability and limitations of our model. Section 6 concludes the paper.The developed cardiovascular model integrates two separate modalities, namely the hemodynamic model and a reduced electrophysiological model, sufficient to derive the compliance function for driving the hemodynamic model. In this section, the layouts of the cardiovascular hemodynamic model of the four-chambered heart along with the EP model, and PPG synthesis have been discussed.lv) and left atrium (la), pumps oxygenated blood to all the tissues of the body. This specific circulation is called systemic circulation  are the set of duration between the R-R peaks those are used to derive the cardiac cycles e(i).For determining the cardiac cycles, we first compute the R-R interval from the ECG signal. Let us assume that e(i); i ∈ q, there exists a set of PQRST [For each cardiac cycle, of PQRST  time-insith cardiac cycle, the activation parameters are estimated as given in For q cardiac cycles, we obtain a set of activation parameters Therefore, for the entire ECG signal, comprising Based on each Based on the valvular functions of the heart, there are four phases of operation during a cardiac cycle . The dyne(i), having a duration of Ti, four different phases of operation in lv can be observed based on the valvular functions of the left heart. The lv-pressure (Plv) and lv-volume (Vlv) are used to generate pressure-volume (PV) loop [Assumption 1, the parameter Vlv can be evaluated as given by Within each cardiac cycle PV) loop  in each The four cardiac phases are briefly mentioned here.Umi = δmi = 0 and Uao = δao = 0. In this phase, the pressure in the lv decreases, however, the volume remain constant as all the valves are closed. The volume of blood that remains in lv is called as the end-systolic volume (ESV). The la pressure continues to rise because of the venous return from the pulmonary system.In this phase of operation, both the valves in the left-heart are closed as the pressure in successor region is greater than the predecessor region; hence, la would be greater than pressure in lv, thus, Pla > Plv. As a consequence, the mitral valve will open (Umi = 1) that subsequently allows the blood to flow from la to lv. Hence, the lv volume increases. However, in this phase, the pressure in sa will be greater than the pressure in lv, so, the aortic valve will remain closed, therefore, Uao = δao = 0.After the relaxation phase, at some point, the pressure in lv, the mitral valve closes because of the increased intra-ventricular pressure, thus Umi = δmi = 0. During this period, the aortic valve still remains closed, thus Uao = δao = 0. In this phase, the lv pressure starts increasing, without changing the lv volume, as all the valves are closed. The volume of blood that remains in lv is called as the end-diastolic volume (EDV).After the filling of sa pressure (i.e. Plv > Psa), the aortic valve opens (Uao = 1). As a consequence, the blood from lv is ejected via aorta. Hence, the lv volume decreases.After the isovolumic contraction phase, the intra-ventricular pressure starts increasing. When it exceeds the la, lv and sa are shown in lv during diastole or insufficient ejection in a systolic phase or whether the cardiac function is normal. The interaction of the pressure-volume of the right ventricle during the ventricular phases is also shown in The above mentioned four phases occur in a cyclic manner and primarily drives the overall hemodynamics. A representative variation in pressure and volume in ki is a scale factor, and li is the length of the ith chamber. In this current work, we have only estimated the diameters for the la, and lv, that can provide indications of possible enlargement or hypertrophy in those chambers.Considering the shape of each cardiac chamber to be ellipsoidal, hence, the diameter of a cardiac chamber can be calculated from its respective volume as given in lv contraction causing the intra-arterial pulse pressure wave in the proximal aorta and the reverse flow during filling of the rv. These two flows give rise to a large systolic peak and a small diastolic peak as shown in Fig 6c. Additionally, on the falling edge of PPG, a dichroic notch is also observed just before the diastolic peak. It is to be noted that the amplitude of the PPG signal is unit-less. Hence the relative temporal relationship between the peaks and notches along with the morphology of the signal, are used to extract the combined pathophysiological condition of the heart and systemic circulation. The steepness of the rising slope of the systolic peak in PPG, is found to be correlated with the blood pressure [Photoplethysmogram signal captures the temporal volumetric change in blood flow by means of detecting the reflection or absorption of incident light on the capillaries of the systemic circulation . Usuallypressure . Likewispressure , or indisa-pressure dynamics (Psa) for the forward flow, and the ra-pressure dynamics (Pra) for the reverse flow. Hence, the function of the modeled PPG signal (p(t)) is represented as given in k1 and k2 are the forward and reverse coefficients to replicate the arteries and arterioles of the systemic circulation. These coefficients are initially tuned to match the experimentally measured PPG signals for healthy subjects. Such a combined cardiovascular and PPG model is then used to study the changes in the peripheral flow, where the hemodynamics is effected due to disorders in mitral valve.In one of our recent works, such effects in the PPG are simulated in the systemic circulation . In the lv filling phase. For the later, during systole, due to improper functioning of the valve, a portion of the stroke volume passes retrogradely from lv to la. The next two sections focus on the dynamics associated with MI disorder.Mitral valve (MI) dysfunctions are a major medical problem worldwide . MI disola, thus raising the la-pressure (Pla). Hence, the la-volume (Vla) increases (enlargement) over time because it has to produce higher pressure when it contracts against the high resistive stenotic valve. Moreover, the mechanical obstruction leads to an increase in pressure within the pulmonary vasculature and the right side of the heart. The reduced filling in lv decreases the ventricular stroke volume (SV), thus the cardiac output (CO) and the aortic pressure (Psa) also reduce. MS is mostly caused by rheumatic heart disease or thickening, shortening, fusion, and calcification of the chordae tendineae [In mitral stenosis (MS), the orifice of the valvular area gets narrower. As a consequence, a high resistance across the stenotic valve causes blood to stay inside the endineae . Progres2 [Normally, the mitral valve has an effective area of 4–6 cm2 . During 2  as mild,2 .Rmi of Eqs AN = 4 cm2, AMS is the geometric orifice area of the stenotic mitral valve, and Rmi = 0.002 mmHg.sec/mL defines the resistance across MI in normal condition [lv-pressure (Plv) and lv-end-diastolic volume (LVEDV).During MS, the blood flow through MI is reduced because of the increasing valvular resistance. In our study, we have created similar scenarios by varying the parameter ondition . So, baslv and atrial volume overload, at the advanced stages, it forces cardiac remodeling, effecting chamber dilation with clinical consequences of atrial fibrillation, and heart failure [MI regurgitation or insufficiency causes blood to leak backward through the mitral valve when the heart contracts . This re failure .δmi in Eqs δmi > 0. Therefore, in isovolumic contraction and ventricular ejection phases, some amount of blood flows in the backward direction (from lv to la) based on the value of δmi.In the study, the effect of the backward blood flow, due to the improper closing of the mitral valve at the ventricular ejection phase, is modeled by the parameter δmi defines the regurgitation severity, indicating the dysfunction of the parameter Umi during Pla < Plv as given in otherwise condition. During MR, there is a volume increment in the la and lv. As a result, enlargement and hypertrophy evolve across those chambers to support the larger stroke volume (SV). The level of severity of MR is usually measured by regurgitation fraction (RF), which is defined as the percentage of lv stroke volume that regurgitates into la as given in Vmi and Vao are the forward blood volume of the mitral and aortic valve respectively during a cardiac cycle.Hence, δmi, the simulated RF can be evaluated from the forward and backward blood flow through the mitral valve. Mild, moderate, and severe MR have been graded [Hence, based on the parameter n graded  as displIntel core-i7 processor in MATLAB software environment. The following parametric values [Simulations have been executed on a system having 8 GB of RAM with c values , as showRmi) to 0.002 , end-systolic (LVESD) dimensions and la end-diastolic (LAEDD) dimension are also within the range experimental observations [To study the performance of the proposed hemodynamic cardiovascular system (CVS) for a normal cardiac condition, representing the cardiac dynamics of a healthy adult, we set the mitral valve resistance (shown in  and δi =rvations .Intel core-i7 processor with 8 GB of RAM). In case of a normal cardiac condition, an example of such initial time progression of PV-loop of lv, before it reaches the steady state, is shown in lv changes with time and finally forms a continuous limit-cycle in the PV state-space.The simulations are performed by solving the differential equations as stated in Eqs la), increasing la pressure and subsequent increase in la volume, compensating for decreasing lv volume. As the la increases in size, there is an increase in pulmonary pressure, often causing pulmonary congestion and increased risk of developing atrial fibrillation. The severity of ‘stenosis’ has been modeled by the parameter Rmi  has been enlarged with respect to the normal value thus signifying the enlargement condition in la.From the  PV-loop , it is elv and decreased MAP [Simulated PPG signal relates systemic blood pressure and change in volumetric flow at the aorta to a distal measurement site like a fingertip. The simulation result for MS is shown in ased MAP . Howeverlv. During this phase, there is no physical manifestation of symptoms. The next phase is termed as the ‘Transitional phase’ where the weakening of myocardium starts and ventricles can no longer compensate for the leak due to regurgitation. Clinical symptoms like fatigue (decreased ability to exercise), shortness of breath begin to appear in this stage. As the disease progresses further, it enters into the ‘Decompensated phase’. In this phase, there is a progressive enlargement of the la and abnormal heart rhythm, mostly Atrial Fibrillation (AF) manifests. Blood pressure in pulmonary arteries increases giving rise to pulmonary hypertension. These changes slowly lead to heart failure like condition.MR pathology and evolution of clinical symptoms are well documented in the literature and are subdivided into three dominant phases that correlate with disease progression from mild to severe . The firlv dynamics  are shown in the To validate the applicability of the proposed model, we have employed three real ECG data from the Physionet PTBI dataset  taken frI and V1 –53. The ormality , 55. A sNext, in order to the drive the CVS model, we extract the required temporal parameters using  from thela-enlargement, whereas, it is low for lv-hypertrophy. Similarly, patient IDs 110 and 188, the possibilities of presence la enlargement and lv hypertrophy are high. Executing the CVS model with the ECG signal, for the above-mentioned patients, we have observed similar consequences. Simulated