At 58 ± 1 days post-banding, piglets underwent cardiac MRIs revealing RV hypertrophy, and RV pressure overload with mildly reduced RV function. Catheterization confirmed RV systolic pressures of 84.0 ± 6.7 mmHg with LV systolic pressure 83.3 ± 6.7 mmHg (p = 0.43). The remaining five PA banded piglets underwent ASO at 51 ± 0 days post-banding. Three of five were weaned from bypass with patent coronary arteries and adequate RV function. We were able to successfully perform an arterial switch with documented patent coronary arteries on standard anatomy great vessels in a healthy animal model. To our knowledge this is the first time this procedure has been successfully performed. The model may have implications for studying the failing systemic RV, and may support a novel approach for management of borderline, pulsatile left ventricles.There are no reports on the performance of the arterial switch operation (ASO) in a normal heart with normally related great vessels. The objective of this study was to determine whether the ASO could be performed in a healthy animal model. Cardiopulmonary bypass (CPB) and coronary translocation techniques were used to perform ASO in neonatal piglets or a staged ASO with prior main pulmonary artery (PA) banding. Primary ASO was performed in four neonatal piglets. Coronary translocation was effective with angiograms confirming patency. Piglets could not be weaned from CPB due to right ventricle (RV) dysfunction. To improve RV function for the ASO, nine piglets had PA banding. All survived the procedure. Post-banding RV pressure increased from a mean of 20.3 ± 2.2 mmHg to 36.5 ± 7.3 mmHg ( The arterial switch operation (ASO) has become the standard of care for D-transposition of the great arteries even in the setting of unusual coronary artery patterns –4. The oThere are no known reports on the performance of the arterial switch in a normal heart with normally related great vessels. In normal hearts with usual coronary artery patterns and normally related great vessels, the right coronary artery may be distant from the main PA root, which is anterior and to the left. Furthermore, translocation of the left coronary artery may result in hairpin looping of the left main to the left anterior descending coronary artery axis. Due to this difficulty in both human and animal models, experimental models of the arterial switch presented in the literature merely replicate the anastomoses required in an arterial switch without chronically switching the subpulmonic and systemic ventricles , 6.In the current study, we report the successful completion of the arterial switch operation in a novel porcine model, in a normal heart. The study not only provides the first animal model of the ASO, it demonstrates that the coronary arteries in normally related great vessels are “switchable”. This first report of the ASO in a normal heart may provide a potentially novel approach to the management of variants of hypoplastic left heart syndrome (HLHS) where the left ventricle has borderline size or function. An arterial switch in a heart with non-apex forming, but pulsatile, left ventricle may be an initial step for palliation of HLHS variants.Approval was obtained from the laboratory’s Institutional Animal Care and Use Committee (IACUC) prior to the start of the experiment.n = 4) the arterial switch was performed on healthy naïve animals, which had not been previously intervened upon. In Group 2a, (n = 4) piglets underwent pulmonary artery (PA) banding and 8 weeks post-banding underwent cardiac MRI and hemodynamic assessment. In Group 2b, (n = 5) piglets underwent PA banding and were recovered for a period of 7–8 weeks prior to the arterial switch operation.Animals undergoing arterial switch were divided into two study groups: (1) naïve and (2) pulmonary artery (PA) banded animals. In Group 1,  Buprenorphine (SQ) was used for pre- and post- operative analgesia at a dose of 0.1–0.3 mg/kg 12–24 h prior to the surgical procedure.2/min, and 1–4% isoflurane. An antibiotic, 5 mg/kg ceftiofur IM, and corticosteroid, 250 mg methylprednisolone IV were administered prior to incision. The animal was positioned in the supine position, aseptically prepped, and draped. Heart rate, respiratory rate, oxygen saturation, body temperature and intravenous fluid infusion rate were monitored.Animals were sedated with 1–8 mg/kg Telazol®/1–3 mg/kg xylazine IM. After allowing 5–10 min for the drug cocktail to take effect, the ear vein was aseptically prepped and a catheter placed. Anesthesia was induced using 2–6 mg/kg Propofol IV. Supportive fluids, 0.9% normal saline (NaCl), were administered through the catheter. Animals were endotracheally intubated for mechanical ventilation at 10–15 breaths per minute, 4 L OA cut-down incision was performed in the left or right inguinal area. The femoral artery and vein were catheterized with a modified Seldinger technique and connected to fluid-filled monitoring lines for measurement of central venous and arterial pressure throughout the case, and the administration of drugs.A midline sternotomy was performed and the pericardium opened and retracted. Polypropylene purse strings were placed in the thoracic aorta and right atrium in preparation for cardiopulmonary bypass (CPB) cannulation. The animal was anticoagulated with 250 units/kg heparin, and CPB cannulas placed and secured. Cardiopulmonary bypass with cooling to 25 °C were initiated.A cross clamp was placed distally on the ascending aorta. Del Nido cardioplegia (20 ml/kg) was administered to the aortic root and coronary arteries. Following arrest, the aorta was transected above the level of the sino-tubular junction and coronary buttons dissected and mobilized as necessary from the aortic root. The main pulmonary artery (MPA) was transected and trap door incisions were made to create two ostia attachment sites for the coronary buttons. The left coronary orifice/ostia is very close to the aortic valve annulus in neonatal pigs, and sits leftward close to the left–right commissure of the aortic valve. The coronary ostia were sewn to the pulmonary artery attachment sites with continuous 7–0 polypropylene suture. The subpulmonic root  was reconstructed with pericardial patch material. A Lecompte maneuver was performed to complete the neo-systemic root  and the great vessels switched. Cardiopulmonary bypass was terminated and a right atriotomy performed. An extensive septectomy was created in the atrial septum and the heart decompressed. Of note, the atrial septum is small, posterior and inferior, and its excision is easily complicated by posterior cardiac perforation. The right atriotomy was closed with continuous 5–0 polypropylene suture and CPB initiated with core warming of the animal to 35 °C.With the arterial switch and septectomy completed, an additional 125 mg methylprednisolone and 3 mg/kg ceftiofur were administered IV. Mechanical ventilation was reinstated and the animal weaned from bypass utilizing epinephrine, phenylephrine and/or dobutamine for hemodynamic support once core warming was accomplished. Angiography was performed using peripheral access via the femoral artery and vein. Diagnostic catheters were advanced to both the right and left sides of the heart under fluoroscopy. Isovue-300 (Iopamidol Injection 61%) was injected into the heart via diagnostic catheters to determine patency of the coronary arteries and mapping of blood flow patterns following the switch.th-space thoracotomy was performed to access the heart. The pericardium was opened and a purse string placed in the MPA for introduction of a pressure catheter. The animal was heparinized prior to placement of the pressure catheter. An umbilical tape was looped around the MPA and tightened while pulmonary artery pressure monitored. The umbilical tape was secured in the cinched position after the peak systolic pressure in the right ventricle had increased 50–75%. Once the umbilical tape was secured, the pressure catheter was removed, heparin was reversed .Animals were anesthetized and prepared for sterile surgery as previously described. Animals were placed in the right decubitus position and a left 4Prior to closing the thoracotomy, a local nerve block was created using 1–2 mg/kg of both lidocaine and bupivacaine, given IM at the incision site. The lungs were inflated and the chest cavity irrigated with a warm saline antibiotic solution .A #20–#30 drainage tube was secured in the chest through the 6th intercostal space, exteriorized through the skin, secured in place with a purse string and connected to a water sealed vacuum drainage reservoir. The ribs were approximated with three size 1 braided polyester sutures. The muscle and skin layers were closed in standard fashion using 2–0 and 3–0 absorbable suture. Isoflurane was discontinued either during or following the closure of the thoracotomy.The chest tube was removed when the animal was breathing normally and negative pressure in the intrapleural space. Once verified to be stable, the animal was moved to the post-operative care unit for recovery. Furosemide 40 mg twice daily was administered to assist with volume status optimization. 