parameters corresponding to left ventricular end-diastolic dimension (LVEDD) and left atrial end-diastolic dimension (LAEDD)  of the patient IDs 188 (having concurrent AR with moderate to severe MR) and 110 (severe MR), it is perceived that the LVESD for both cases is approximately within a similar range  have no symptoms till they are at the near severe stage, and abnormal heart rhythm starts generating due to ventricular remodeling or there is a sign of pulmonary hypertension . HoweverPpa). This sudden increase in Ppa due to stress, coupled with varying changes in physiology due to onset of stenosis, gives rise to symptoms for diagnosis which under normal resting condition is not manifested until the disease progresses to a significant level [Ppa, increasing the workload of the right side of the heart, making it difficult to provide an adequate amount of oxygenated blood to the body and manifesting symptoms of breathlessness, pulmonary congestion, and fatigue [For MS, as indicated in nt level . Similar fatigue .The holistic approach of integrating the cardiac source model and electrophysiology further provide enhancements to the hemodynamics that can be used to aid clinical decision support tools. With the proposed coupled electrophysiology-hemodynamics system, we demonstrate a pipeline for ECG synthesis from cardiac TMP, which in turn triggers and modulates the hemodynamic chain of operations. However, the proposed model can also be fed-in with measured true ECG and generate the hemodynamic parameters. This feature enables to estimate hemodynamic features, clinically revealed through echocardiography study to be predicted by the model only with ECG information. The ECG genesis mode is more suitable for EP driven diseases like myocardial ischemia  or conduThe concept of cardiac remodeling and associated ventricular shape changes due to change in sarcomere contraction and calcium dynamics is a topic of active research and we are working on integrating electrophysiology and cardiac biomechanics to replicate some of the aspects of cardiac remodeling. We are also working on the effect of ischemia and its effect on hemodynamic parameter variation . PresentFurther improvement in the model in the line of integrating biomechanical properties to the time-varying compliance model, will further enhance the effect of ‘preload’ and ‘afterload’ phases and will also increase the plethora of ‘what if’ analysis. EP model can be further enhanced to introduce the effect of arrhythmia, as seen in advanced stages of the valvular disease, and also incorporate the effect of ventricular remodeling on the sarcomere excitation-contraction mechanism and its eventual effect on the hemodynamics.In this paper, we report the development of a multiscale-multimodal cardiac model to capture the changes in hemodynamics due to mitral valve disorders. The proposed approach couples electrophysiology with hemodynamics, enhancing a holistic understanding of underlying pathophysiological changes associated with mitral valve stenosis and regurgitation. The simulated results of the healthy condition and diseased conditions are in accordance with clinical reports. The developed model and the simulation platform can establish the trend of physiological parameters with disease progression. Real-time simulation of the multiscale model may aid in the personalized cardiac model generation that can be used to understand the qualitative interaction of cardiac variables and also aid in patient-specific outcome prediction.The uniqueness of the developed model is not any particular advanced modeling solutions in each sub-part, but rather the integrated holistic approach giving a comprehensive overview of cardiovascular hemodynamics in healthy and mitral valve disease in an in-silico environment. The possibility to change the model parameters and create ‘what if’ analysis facilitates a comprehensive understanding of pathological manifestation, whereas the real-time simulation and feedback impart features that could be used in a clinical decision support scenario in intensive care or surgical use cases. The model will be further enhanced to improve the understanding of complex hemodynamic states and validation through patient data.The criteria to generate the score for la enlargement from the Lead II and V1 of ECG signals are briefly given below .For ECG lead II, the duration between two peaks of the bifid P wave, that is greater than 40 milliseconds, and the net duration of the P wave, that is greater than 110 milliseconds.For lead V1, the duration of the terminal negative portion of the biphasic P wave, that is greater than 40 milliseconds, and the amplitude of the terminal negative portion of the biphasic P wave, that is greater than 1 millimeter (0.1 millivolt).lv hypertrophy, the scores are computed from the time and amplitude of various segments in ECG signals [For the assessment of the  signals . These cVoltage criteria—(i) The amplitude of R wave or S wave in limb leads is greater or equal to 20 millimeters, (ii) the amplitude of S wave in Leads V1 or V2 is greater or equal to 30 millimeters and (iii) the amplitude of R wave in V5 or V6 is greater or equal to 30 millimeters. If any of these three criteria is satisfied then the score would 3.Abnormality in ST segment—(i) If the ST-T vector is opposite to QRS without digitalis then the score is 3, (ii) if the ST-T vector is opposite to QRS with digitalis then the score is 3.Additional conditions—(i) If the left-atrial enlargement is present then the score is 3, (ii) if QRS duration greater than or equal to 90 milliseconds, then the score is 1, (iii) delayed intrinsicoid deflection in Leads V5 or V6 is greater than 50 milliseconds, then the score is 1.lv-hypertrophy is approximately 83%-97% [Finally, adding all the above scores, if it is greater than 5, then the possibility of the presence of  83%-97% .S1 Data(ZIP)Click here for additional data file.


Plasma concentrations of many cardiovascular and inflammatory proteins are altered after ST-elevation myocardial infarction (STEMI) and may provide prognostic information. We conducted a large-scale proteomic analysis in patients with STEMI, correlating protein levels to infarct size and left ventricular ejection fraction (LVEF) determined with cardiac magnetic resonance imaging. We analysed 131 cardiovascular and inflammatory proteins using a multiplex proximity extension assay and blood samples obtained at baseline, 6, 24, and 96 h from the randomised clinical trial CHILL-MI. Cardiac magnetic resonance imaging data at 4 ± 2 days and 6 months were available as per trial protocol. Using a linear regression model with bootstrap resampling and false discovery rate adjustment we identified five proteins  with elevated values corresponding to larger infarct size or worse LVEF and four proteins  with values inversely related to LVEF and infarct size, concluding that among 131 circulating inflammatory and cardiovascular proteins in the acute and sub-acute phase of STEMI, nine showed a relationship with infarct size and LVEF post-STEMI, with IL-6 and ST2 exhibiting the strongest association. In the CANTOS trial, canakinumab, an interleukin-β1 inhibitor, resulted in lower rates of nonfatal MI, stroke, and cardiovascular death without lowering lipid levels. Although methotrexate did not impact clinical outcome in the Cardiovascular inflammation reduction trial (CIRT), the recently-published results of the Colchicine Cardiovascular Outcome Trial (COLCOT) and Colchicine in Patients with Chronic Coronary Disease Trial (LoDoCo2) further support this concept4. However, the influence of inflammation in myocardial infarction extends beyond chronic inflammation, as acute inflammatory processes are believed to play a role in reperfusion injury and tissue repair in the infarcted myocardium. This is suggested by observational and experimental studies showing elevation of a number of inflammatory and cardiovascular proteins in the acute phase of MI5, correlating with infarct size, particularly in the setting of reperfusion8. Current understanding is that a balance between inflammation and its resolution, the result of fine-tuned interplay between pro-inflammatory and anti-inflammatory proteins, is central to adequate tissue healing and salvage of compromised myocardium9. Excessive inflammation is thought to contribute to tissue remodelling, fibrosis, and scarring of the heart10, whereas a lack of inflammation may result in inadequate tissue healing12.Myocardial infarction is a consequence of atherosclerosis, and chronic inflammation has long been thought to contribute to the progression and instability of atherosclerotic plaques. However, causality was not proven until recently with the Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS)15.Biomarker studies provide an important route to understanding myocardial injury, which is vital to development of innovative therapies. However, few studies have assessed the relative importance of proteins by assessing a large number of circuating proteins simultaneouslyThe objective of this study was to perform a large-scale proteomic analysis using a novel proximity extension assay (PEA) to evaluate the hypothesis that plasma concentrations of 157 inflammation- and cardiovascular-associated proteins correlate to infarct size and ejection fraction in the acute and chronic phase post-STEMI as assessed by cardiac magnetic resonance imaging (CMR).16 were included in this post-hoc analysis. The study design for the CHILL-MI trial has been previously published16. In brief, it included patients with STEMI who underwent percutaneous coronary intervention (PCI) from July 2011 through March 2013 at nine sites in four countries. Participants were randomized to hypothermia induced by rapid infusion of cold saline and endovascular cooling or to standard care. Patients with cardiac arrest, previous myocardial infarction (MI), previous PCI or coronary artery bypass grafting, known congestive heart failure, end-stage kidney disease or hepatic failure, recent stroke, coagulopathy, pregnancy, or Killip class II to IV at presentation were excluded. One hundred twenty patients were randomized and 117 underwent PCI. The primary endpoint in CHILL-MI was infarct size/myocardium at risk assessed by CMR on day 4 ± 2, which was not significantly reduced by hypothermia  and all patients were followed-up with a second CMR after 6 months. Blood samples used in this biomarker study collected at baseline, 6, 24, and 96 h post-PCI were available from 119 patients. The protein profile was analysed by Olink Bioscience . The co-primary study endpoints were infarct size (% of left ventricular mass) and ejection fraction (%) assessed in the acute phase (within 4 ± 2 days) and non-acute phase (after 6 months). The area under the curve value for each biomarker was established relative to early infarct size (4 ± 2 days post-MI) and long-term ejection fraction (6 months post-MI) as the co-primary analyses. Secondary analyses included the assessment of ∆ ejection fraction, ∆ stroke volume, ∆ left ventricular mass, myocardial salvage index (%) and microvascular obstruction (expressed as % of left ventricular mass).All patients from the Randomized Controlled Study of the Use of Central Venous Catheter Core Cooling Combined With Cold Saline as an Adjunct to Percutaneous Coronary Intervention for the Treatment of Acute Myocardial Infarction (CHILL-MI) trialThe Ethics Committee of Lund University, in agreement with the declaration of Helsinki, approved the study. All participants provided informed consent. This study adheres to the REMARK guidelines for biomarker studies.16. After scout images to locate the heart and the standard imaging planes, 0.2 mmol/kg body weight of an extracellular gadolinium-based contrast agent was administered. For visualization of the MaR and evaluation of LVEF, early contrast-enhanced steady-state free precession cine images were obtained approximately five minutes after contrast injection. For infarct visualisation, late gadolinium enhanced images were acquired 15–20 min after administration of the contrast agent. Cine and late gadolinium enhanced images were acquired in the short-axis view, from base to apex, and in three standard long-axis views , in a breath-hold image sequence. The analysis of ventricular dimensions, MaR, and infarct size was performed by the core lab  using post-processing software . Infarct size was available for 97 of 101 patients at 4 ± 2 days and 82 of 86 at 6 months and is expressed as a percentage of the left ventricular myocardium. Ejection fraction was available for all patients that underwent CMR. Observers blinded to all other data conducted the assessment of infarct size and ejection fraction.A total of 101 patients underwent CMR on day 4 ± 2 days and 86 at 6 months post-STEMI. Reasons for dropout of CMR are available17. Briefly, 1 μL plasma samples were mixed with 3 μL incubation mix containing pairs of highly specific oligonucleotide-labelled antibodies for each target protein. The oligonucleotides were subsequently joined using a DNA polymerase, and the PCR template was extended, after which uracil-DNA glycosylase was added, digesting the DNA templates and the remaining universal primers. Sample mix was quantified by microfluidic real-time PCR, and protein values were converted to normalized protein expression units on a log2-scale in which protein values indicate concentration as opposed to absolute quantity.Whole blood samples were centrifuged on site within 1 h, and plasma was separated and stored at − 80 °C in aliquots of 100 μL. One hundred μL of plasma EDTA samples was sent to the core laboratory to be analysed, and 1 μL was prepared according to the manufacturer’s instruction and analysed using a high-throughput technique: Proseek Multiplex CVD I96 × 96 and Proseek Multiplex Inflammation I96 × 96. The PEA assay design has been described in detailhttps://www.olink.com/products/complete-protein-biomarkers-list/). Biomarkers with missing values or values below the LOD exceeding 25% of all measurements were excluded from the primary analysis: IL17a, IL20Ra, IL2rb, IL1alpha, TSLP, IL2, IL10Ra, IL22Ra1, PDL1, IL24, IL13, ARTN, TNF, IL20, IL33, IFN-gamma, IL4, LIF, NRTN, ST1a1, IL5, ITGB1BP2, MAMP, BNP, and PSGL1. Due to the well-established association of NT-proBNP to ejection fraction, NT proBNP was excuded. For markers included in the final analysis, values below LOD were replaced by LOD/2. A list of all markers, abbreviations, distribution, LOD, lower limit of quantification, upper limit of quantification, and inter- and intra-assay variation are presented in Supplementary Table Laboratory personnel blinded to patient characteristics, clinical outcomes, and treatment allocation performed all biochemical analyses. The limit of detection (LOD) was determined for each protein biomarker based on the mean value of negative controls plus 3 standard deviations calculated from large datasets by Olink Bioscience. Standard curves for all target proteins are available online  and figures generated in R v.3.2.2 for Macintosh . A linear regression model with bootstrap resampling with 1000 replications was used as the primary statistical model to assess the relation between protein to endpoint. Univariable as well as multivariable analyses adjusting for age, sex, and body mass index along with treatment group (hypothermia or standard care) were conducted. Adjustment for false discovery rate in multiple testing was made using the Benjamini–Hochberg method. A two-sided Patient characteristics and CMR results are presented in Table Several proteins were associated with the study outcomes. ST2, myoglobin (MB), interleukin-6 (IL-6), and pentraxin-3 (PTX3) were significantly positively correlated with infarct size at 4 ± 2 days in both univariable and multivariable analyses adjusted for age, sex, and body mass index as well as treatment arm Fig. . Only STTwo proteins, ST2 and MB were negatively associated with myocardial salvage index  showing a positive relationship with infarct size or negative with ejection fraction and four  with elevated values corresponding to higher ejection fraction, smaller infarct, or improved stroke volume. The proteins with most evident associations were IL-6 and ST2.20, and our study also confirms previous reports of IL–6 correlation with infarct size and ejection fraction7. Besides IL-6, Renin was the only other protein with levels negatively related to long-term ejection fraction after STEMI (Fig. 21. It has been suggested that IL-6 induces overexpression of angiotensin 2 type 1 receptors in vascular smooth muscle, resulting in oxidative stress and endothelial dysfunction; possibly linking these findings22. Direct inhibition of renin in experimental models protects against isoproterenol-induced MI, reperfusion injury and the renin–angiotensin–aldosterone system have also been reported involved in fibroblast scarring and activation of infarct myofibroblasts9.Our study confirms previous experimental results, links findings to the clinical setting as well as adding to knowledge of the relative importance of these proteins, not possible with single marker studies. Among studied proteins, ST2 and IL–6 were unique in their correlation with early and final infarct size in both univariable and multivariable analyses. IL–6 was also the only protein to show a link with both early and final ejection fraction, emphasizing its role and importance in the post-infarcted myocardium. IL-6 is a pleiotropic interleukin with both pro- and anti-inflammatory effects, involved in T-cell activation and induction of a pro-inflammatory cascade. In STEMI settings, IL-6 has been shown to predict short- and long-term mortality as well as progression to heart failureEMI Fig. . Whereas23. In experimental studies, knockout of the IL-33 gene has resulted in increased cardiac remodelling24. Administration of recombinant IL-33, on the other hand, has been shown to reduce infarct size and improve ventricular function, an effect mediated through ST2 signalling, as IL-33 does not improve outcome in ST2-knockout mice25. The soluble form of ST2, measured in this study, antagonizes the binding of IL-33, functioning as a decoy receptor for IL-3326. Elevated levels of soluble ST2 have been observed in patients with poor outcome after MI related to cardiac fibrosis and LV remodelling28. An interesting finding is that despite the strong link of ST2 levels to infarct size in our study, we observed no correlation with ejection fraction or ∆ ejection fraction, ∆ LVM, or ∆ stroke volume, surrogate measures of LV remodelling28. The chemo-attractant protein IL-16 and cathepsin enzyme inhibitor CSTB were the only proteins found elevated in patients with improved stroke volume. Elevated levels of IL-16 in patients with STEMI have been previously linked to cardiac fibrosis30. Considering the pro-inflammatory role of IL-16 as a chemoattractant, this finding is contradictory. However, the complexities of the balance of pro- and anti-inflammation in the acute and subacute phase of STEMI are largely unknown.ST2, well-studied in cardiovascular settings, showed a strong correlation with infarct size and was the only protein negatively associated with myocardial salvage index. ST2 is a member of the IL-1 receptor family and exists in a transmembrane isoform and in a soluble isoform. IL-33 is the functional ligand of the ST2 transmembrane isoform, and the IL-33/ST2 signalling pathway results in an immune response through nuclear factor kappa B signalling31. In humans, high levels of PTX3 have been observed after MI32, and, in experimental studies, PTX3-deficient mice show larger infarcts and greater no-flow area33. Proteins with less well established connections to outcome after STEMI were also identified, including TRAIL and TRANCE. TRAIL was negatively correlated to infarct size at 6 months; a finding in line with previous studies showing low levels of TRAIL in patients with poorer outcome post-MI34. Finally, we observed levels of IL-10, an anti-inflammatory cytokine with the ability to inhibit release of pro-inflammatory cytokines by macrophages, to be elevated in patients with larger infarcts. Previously, high levels of IL-10 have been found in heart failure after acute myocardial infarction36.PTX, an acute phase reactant, was a factor in early infarct size in both the univariable and multivariable analyses. PTX3, a long pentraxin belonging to the same family of proteins as C-reactive protein, is believed to be an important regulator of inflammation and cardio-protection38. However, our results indicate that, among hundreds of circulating proteins not routinely assayed in clinical setting of MI, IL-6 and ST2 appear to potentially carry valuable prognostic information. Ongoing randomized trials of tocilizumab, a monoclonal antibody targeting IL-6 receptors may add further insight39.The findings presented in this study highlight the difficulty of interpreting results of single protein studies in patients with STEMI due to the large amount of proteins that are altered and because of their pleiotropic effects. Whether these proteins are markers of myocardial damage, mediators of processes occurring in the infarcted myocardium or both is yet to be established. Many proteins inversely related to outcome in clinical studies are, nonetheless, associated with smaller infarcts, improved ejection fraction, and reduced LV remodelling in loss-of-function models40. Regardless of the limited effect of hypothermia, we chose to adjust for this treatment arm, possibly influencing results for some proteins.This study has a number of limitations. We studied the levels of a large number of proteins relative to several endpoints. This confers a risk of type I error that was controlled for by adjusting for false discovery rate. The OLINK assay is highly sensitive but was unable to detect a number of important proteins. The data are presented as relative units, rendering it difficult to compare results to other studies. Our younger study population with relatively few comorbidities and first-time STEMI, excluding patients with cardiogenic shock at presentation, may not have been entirely representative of the general STEMI population, but provided fewer comorbidity-confounded protein values. Analyses of ejection fraction at 6 months, ∆ left ventricular mass, ∆ ejection fraction, and ∆ stroke volume might have been confounded by discharge medications such as ACE-inhibitors, as they improve ejection fraction as well as reduce remodelling. However, a study without these medications cannot be performed. We have previously shown minor differences in peak levels of some of the assessed proteins in patients treated with hypothermia as compared to a group receiving standard care, possibly due to only modest coolingAmong 131 circulating inflammatory and cardiovascular proteins in the acute and sub-acute phase of STEMI, IL-6 and ST2 were the most clearly associated with infarct size and ejection fraction as evaluated by CMR in the acute and long-term phase after STEMI. Our study confirms previous experimental findings and provides a link to the clinical setting as well as adding to current knowledge of the importance of these proteins.Supplementary Information.