7–8 weeks following MPA banding, five animals were anesthetized for cardiac imaging and five animals were anesthetized for the arterial switch operation as described.All studies were performed with a Siemens 1.5 T Aera scanner  with phased-array coil systems. The examination included localizers to assess cardiac position and a standard segmented steady-state free-precession cine sequence to assess cardiac volumes and function. The imaging parameters were as follows: typical repetition time of 3.0–3.5 ms, echo time of 1.2–1.5 ms, in-plane spatial resolution of 1.8 × 1.4 mm, and temporal resolution of 35–40 ms. Short-axis images were acquired with a slice thickness of 6 mm from the level of the mitral valve to the apex of the left ventricle. Long axis cines were also obtained in the four-chamber and three-chamber views. The cardiac magnetic resonance examination sequences were gated with electrocardiography. Following this, contrast-enhanced magnetic resonance angiography was performed to evaluate the pulmonary arterial tree. Another smaller contrast injection was delivered and timed to opacify the main pulmonary artery and the proximal branch pulmonary arteries using automatic contrast bolus detection.CMR analyses were performed by an experienced CMR cardiologist using standard software . Left and right ventricular end-diastolic and end-systolic volumes and ejection fractions were quantified by planimetry of the end-diastolic and end-systolic endocardial borders on the short-axis cine images.t-tests were used to compare groups, with statistical significance defined as p < 0.05.Data are presented (mean ± SD) and analyzed using Microsoft Excel 2016. Paired n = 4) in Group 1. The switch was successfully completed from a technical standpoint with documented patent coronary arteries on standard anatomy great vessels  had PA banding at an average age of 30.3 ± 1.5 days and weight of 5.8 ± 0.2 kg. RV pressure increased from 20.3 ± 2.2 to 36.5 ± 7.3 mmHg (p = 0.007) after placing the band. All survived the banding procedure. At 58 ± 1 days post-banding, piglets (n = 3) underwent cardiac MRIs revealing RV hypertrophy, evidence of RV pressure overload with mildly reduced RV function with RVEF 41 ± 3% and normal left ventricular function (LV) with LVEF 60 ± 2%  confirming that the RV pressures were equal to the LV peak systolic pressures averaging 83.3 ± 6.7 mmHg (p = 0.43). Cardiac hemodynamic data are presented in Table Piglets in Group 2a (n = 5) had PA banding at an average age of 31.8 ± 0.8 days and weight of 5.9 ± 0.2 kg. RV pressure increased from 21.6 ± 3.0 to 38.4 ± 7.5 mmHg (p = 0.003) after placing the band. All animals survived the banding procedure. At 51 ± 0 days post-banding piglets were prepared for the ASO. Piglets were 82.8 ± 0.8 days of age and 24.9 ± 2.8 kg at the time of the ASO. The arterial switch operation was completed in all five piglets. Three of the five piglets were successfully weaned from bypass for 35–55 min prior to termination utilizing epinephrine, phenylephrine and/or dobutamine for hemodynamic support. Of the three piglets weaned from CPB, the systolic arterial blood pressure was 68.0 ± 5.5 mmHg, diastolic blood pressure was 38.0 ± 4.9 mmHg, heart rate ranged from 98 to 138 bpm and hemoglobin O2 saturation ranged from 68 to 73%, presented in Table Piglets in Group 2b  operation in 4-week-old piglets with the intention of placing the RV in the systemic circulation with a septated heart to study the evolution of RV failure. Unfortunately during the initial procedures, we determined that given the shallow nature of the piglet atria and the acute angle at which the IVC enters the right atrium that an atrial switch would not be anatomically possible at this age. We opted to proceed with performing an arterial switch with a concomitant creation of an atrial septal defect via an atrial septectomy to allow adequate systemic oxygenation. This model would allow us to create a high pressure right ventricle and a low pressure left ventricle, but would necessitate some degree of hypoxia. We were able to successfully perform an arterial switch with documented patent coronary arteries on standard anatomy great vessels in a large animal model. To our knowledge this is the first time such a procedure has been successfully performed. Although the arterial switch and atrial septectomy were successful, the piglets could not be weaned from the cardiopulmonary bypass circuit due to right ventricular failure and issues with oxygenation. This was an anticipated complication. In an effort to allow sufficient RV function post arterial switch we performed PA banding 7–8 weeks prior to the arterial switch and atrial septectomy to allow RV “training” for high pressure needed to support systemic circulation post-ASO.2 desaturation. We remained concerned that atrial mixing would continue to be an issue in the banded animals due to several factors. The prominent Eustachian valve/ridge and angle of the IVC to the atrial septum created a strong streaming current of deoxygenated blood from the IVC through the atrial septectomy to the left atrium. This limited the mixing of oxygenated blood returning to the left atrium with the right atrial blood. This impairment of mixing was exacerbated by the presence of significant RV hypertension causing ventricular stiffness and non-compliance, which further impaired left atrial to right atrial diastolic