The morphological changes that occur in myxomatous mitral valve disease (MMVD) involve various components, ultimately leading to the impairment of mitral valve (MV) function. In this context, intrinsic mitral annular abnormalities are increasingly recognized, such as a mitral annular disjunction (MAD), a specific anatomical abnormality whereby there is a distinct separation between the mitral annulus and the left atrial wall and the basal portion of the posterolateral left ventricular myocardium. In recent years, several studies have suggested that MAD contributes to myxomatous degeneration of the mitral leaflets, and there is growing evidence that MAD is associated with ventricular arrhythmias and sudden cardiac death. In this review, the morphological characteristics of MAD and imaging tools for diagnosis will be described, and the clinical and functional aspects of the coincidence of MAD and myxomatous MVP will be discussed. Since the recognition that mitral valve (MV) leaflets can be affected by myxomatous degeneration ) ,2, with Yet, MMVD is more complex than isolated MVP, as the morphological changes involve various components of the MV apparatus, ultimately leading to impairment of the MV function. In this context, intrinsic mitral annular abnormalities are increasingly recognized and have clinical ramifications ,9,10.In this article, we focus on mitral annular disjunction (MAD), a specific anatomical abnormality associated with MVP characterized by a distinct separation between the mitral annulus and the left atrial wall and the basal portion of the posterolateral left ventricular (LV) myocardium. The first description of MAD was reported in 1986 by Hutchins et al. , who fouMAD can also occur in normal subjects as a normal anatomical variation of the mitral annulus fibrosus , but theIn the following, the morphological characteristics of MAD and imaging tools for diagnosis will be described, and the clinical and functional aspects of the coincidence of MAD and myxomatous MVP will be discussed based on two case studies.Although the term annulus implies a complete ring or fibrous cord-like structure around the mitral orifice that hinges the leaflet while separating the adjacent atrial and ventricular walls, this arrangement is uncommon. McAlpine  in 1975 Since the MV annulus has no dynamics of its own, the movement and contraction pattern of the annulus depends on the contractility of the LV myocardium with which the annulus is normally connected, as well as on the movements of the aortic root .Thus, in normal subjects, the MV annulus moves in systole towards the LV apex and in diastole towards the left atrium . In addiIn the presence of MAD, the annulus is functionally decoupled from the LV, and a paradoxical annular dynamic occurs as the annulus moves in concordance with the left atrium during the cardiac cycle and not with the LV. Thus, expanding and flattening of the annulus occurs in systole, causing the section of the LV wall adjacent to the MAD to move outwards in systole and inwards in diastole . Such sySince the region between the aorta and the anterior MV leaflet  is fibrous tissue between two robust fibrous trigones, this region is less prone to dilation. MAD is therefore predominantly found in the area of the posterior  leaflet  and middle (P2) posterior scallops are affected ), where The extent of a MAD is variable and is determined by the distance from the insertion of the posterior leaflet to the LA wall to the transition of the LA wall into the LV wall, which can range from a few millimeters to more than 10 mm ,26, and The diagnosis of a MAD is made in systole. It cannot be made in diastole, because the myocardium of the LV is then appropriately positioned under the MV annulus. During systole, the annulus “slides” when the posterolateral portion of the LV contracts and the detachment from the LV myocardium becomes visible. This dynamic nature of a MAD explains why the diagnosis is difficult to make when the heart does not contract—for example, during heart surgery, when the surgeon is viewing the MV from the atrium —or iNoninvasive imaging modalities that allow for an assessment of the MV apparatus and surrounding structures during the cardiac cycle, such as transthoracic (TTE), transesophageal echocardiography (TEE), cardiac computed tomography (CCT), and cardiac magnetic resonance (CMR) imaging, can be used for the detection and quantitative analysis of a MAD.However, regardless of the imaging modality used, the posterior annulus should be carefully assessed for the presence of a MAD, as it can easily be overlooked. Recognition on its relevancy is not yet widespread.The diagnosis of a MAD is generally made by measuring the distance between the posterior leaflet insertion into the left atrial wall and the base of the LV free wall in systole. However, the cutoff for diagnosing is not uniformly defined. In the original histological description by Hutchins et al. , a MAD wDetecting a MAD by echocardiography requires a careful frame-by-frame analysis of high-resolution images.When 2D TTE imaging is used, a MAD is assessed by measuring the distance from the site of the posterior leaflet insertion into the left atrial wall (upper border of the disjunction) to the connection between the left atrium and the ventricular myocardium (lower border of the disjunction). This should be performed in a parasternal long axis TTE view at end-systole , 90% had a MAD. The prolapse was localized posteriorly in 77.8% of cases .In the largest 2D TTE study of MAD to date, 979 patients with either MMVD (Barlow’s disease (637 patients) or fibroelastic deficiency (342 patients), a lower than previously reported prevalence of MAD of any length was found (MMVD: 21.8%). The maximum disjunction distance in patients with MMVD was 6.7 ± 2.2 mm, and the main MAD localization was in the region of the lateral (P1) and middle (P2) segments of the posterior leaflet (69.2%) compared to the medial (P3) segment (37.7%) .Using 2D TEE, the degree of annular displacement can be best measured at the P2 level by using a 4-chamber mid-esophageal view at 0 degrees during systole ,27. UsinReal-time 3D TEE (RT-3D TEE) allows for a more detailed and quantitative analysis of the mitral annular dimensions and dynamics than 2D TEE ,10,31,32A RT-3D TEE study comparing the dynamics of the mitral annulus in normal patients and in patients with MMVD showed that, in contrast to normal subjects, the MV annulus in MMVD is still dynamic, but there is no early systolic area contraction and no deepening of the saddle shape, despite a similar magnitude of ventricular contraction, indicating functional ventricular–annular decoupling. In late-systole, the saddle shape deepens, but there is significant enlargement of the annular area, which may also contribute to MV incompetence . By usinCCT can also be used to readily identify a MAD by taking advantage of the 3D nature of this modality. Putnam et al. reported on 90 retrospectively studied patients with MVP who underwent a preoperative CCT. The presence and degree of the MAD was assessed by rotating the view plane around the center of the MV to visualize the disjunction along the annular circumference. A MAD was identified in 20% of the patients, and it was typically located adjacent to a prolapsed or flail posterior mitral leaflet scallop. Of these patients, 75% had a maximum disjunction distance >4.8 mm and 90% >3.8 mm. The presence of a MAD was associated with the female gender, a smaller annulus size, and a greater posterior leaflet length .In a study comparing different imaging modalities (CMR versus. TEE versus TTE) in the detection of a MAD, a significantly higher prevalence of a MAD of any length  was found in 131 patients with MVP by CMR imaging . The MAD distance was 5.0 (4.0–7.0), 7.0 (5.0–8.0), and 8.0 (7.0–10.0) mm by CMR, TEE, and TTE, respectively. The agreement on MAD identification and on MAD measurement was moderate between TTE and CMR and good between TEE and CMR .A CMR study by Dejgaard et al. demonstrated that the circumferential extension of MAD is variable and varies between 30° and 240° (median 150°), which means that a MAD can take up to two-thirds of the circumference. A MAD was found exclusively along the circumference of the posterior leaflet .CMR imaging has advantages in identifying MAD, as well as providing additional information about the distribution and extent of myocardial fibrosis . Since eThe patient is a 47-year-old yoga teacher who suffered SCD during one of her yoga classes. Bystander cardiopulmonary resuscitation was performed; she was found to be in ventricular fibrillation and was successfully defibrillated by the paramedics. Prior to this episode, the patient was entirely asymptomatic and had excellent functional capacity.At the hospital, a physical examination was normal other than mid-systolic click and a mid-late systolic murmur upon cardiac auscultation. The ECG showed no abnormalities, except for frequent polymorphic premature ventricular contractions (PVTs). The laboratory results were within the normal limits. A TTE demonstrated normal LV size and function. The mitral valve appeared myxomatous, and bi-leaflet MVP was present. MR was purely late-systolic (which confirmed the auscultation findings), and by the multimodal quantification of MR, it was moderate. In addition, a MAD was seen. The echocardiographic findings are summarized in Coronary heart disease was excluded with computed tomography coronary angiography. Due to the aborted SCD and the frequent premature ventricular contractions (PVCs) on the ECG, as well as MAD with MVP, an electrophysiological study was performed, which showed inducible polymorphic ventricular tachycardia (VT).CMR imaging confirmed the diagnosis of moderate MR (regurgitation fraction was 24%) with mild mitral annular dilation and the presence of a MAD E. The ovAfter the completion of her diagnostic evaluation, the patient underwent automatic implantable cardioverter defibrillator (AICD) implantation and treatment with a betablocker (Atenolol). During her subsequent five-year follow-up, she has done well, having only occasional palpitations but no dyspnea and no chest pain. In addition, she has not had any further presyncope, syncope, VT detected, or AICD discharges.This patient is a 46-year-old woman with known bi-leaflet prolapse and a known MAD. She has occasional palpitations and mild dyspnea on exertion but was able to function as a yoga and Pilates instructor. She had serial TTE examinations over a period of eight years to monitor her moderate MR. Over this time period, a reduction of the LVEF from 68% to 60% was observed, as well as a slight increase of the LV-end systolic diameter from 37 to 40 mm. Brain natriuretic peptide levels were in the normal range, with 89 pg/mL.TTE and TEE imaging confirmed the diagnosis of a bi-leaflet prolapse with myxomatous changes of both mitral leaflets (Barlow’s disease) and significant MR . A Zio XA stress echocardiography revealed above-average functional capacity. However, she had evidence of an impaired contractile reserve. Namely, she did not have an augmentation of her LVEF with exercise—the increase was <5% during maximal stress. The peak exercise systolic pulmonary artery pressure was 43 mmHg. There were no signs of a stress-related ischemia.CMR imaging confirmed a mildly impaired LV function (LVEF 53%) and a regurgitant fraction of 45% consistent with moderate-severe MR. The extracellular volume fraction was 34% , consistent with diffuse myocardial fibrosis. Focal mid-wall and subendocardial fibrosis was observed in the mid-inferior wall F.Regarding the decision-making process, different considerations played a role:(1) Diffuse myocardial fibrosis, as seen in CMR imaging in this patient, is known to be an independent predictor of increased adverse clinical outcomes in patients with chronic MR undergoing MV repair ,35 and i(2) A lack of contractile reserve is known to be independently associated with a two-fold increase in the risk of cardiac events in patients with primary MR  and to b(3) Even though modern reconstructive surgery shows promising results in anterior and bi-leaflet MVP repair , Barlow’(4) The patient preferred to avoid surgical intervention if possible.Thus, based on all of the findings, an increased perioperative morbidity in this MR patient was hypothesized and, also, to comply with the patient not wanting surgery, the decision was made to proceed with a percutaneous MV repair strategy. Subsequently, two MitraClips (XTR)  were implanted with an excellent result, with minimal residual MR . One yeaIn the first patient with a MAD and myxomatous MVP, the arrhythmogenic event was clinically in the foreground, while the MR was erroneously assessed as being severe. The echocardiographic evaluation of patients with MR by an MVP should carefully assess whether the MR is holosystolic or purely mid-late systolic. MR that occurs only mid-late systolic and not holosystolic is unlikely to be severe or to create hemodynamic consequences and is associated with a more benign course and more favorable long-term outcomes . The evaVan Wijngaarden et al. demonstrated that symptomatic ventricular arrhythmias are not uncommon in patients with an MVP (11% of patients) and are associated with significant annulus abnormalities, such as a MAD and annulus dilatation. However, severe arrhythmias (with an increased risk of SCD) were primarily found in a selected subgroup of patients—namely, young women with Barlow’s syndrome —while the overall risk was rather low in patients with an MVP (3%), suggesting that these patients should be consistently monitored diagnostically but the risk of SCD is low .However, there is growing evidence that myxomatous MVP and MAD are associated with an increased risk of VTs and SCD ,16, as sCarmo et al. found that the severity of MAD was significantly correlated with the occurrence of nsVT on Holter monitoring. A disjunction distance >8.5 mm was thereby a strong predictor for nsVT .p = 0.018), late-systolic murmur , complex ventricular arrhythmias originating from the LV , and the presence of bi-leaflet MVP  was found as compared with those without late-gadolinium enhancement. Moreover, patients with MVP and late-gadolinium enhancement had a larger disjunction distance . A larger disjunction distance was also associated with a higher prevalence of SCD in the patient group with MVP and LV fibrosis [In a further study involving 36 patients with arrhythmic MVP  with concomitant LV fibrosis with LV late-gadolinium enhancement on CMR and no or trivial MR and 16 MVP patients without LV late-gadolinium enhancement examined with morpho-functional CMR, the MAD was identified as constant feature of arrhythmic MVP with LV fibrosis . In patifibrosis .Thus, it can be postulated that the excessive mobility of the mitral leaflets in the presence of MMVD and MVP in the area of the posterior leaflet, which is augmented by MAD, leads to increased mechanical stress of the posterolateral LV wall and the papillary muscles, which may lead to LV localized myocardial fibrosis, the morphological substrate of arrhythmic MVP ,45.A recently published study including 116 patients with MAD found that ventricular arrhythmias were frequent in patients with MAD. Of note, 22% of the patients with MAD did not have MVP, and MVP was not associated with the arrhythmic events. This is consistent with MAD being itself an arrhythmogenic entity .Thus, a careful assessment of MV anomalies, including MAD in particular, especially in association with an auscultatory audible mid-systolic click, may help to better characterize patients who would benefit from risk stratification for significant arrhythmias. In this context, CMR helps to identify patients with myocardial fibrosis and, thus, an increased risk for arrhythmogenic events. It also means that MMVD, MVP, and MAD should be ruled out in patients with unexplained palpitations, especially younger ones.The second case focuses on the severity of MR and the need for treatment in a relatively young, symptomatic patient with advanced MMVD, bi-leaflet MVP, and MAD.According to the current societal guidelines (ACC/AHA and European), chronic symptomatic severe MR is an indication for surgery, preferably MV repair ,47, withAs the degenerative process may persist even after MV repair, achieving MR reduction by edge-to-edge repair alone may not be sufficient in the long term in the presence of MAD, and further studies are needed to clarify whether additive annular therapy for MAD is necessary in these cases. For this reason, MAD should not be overlooked in patients with MMVD and MVP undergoing MitraClip implantation.In addition to the MR reduction, there was a significant reduction of ventricular arrhythmias observed after MitraClip implantation, and LV function also improved. This may indicate that, with adequate reduction of MR, the mechanical stress on the mitral leaflets and, consequently, on the mitral annulus, the chordae, and the papillary muscles, diminishes even in the presence of MAD, thus minimizing, or at least reducing, a trigger for ventricular arrhythmias in the presence of a morphological substrate .p = 0.01), and the PVC decreased from 16% to 4% (p = 0.04). Patients with persistent or new nsVT and/or sVT at follow-up showed a significant decrease in LVEF from 38% to 33%. Whether these data are applicable to patients with MMVD and MAD is unclear. Studies are needed to better assess in MMVD with MVP and MAD to what extent ventricular arrhythmias can be reduced by sufficient MR reduction from surgery, as well as by MitraClip implantation. The impact on LV function also appears important.Ledwoch et al.  recentlyThe causal relationships between myxomatous MVP, MAD, and the mitral annulus are not yet fully understood. However, it is evident that the presence of a MAD in patients with MMVD has both functional and clinical implications and contributes to an increased incidence of ventricular arrhythmia and SCD. Thus, a MAD should not be overlooked in patients with MMVD, especially as this may influence the choice of therapy. The two cases we reported demonstrated the complexity of the decision-making process regarding therapy, especially when relevant MR is present, as these are mostly younger patients. The clinician should integrate the clinical, laboratory, and imaging findings. In this context, CMR provides important data on the severity of MR, effect on LV remodeling, and myocardial fibrosis. Surgical MV repair is standard for young patients with severe degenerative MR. However, transcatheter edge-to-edge repair can be a safe and effective option for high-risk patients. Whether the elimination of relevant MR  in the presence of a MAD is an effective long-term therapy needs to be confirmed, ideally in a prospective randomized controlled study.