shunting. A more aggressive septectomy did allow for some improvement in left to right atrial diastolic shunting, and that, plus improved RV function of the post-PA-banded “trained” RV, allowed for animals to be weaned from cardiopulmonary bypass.Piglets with banded PAs and a “trained RV” had successful arterial switch and atrial septectomy in the setting of a more complex surgical field due to significant adhesions from the prior PA banding surgery. The animals displayed adequate RV function but still encountered significant issues with inadequate atrial level mixing and hemoglobin OA number of strategies have been developed to treat or palliate the newborn with “hypoplasia” of the non-apex forming LV, including the modified Norwood procedure, biventricular repairs and staged ventricular recruitment . We haveHeart failure is a significant cause of morbidity and mortality in patients with congenital heart disease, especially for the subset whose right ventricle functions as the systemic ventricle. The physiological and molecular differences in the right ventricle (RV) and left ventricle (LV) lead to different abilities to adapt to adverse conditions and respond to pharmacological therapeutics. Currently data describing the molecular changes that occur in the systemic RV are lacking. Available animal models create an RV with volume and/or pressure overload; however, the LV remains at high pressure. Ventricular-ventricular interactions have a critical impact on cardiac function and are likely to alter gene expression independent of RV function. A novel large animal model as reported herein creates a high pressure systemic RV with a low pressure subpulmonic LV by performing an arterial switch followed by an atrial septectomy to allow sufficient oxygenation via atrial mixing. To identify molecular regulatory networks and signaling pathways that are perturbed in the systemic RV, transcriptomic analysis can be performed to compare the gene expression profiles of the systemic RV and normal RV. One can then determine whether gene expression of the reloaded ventricle  recapitulates a fetal RV gene program or whether new gene expression pathways are activated, potentially providing novel therapeutic targets.Possible modifications for this model include the use of strategies to further enhance atrial mixing and optimize midterm survival. The major issues with the current model are hypoxia and bleeding. We are considering incorporation of the Baffes’ procedure to the arterial switch. Baffes excised and transferred the right pulmonary veins to the right atrium and used an aortic homograft to join the IVC to the divided proximal end of the pulmonary veins . This diWe report a porcine model of RV failure that is created with an arterial switch operation on standard anatomy great vessels. The model may have implications for studying the failing systemic RV and may support a novel approach for the management of borderline, pulsatile left ventricles.


The transcriptional co-regulators YAP and TAZ pair primarily with the TEAD family of transcription factors to elicit a gene expression signature that plays a prominent role in cancer development, progression and metastasis. YAP and TAZ endow cells with various oncogenic traits such that they sustain proliferation, inhibit apoptosis, maintain stemness, respond to mechanical stimuli, engineer metabolism, promote angiogenesis, suppress immune response and develop resistance to therapies. Therefore, inhibiting YAP/TAZ- TEAD is an attractive and viable option for novel cancer therapy. It is exciting to know that many drugs already in the clinic restrict YAP/TAZ activities and several novel YAP/TAZ inhibitors are currently under development. We have classified YAP/TAZ-inhibiting drugs into three groups. Group I drugs act on the upstream regulators that are stimulators of YAP/TAZ activities. Many of the Group I drugs have the potential to be repurposed as YAP/TAZ indirect inhibitors to treat various solid cancers. Group II modalities act directly on YAP/TAZ or TEADs and disrupt their interaction; targeting TEADs has emerged as a novel option to inhibit YAP/TAZ, as TEADs are major mediators of their oncogenic programs. TEADs can also be leveraged on using small molecules to activate YAP/TAZ-dependent gene expression for use in regenerative medicine. Group III drugs focus on targeting one of the oncogenic downstream YAP/TAZ transcriptional target genes. With the right strategy and impetus, it is not far-fetched to expect a repurposed group I drug or a novel group II drug to combat YAP and TAZ in cancers in the near future. The transcriptional co-regulators YAP (Yes-associated protein) and TAZ  are key players that mediate various oncogenic processes and targeting their activities has emerged as an attractive option for potential cancer therapy. YAP, as the name