The independent role of pericardial adipose tissue (PAT) as an ectopic fat associated with cardiovascular disease (CVD) remains controversial. This study aimed to determine whether PAT is associated with left ventricular (LV) structure and function independent of other markers of general obesity.We studied 2471 participants (50.9 % women) without known CVD from the Korean Genome Epidemiology Study, who underwent 2D-echocardiography with tissue Doppler imaging (TDI) and computed tomography measurement for PAT.P < 0.001). Greater pericardial fat levels across quartiles of PAT were associated with increased LV mass index and left atrial volume index  and decreased systolic (P = 0.015) and early diastolic (P < 0.001) TDI velocities, except for LV ejection fraction. These associations remained after a multivariable-adjusted model for traditional CV risk factors and persisted even after additional adjustment for general adiposity measures, such as waist circumference and body mass index. PAT was also the only obesity index independently associated with systolic TDI velocity (P < 0.001).Study participants with more PAT were more likely to be men and had higher cardiometabolic indices, including blood pressure, glucose, and cholesterol levels (all PAT was associated with subclinical LV structural and functional deterioration, and these associations were independent of and stronger than with general and abdominal obesity measures. Pericardial adipose tissue (PAT), which refers to the combination of epicardial adipose tissue  and paracardial fat , is associated with the development of cardiovascular disease (CVD) and events . In partIn this study, we investigated the relationship of PAT with LV structure and function using the tissue Doppler imaging technique after accounting for clinical measures of general obesity in a large community-based cohort study.The study population was recruited from an ongoing population-based Ansan cohort embedded in the Korean Genome Epidemiology Study, which is described in detail elsewhere . BrieflyThe protocol of the study was approved by the Human Subjects Review Committee at the Korea University Ansan Hospital, and all participants provided written informed consent at every site visit.2 for women and > 115 g/m2 for men. Subclinical LV diastolic dysfunction was defined if at least two of the following conditions were met: (i) septal TDI Em velocity ≤ 7 cm/s; (ii) septal E/Em ratio > 15; (iii) LA volume index ≥ 34 mL/m2 ) and percent study characteristics are presented across quartiles of PAT. Quartiles included the following PAT ranges . For those in the top PAT quartile, the mean WC was more than 15 cm higher than that of participants in the bottom quartile (least PAT). The mean BMI was nearly 5 kg/m2 higher. PAT showed strong positive correlations with WC  and BMI . The participants with more PAT were older, more likely to be men, consumed higher alcohol amounts and smoked more, and had comorbidity diseases, including hypertension, T2D, or dyslipidemia , compared to those in the lowest quartile. However, there was no difference in the level of physical activity (P = 0.383).The baseline demographic, clinical, and biochemical measurements stratified by PAT quartiles are shown in Table P < 0.001), compared to those in the lowest quartile. There was no significant difference in LV ejection fraction among the PAT quartiles (P = 0.326). Similarly, using the predefined definitions of LVH and LV diastolic dysfunction, the prevalence of LV hypertrophy and LV diastolic dysfunction increased with higher quartiles of PAT . However, in a fully adjusted model , these statistically significant associations were identified in BMI (P < 0.001 for LV mass and LA volume and P = 0.009 for TDI Ea velocity) and PAT , but not WC. On the basis of the standardized β, the magnitude of the associations was higher with PAT than with BMI. Interestingly, a statistical significance between systolic TDI velocity and adiposity measures was only observed in association with PAT (P < 0.001) in both univariate and multivariate regression models.Graded relations between the adiposity measures  and LV structural and functional measurements were then explored Table . In the In this large population-based cohort of community-dwelling adults, we found strong associations among PAT, cardiometabolic risk factors, and LV structure and function. Although these relationships with LV structure and function were also observed with general adiposity measures, such as WC and BMI, the magnitude of the associations was strongest with PAT than with WC or BMI. Interestingly, only pericardial fat was associated with subclinical LV systolic function, and the association persisted in a multivariate-adjusted model including WC and BMI. The present findings strongly support the role of a local pathogenic effect of PAT on the structure and function of the heart.Although heterogeneous and inconsistent terminology, such as cardiac ectopic fat, intra-pericardial fat, extra-pericardial fat, intra-thoracic fat, mediastinal fat, and total thoracic fat, has been used to refer to adipose tissue around the heart by authors in any individual study, PAT is generally defined as EAT plus paracardial fat . In the EAT and paracardial fat are embryologically and anatomically different. Because of its direct anatomical proximity to the myocardium, EAT seems to be more strongly associated with the development of CVD than abdominal visceral fat . A studyThe precise mechanisms by which EAT and paracardial fat contribute to CVD development remain unclear. Both increased EAT and paracardial fat could affect LV diastolic filling and LA dilation by a possible mechanical force . In addiper se did not show a significant association with LV mass [Numerous studies have shown that general obesity and abdominal fat are associated with increased LV mass and LA volume. On the other hand, there is limited evidence for the associations of EAT or PAT with LV chamber measures. Some have only shown significant associations in univariate analysis . Others  LV mass , the mea LV mass . In lineper se is an independent predictor of LV diastolic function. In a sample of 1,004 subjects, Christensen et al. demonstrated that only high EAT volume was associated with impaired LV diastolic function in patients with T2D, whereas paracardial fat did not show any significant association with LV diastolic function in both patients with and without T2D [Although a few studies failed to reveal an independent effect of EAT on LV diastolic function , most prhout T2D . Specifihout T2D . The prehout T2D . OverallIn contrast to the solid evidence regarding the impact of EAT on LV diastolic function, an association of EAT or PAT with LV systolic function is still unclear. A series of recent studies using 2D/3D speckle tracking strain techniques for measuring LV systolic function in lieu of LV ejection fraction, although limited by small sample size, has indicated that EAT is associated with subclinical deterioration of LV systolic myocardial function, independent of general measures of obesity, such as BMI and waist/hip ratio , 36, 37.r = 0.92, P < 0.001) [The major strengths of our study include the relatively large sample size from a population-based cohort, which reduced the potential for referral bias, and the use of a highly reproducible CT method for assessing PAT, which is the gold standard for fat quantification. Also, we assessed LV systolic and diastolic function using TDI measures, which can detect early subclinical deterioration in LV function. However, we did have limitations including use of a cross-sectional study design and evaluation of a single racial group. Thus, our findings may not be generalizable, and we cannot establish causality. Additionally, it should be mentioned that our study results may not be directly comparable with prior studies that measured only EAT instead of PAT because EAT and paracardial fat may contribute to the changes of LV structure and function in different ways. However, considering the fact that EAT and PAT are highly correlated (< 0.001) , 34 alth< 0.001) , paracar< 0.001) , 23, 34.< 0.001) . Finally< 0.001) .PAT accumulation is significantly associated with myocardial remodeling and subclinical impairment of LV systolic and diastolic function. Associations between PAT and cardiac structure and function are stronger than with other measures of general adiposity and thus represent a useful marker for obesity-associated cardiac changes.


The Coronavirus Disease 2019 (COVID-19) pandemic, being caused by an easily and rapidly spreading novel betacoronavirus, has created a state of emergency for people, the scientific community, healthcare systems and states, while the global financial consequences are still unfolding. Cardiovascular complications have been reported for COVID-19-infected patients and are associated with a worse prognosis. ECG and biomarkers may raise suspicion of cardiac involvement. However, transthoracic echocardiography is a fast and reliable bedside method to establish the diagnosis of cardiac complications, including acute coronary syndromes, pericarditis, myocarditis, and pulmonary embolism. Early detection of cardiac dysfunction by speckle tracking echocardiography during off-line analysis may be used to identify a high-risk population for development of heart failure in the acute setting. Precautionary measures are mandatory for operators and equipment to avoid viral dispersion. No specific treatment is yet available for severe acute respiratory syndrome coronavirus 2 (SARS-CoV 2), and a variety of antiviral, immune-modifying, and antioxidant agents are therefore under intense investigation. Echocardiography, including assessment of myocardial deformation, may provide a useful tool to monitor the effects of the various treatment regimens on cardiac function both acutely and in the midterm. A novel enveloped, single-stranded, positive-sense RNA betacoronavirus belonging to the family of coronaviruses has been identified as the causative agent of the novel viral pneumonia that started in the city of Wuhan, Hubei Province, China, on December 12, 2019, . CompareCardiovascular complications are relatively common, occurring in up to 25% of COVID-19 patients , 8 Tabl. MyocardPulmonary embolism , 21, 22 Echocardiography is a first-line imaging method to diagnose overt and subtle myocardial dysfunction . LocalizOn the contrary, when two of the initial diagnostic parameters are abnormal, a complete TTE should be performed to diagnose possible cardiac involvement and ventricular dysfunction. Even the combination of two elevated laboratory biomarkers alone, should lead to a complete TTE, as hsTrop T and NT-proBNP levels were linearly correlated and considerably increased in non-survivor COVID-19 patients . As cardNotable considerations exist when estimating left and right ventricular systolic function, one being the presence of tachycardia, related to numerous factors such as fever, hypoxemia, cytokine production, and systemic inflammation. Ventricular systolic function is negatively affected in the presence of tachycardia due to the force–frequency relationship. Diastolic function estimations parameters are also affected by tachycardia, since fusion of transmitral E and A waves makes estimation of their ratio and the DT time inaccurate . In thatEchocardiography exams should be performed by experienced practitioners to ensure quick acquisition of high quality images  and thusTEE carries a high risk of spreading aerosolized viral material within an exam environment. It should be avoided during the pandemic . It shouSafety is of utmost importance for the personnel involved in echocardiography of suspected or confirmed COVID-19 patients. Frequent and meticulous handwashing is mandatory. Personal Protective Equipment (PPE) should be used depending on the risk level. Face masks, headcovers, eye shields, gloves, gowns, and shoe covers should be used when examining high risk patients. Detailed description for the PPE is provided by WHO, ASE and EACVI , 34, 41.Equipment used for Echocardiography studies should be thoroughly disinfected at the end of the exam, in the examination room and again at the hallway . DedicatA number of different pharmacological agents —antivirain vitro that chloroquine can inhibit viral binding to ACE2 receptor  has experimental  and clinConvalescent plasma treatment may be promising in terms of viral load and even mortality .Corticosteroids have conflicting evidence for their effect on SARS CO-V 2 infection as they may delay viral clearance from blood and respiratory tract based on data from previous coronaviruses outbreaks . On the in vitro model of human epithelial airway cells  from FDA for suspected or confirmed COVID 19 adult and children patients with severe disease since May 2020 . It has ay cells  and is aay cells –60. Prelay cells .The combination lopinavir/ritonavir is used in treating HIV-1 infection—they are both aspartase protease inhibitors, and ritonavir increases its plasma half-life. This drug combination has been reported to reduce viral load in clinical case reports , althougMonoclonal antibodies, such as tocilizumab , sarilumAdditional protective mechanisms for IL-6 and IL-1 inhibitors may be related to regulation of ROS production, which hampers cellular functions, such as with the proteasome, leading to impaired endogenous protein degradation and mitochondrial dysfunction, augmenting the damage promoted by the direct interaction of SARS-COV proteins with the proteasome . ROS mayThe COVID-19 pandemic, still unfolding around the world, has created a significant worldwide human, scientific, financial, and psychological burden, requiring innovative and cooperative strategies to combat the pandemic and its unprecedented consequences. TTE is required to guide clinical management of patients with abnormal ECG and/or biomarkers, as it may diagnose early cardiac involvement in the acute setting. Antiviral, anti-inflammatory, and antioxidant treatment agents as well as hyperimmune plasma are being investigated in a multitude of clinical trials. Echocardiography provides a valid method to monitor myocardial effect of potential treatments for COVID-19 during hospitalization and in the mid-term follow up.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.II had the original idea of the manuscript. JP reviewed the biomarkers and treatment section. A-RV wrote the initial version of the manuscript including figure. All authors offered comments on the manuscript's sections.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Myocardial infarction remains a major health-related problem with significant acute and long-term consequences. Acute coronary occlusion results in marked electrophysiologic alterations that can induce ventricular tachyarrhythmias such as ventricular tachycardia or ventricular fibrillation, often heralding sudden cardiac death. During the infarct-healing stage, hemodynamic and structural changes can lead to left ventricular dilatation and dysfunction, whereas the accompanying fibrosis forms the substrate for re-entrant circuits that can sustain ventricular tachyarrhythmias. A substantial proportion of such patients present clinically with overt heart failure, a common disease-entity associated with high morbidity and mortality. Several lines of evidence point toward a key role of the growth hormone/insulin-like growth factor-1 axis in the pathophysiology of post-infarction structural and electrophysiologic remodeling. Based on this rationale, experimental studies in animal models have demonstrated attenuated dilatation and improved systolic function after growth hormone administration. In addition to ameliorating wall-stress and preserving the peri-infarct myocardium, antiarrhythmic actions were also evident after such treatment, but the precise underlying mechanisms remain poorly understood. The present article summarizes the acute and chronic actions of systemic and local growth hormone administration in the post-infarction setting, placing emphasis on the electrophysiologic effects. Experimental and clinical data are reviewed, and hypotheses on potential mechanisms of action are discussed. Such information may prove useful in formulating new research questions and designing new studies that are expected to increase the translational value of growth hormone therapy after acute myocardial infarction.  Myocardial infarction (MI) remains a major health-related problem worldwide, despite major treatment advances such as the widespread use of prompt reperfusion strategies . Acute cGrowth hormone (GH), a 191-amino-acid single-chain peptide extracted from human pituitary glands, is abundantly expressed in the body, including the ventricular myocardium . In factAcute interruption of blood supply to the ventricular myocardium inhibits oxidative metabolism, decreases cellular energy storages, and alters intra- and extra-cellular ion concentrations. These profound changes in the electrophysiologic milieu, occurring mainly in the region of injury, result in a wide spectrum of VTs. The reported incidence of primary VTs, a devastating complication of acute coronary occlusion, has varied widely in published registries, confounded by the inevitable delays in pre-hospital monitoring. Moreover, the post-mortem diagnosis of type-3 MI, caused by fatal VTs prior to medical attendance, requires demonstration of acute thrombosis in a coronary artery, raising occasional difficulties in its differentiation from other causes of sudden cardiac death . AllowinGH  and its The first study, performed by our group, quantified VTs from continuous electrocardiography, obtained by means of implanted miniature telemetry transmitters . These dThe explanation for the antiarrhythmic actions of GH during acute MI remains controversial, and several factors may be operative . CytoproSeveral mechanisms may be operative in mediating the cytoprotective effects of GH. Activation of pro-survival pathways by GH is a strong candidate, an action exerted via Akt-phosphorylation, which is dependent on the activation of the phosphoinositide 3-kinase . In turnDespite the considerable evidence favoring the cytoprotective actions of GH on the ischemic myocardium, the finding of decreased infarct size could not be reproduced in our laboratory using an identical setting ; specifiIn addition to ischemia/reperfusion, two important amendments should be pointed out in our protocol : First, We measured the ischemic- and infarcted-zones 24 h post-MI using green-fluorescent microspheres and triphenyltetrazolium; the final size of myocardial necrosis  did not differ between the GH-treated group and the controls . Thus, iSignificant evidence favoring the inhibitory effects of GH on norepinephrine release stems from an experimental study in rats, where GH-treatment early post-MI not only improved myocardial energy reserve, but also markedly decreased myocardial norepinephrine content and plasma levels . These oThe hitherto available evidence ,15,26,30The ensuing electrophysiologic effects of high interstitial norepinephrine-levels are multifaceted, including elevated resting membrane potential, delayed after-depolarizations, and dispersion of repolarization that forms functional re-entrant circuits . AdrenerFollowing acute coronary occlusion, regional myocardial necrosis elevates local wall stress, leading to the expansion of the non-contractile region. Infarct expansion early post-MI is intertwined with healing mechanisms, with their balance largely determining subsequent changes in non-infarcted regions . In thisThe GH/IGF-I axis is activated within hours after acute coronary occlusion and participates in the inherent infarct-healing process; for example, a threefold increase in plasma GH levels was found in MI patients as early as 6 h after the onset of symptoms, rapidly declining three days thereafter . Such acThe favorable effects of GH on the ischemic and non-ischemic myocardium may have translational value in the post-MI setting, as indicated by a number of experimental studies using in vivo animal models. In a seminal work, Cittadini et al.  demonstrOur group has further examined the efficacy of a single dose of GH, administered selectively in the infarcted area via the intracoronary route in a large animal (porcine) model; we reported increased infarct thickness and enhanced angiogenesis in the peri-infarct area , leadingIn addition to structural LV alterations, post-MI remodeling is also associated with abnormal electrophysiologic properties, with the resultant arrhythmogenesis accounting for approximately 50% of mortality in such patients . At the In contrast to the available information on structural LV alterations, very little is known on the effects of GH on arrhythmogenesis during the sub-acute and chronic MI-phases. Attempting to bridge this gap, our group investigated indices of electrophysiologic remodeling after intra-myocardial GH administration in rats ; the assGH has been shown to exert positive inotropic effects in animal models of heart failure . The undFibrosis in the non-infarcted myocardium accompanies LV remodeling and is considered the hallmark of arrhythmogenesis during the remodeling period and the chronic phase . There iThe anti-fibrotic effects of GH in the remote, non-infarcted myocardium may seem contradictory to the well-described wound healing GH properties exerted by fibroblast activation; along these lines, we have reported a six-fold higher myofibroblast count after chronic GH administration, but, importantly, these were confined into the infarct and peri-infarct areas . Such fiAn interesting finding after short-term GH administration in our experiments  was the GH treatment post-MI appears to elicit two distinct effects, namely enhanced healing in the infarcted  and surrIn a substantial proportion of post-MI patients, LV remodeling progresses into overt heart failure, particularly in those with extensive anterior infarcts. The prevalence of heart failure is increasing, with its ominous prognosis posing a major health-related problem worldwide due to the epidemiology of coronary artery disease. Driven by its beneficial effects in animal studies, GH was examined as a potential adjunctive therapy in patients with remote MI and HF. Perhaps surprisingly, only two very small clinical studies have been reported in such patients ,62. The Clinical interest in GH post-MI has recently resurfaced after the publication of two small-scale clinical trials ,65 that Patients with remote MI and congestive heart failure present complex neuro-hormonal responses including enhanced sympathetic drive and activation of the renin–angiotensin–aldosterone system. However, the beneficial effects of GH may still ensue, even in patients with advanced heart failure, after careful selection that will take into account multiple metabolic parameters ,65. Following acute coronary occlusion, GH exerts cytoprotective actions and attenuates local myocardial norepinephrine release, thereby limiting infarct size and lowering arrhythmogenesis. During subsequent stages, GH facilitates infarct healing and decreases infarct expansion, leading to improved local LV hemodynamics. The preserved electrophysiologic properties of the peri-infarct area, along with the prevention of fibrosis in the remote, non-infarcted myocardium, attenuate adverse structural LV remodeling and arrhythmogenic substrate formation. Multiple mechanisms are likely operative, many of which remain incompletely understood, necessitating further research on this promising approach in the post-MI setting. The conclusions derived from in vitro and in vivo experiments could be tested in clinical trials, targeting specific patient populations and end-points.


Myocardial edema is one of the most common complications of coronary artery bypass grafting (CABG) that is linearly related to many coronary artery diseases. Myocardial edema can cause several consequences including systolic dysfunction, diastolic dysfunction, arrhythmia, and cardiac tissue fibrosis that can increase mortality in CABG. Understanding myocardial fluid balance and tissue and systemic fluid regulation is crucial in order to ultimately link how coronary artery bypass grafting can cause myocardial edema in such a setting. The identification of susceptible patients by using imaging modalities is still challenging. Future studies about the technique of imaging modalities, examination protocols, prevention, and treatment of myocardial edema should be carried out, in order to limit myocardial edema occurrence and prevent complications. Myocardial edema is a medical condition that can be detected in many cardiac conditions , 2. One Myocardial edema is the earliest sign of cardiac dysfunction that later can contribute to post-CABG mortality , 11. A sοιδεω” (means to swell). It is an acute, nonspecific, and reversible condition that can be acquired during cellular injury. In this context, the word myocardial edema refers to cardiac muscle cell swelling or vasogenic  swelling in nature [The word edema is derived from the ancient Greek word “n nature . Myocardn nature . Myocardn nature . Expertsn nature  mention n nature . Unfortuin vivo [Dysfunctions that are caused by myocardial edema include systolic dysfunction, diastolic dysfunction, cardiac arrhythmia, and tissue fibrosis. One of the consequences of myocardial edema is increased in hydrostatic pressure within the interstitial compartment that can exacerbate the extent of necrosis by capillary compression , 21. Myoin vivo , 22.In a physiological condition, the interstitial fluid pressure of myocardial tissue range between 15 and 120 mmHg (from end-diastolic to end-systolic phase). Myocardial tissue has a wide cyclical variation of interstitial fluid pressure, but it could not show a negative value during the cardiac cycle , 24. MyoAs mentioned earlier, interstitial myocardial edema is also controlled by the action of lymphatic flow, as this pathway helps the removal of fluid in the interstitial compartment. Edema resolution is affected by the contraction of myocardial tissue itself, the force of contraction, and heart rate. When the myocardial contraction mechanism is crippled, lymphatic flow decreases edema resolution, causing tissue malfunction. Lymphatic vessel of the heart is equipped by a valve that can prevent backflow of fluid, as the heart contraction changes from systolic to diastolic phase over time. .Water occupies 80% of the myocardium, and approximately 78% of the water is in the intracellular compartment . ResearcFluid regulation is essential in order to support an organism's life. Homeostasis of water in cardiac tissue is determined by microcirculation and lymphatic drainage. Cardiac muscle cells can control their cellular volume by modulating water transport across the plasma membrane based on their osmotic gradient and hydrostatic pressure. The myocardial cells can adjust their volume by water transport across the plasma membranes down the osmotic gradient and the hydrostatic pressure . Water m+-K+-ATPase). This mechanism carries three sodium molecules from inside the cell to interstitial fluid and two potassium molecules from outside the cell to the intracellular compartment. The action of the sodium-potassium pump depends on the availability of adenosine triphosphate (ATP) as the energy source. In a condition where ATP is limited, the sodium-potassium pump action can cause sodium ion accumulation inside the cell, thus pulling water to the intracellular compartment [The water molecule moves through a cell membrane passively. The movement is affected by osmotic gradient and membrane permeability to water. In state of homeostasis, cardiac muscle cells retain their membrane potential by the action of the sodium-potassium pump  are released from an intracellular compartment in order to reduce cell volume, and cell shrinkage activates a particular ion transporter that increases organic osmolytes in order to restore the osmotic balance between the two compartments. This mechanism is achieved through activation of Naexchange . GlycogeThere are three types of transmembrane channels involved in cellular fluid regulation: aquaporin (AQP), connexins (Cx), and pannexins . AquaporMechanical and biochemical processes regulate the detection of cell volume . The mecMacromolecule in the cardiac muscle cell is surrounded by a fluid called bound water . The macIn ventricle muscle cells, mitochondria can manage 40% of the total volume between myofibril and plasma membrane . MitochoOne of the endothelium functions serves as a physical barrier between intravascular and perivascular tissues, as well as permeable membrane . PermeabAt the organ level, the fluid balance depends on net water filtration in capillary tissue and lymphatic drainage . CapillaLymphatic drainage is managed by the cardiac pump cycle and depends on central venous pressure . Any conCABG can be carried out via two methods: on-pump or off-pump method. On-pump CABG is carried out using a cardiopulmonary bypass (CPB) machine . In CABGOther methods of CABG are called off-pump CABG and minimally invasive direct coronary artery bypass (MIDCAB) . These pα, IL-8, IL-10, and complement) increase and they are of higher levels than the levels present in on-pump CABG. After the procedure, there are no differences between the two. Castelheim [There are two main differences between on-pump and off-pump CABG. In off-pump CABG, a CPB machine is officially unused, and the ischemic-reperfusion injury is minimal . Unfortustelheim  researchIn cardiac arrest, there is a decrease in lymphatic drainage that can contribute to myocardial edema , 26. WhiDuring cardioplegic agent administration, the myocardium is in ischemia and reperfusion states. In that condition, myocardial edema is limited by cardioplegic agent composition and temperature, because hypothermia can alter cellular metabolism and ion channel activation.2+ overload. Other factors contribute to I/R injury, such as complement activation, leukocyte adhesion to endothelium, aggregation of platelets and leucocytes, increased microvascular permeability, and decrease in endothelial compliance.Ischemia-reperfusion injury (I/R injury) is defined as the cellular alteration of the previously viable cell after reperfusion . I/R injmyocyte lethal reperfusion injury—in this condition, there is necrosis of cardiac muscle cells that were previously viable; histopathologically, the necrosis is called contraction band necrosis; (2) vascular reperfusion injury—in this condition, there is progressive microvascular damage that can cause no-reflow phenomena; (3) stunned myocardium—in this condition there is myocyte dysfunction that is prolonged due to abnormal intracellular metabolism; (4) reperfusion arrhythmia—there is a nonsustained ventricular tachycardia or ventricle fibrillation right after reperfusion procedure [Generally, there are four manifestations of I/R injury: (1) rocedure .Myocardial condition after I/R injury is marked by myocardial edema . MyocardCardiac imaging studies have been advancing, especially for echocardiography, computed tomography scan (CT scan), and magnetic resonance imaging (MRI). Echocardiography still becomes one of the most frequently used modality in cardiology despite its two-dimensional image. It is still popular due to its availability, being a more effortless operation, economic reasons, and real-time imaging . DetectiIn the study, the myocardial water content can be characterized by the technique, allowing quantification of changes in myocardial properties. Detection of myocardial edema is demonstrated by Powell et al. . The modIdentification for susceptible patients with myocardial edema is crucial. Providing availability of diagnostic modalities, such as echocardiography, CT scan, and MRI, is one of the critical challenges. Recent studies show the benefit of using MRI as a diagnostic tool for myocardial edema detection. However, the availability and information about the technique of identification are still limited. MRI examination protocols should be provided for more consistent image quality. The development of T2 mapping may contribute to a better imaging of myocardial edema. Visual interpretation is mostly subjective. Thus, studies regarding T2 mapping should be further investigated in order to provide a universal protocol for the detection of myocardial edema . InformaIn the last two decades, there are improvements in identification, therapy, and interventional procedure in cardiovascular medicine that help cardiologist fight against cardiovascular diseases . Most chComputational cardiology helps the biologist and clinician to better understand the fundamentals of cardiology and to apply them into clinical application. Some identified roles and challenges of computational cardiology include the identification of new biomarkers without ambiguous information on diseases, the prediction of outcome  for current and developed pharmacotherapies and interventional cardiology, a real-time approach for integration of data in the hospital and a bigger scale for instance at population level, early identification of health hazards in order to prevent disease, supporting data to health economic approach in high-burden cardiovascular disease, improvement of phenotyping point of care and decentralized care to relieve the burden of hospital setting, introduction to novel or personal drug targets , and an automated monitoring to newly introduced treatment for the early recognition of treatment success and side effects . The innAs a recall to our topics, despite the fact that it is invasive and has a significant sampling error, endomyocardial biopsy is considered the gold standard for detecting myocardial inflammation, a condition that can lead to myocardial edema. New diagnostic tools have been studied to limit the invasiveness and increase diagnostic accuracy. Cardiac magnetic resonance (CMR) provides noninvasive assessment of cardiac function, anatomy, and tissue characterization. New techniques have been developed rapidly, and T2 parametric mapping allows detection of myocardial edema by identifying increased water content at the edematous area with greater accuracy . The intPrevious studies have proven that mathematical or computational models are increasingly popular in biomedical science and applied science. Although they are a simplification of reality, computational models are able to connect multiple processes to each other . It can Specific for device development purpose, the major computational model and technological challenges have been addressed and the authorities and the regulator immediately recognized the benefit. Continuous investment will enable engineers to resume model refinement and develop novel applications, targeting increases in personalization, precision, and speed. In the development, these relatively new approaches should be compared to current practice in terms of some parameters so that the risk and benefit can be measured. Beyond this, efficacy must be demonstrated in large multicenter clinical trials. It is legitimate that these techniques have the potential to change the approach to clinical practice. The future benefit will be in favor of patients, physicians, clinicians, and healthcare providers . Last bu