suggests, was initially identified as a protein that associates with Yes, a src family kinase (SFK) YAP and TAZ do not have a DNA-binding domain and they need to associate with a transcription factor in order to access DNA. It has now emerged that YAP/TAZ use predominantly the TEAD (TEA domain) family of transcription factors Drosophila but the pathway components are evolutionarily conserved. It is now known that the primary function of the Hippo pathway is to suppress the activity of Yorkie - the Drosophila homolog of YAP YAP/TAZ are now considered as effectors of a physiologically and pathologically important signaling pathway - popularly called the Hippo pathway YAP and TAZ were first shown to transform mammary epithelial cells Over a decade of research has revealed that YAP/TAZ integrates the inputs of various oncogenic signaling pathways, such as EGFR, TGFβ, Wnt, PI3K, GPCR and KRAS. Through expression of the ligand AREG, YAP was first shown to communicate with the EGFR pathway YAP and TAZ regulate the expression of crucial transcription factors like Sox2, Nanog and Oct4 and are able to maintain pluripotency or stemness in human embryonic stem cells (ESCs) and in induced pluripotent stem (iPS) cells A TAZ fusion gene (TAZ-CAMTA1) alone, in the absence of any other chromosomal alteration or mutation, is sufficient to drive epithelioid hemangioendothelioma (EHE), a vascular sarcoma There are more than fifty drugs that have been shown to inhibit YAP/TAZ activity Group I drugs target the upstream proteins Figure , inhibitDrugs targeting the EGFR, GPCR, Integrin, VEGFR and adenylyl cyclase families as well as those targeting receptors like the γ-secretase complex and Agrin are shown to inhibit YAP/TAZ activity YAP/TAZ exploits the transformative abilities of the ErbB receptors (EGFR family) to drive cell proliferation. By transcribing ErbB ligands, such as AREG Signaling from G-protein coupled receptors (GPCRs), transduced by the associated Gα subunit or by the Gβγ subunits, modulates YAP/TAZ activities Integrin signaling negatively regulates the Hippo pathway complexes to drive YAP/TAZ activity Among the kinase inhibitors tested in a biosensor screen for LATS activity, the VEGFR inhibitors are shown to potently activate LATS and thereby inhibit YAP and TAZ activity Enhancing cyclic AMP (cAMP) levels using the adenylyl cyclase activator forskolin activates the LATS kinases through Protein kinase A (PKA) and Rho Notch and YAP/TAZ signaling are also closely linked, inhibiting notch activity by targeting the γ-secretase complex, either using DAPT or dibenzazepine has been shown to decrease YAP/TAZ expression levels in mouse livers and also reduce YAP activation and YAP-induced dysplasia in the intestine Integrin signaling activates focal adhesion kinase (FAK), SFK and integrin- linked kinase (ILK). Growth factor and GPCR signaling occurs through mitogen-activated protein kinase (MAPK) and phosphoinositide 3-OH kinase (PI3K) signaling. There is also significant crosstalk in the signaling from these membrane receptors. Given the availability of potent small molecule drugs targeting the downstream kinases, they are leveraged on to inhibit YAP or TAZ activities.Members of downstream integrin signaling pathway including FAK, its counterpart PYK2, and ILK have emerged as negative regulators of the core Hippo pathway and thus activate YAP/TAZ. Membrane receptors, such as ErbB and GPCRs are unable to activate YAP upon genetic deletion of ILK. Therefore, pharmacological inhibition of ILK using a specific ILK inhibitor, QLT0267 potently inhibits YAP-dependent tumor growth in xenograft models The SFK member Src prevents the activation of LATS MEK (MAP kinase kinase) and YAP interact with each other and maintain transformed phenotypes in liver cancer cells PI3K inhibitors Wortmannin/LY294002 as well as the drug BX795, an inhibitor of its effector 3'-phosphoinositide-dependent kinase-1 (PDK1) prevents nuclear entry of YAP YAP/TAZ inhibition is an additional unexpected activity possessed by the few kinase inhibitors mentioned above. However, apart from YAP/TAZ inhibition, all other signaling events initiated by the target kinase are also shut down due to inhibitor treatment. If these signaling events are critical for cellular homeostasis, then, toxic side effects will outweigh clinical benefits and this cannot be uncoupled from YAP/TAZ inhibition. Therefore, kinase inhibitors that failed in the trials due to unacceptable toxcity or poor pharmacokinetics may not be repurposed as YAP/TAZ inhibitors in the clinic. Focus should be on the kinase inhibitors that are already in the clinic like EGFR, VEGFR, MEK, PI3K or mTOR inhibitors but efficacy needs to be proven in order to repurpose them as YAP/TAZ inhibitors. The kinase targeted by the inhibitor must activate YAP/TAZ in tumors, for the treatment to be efficacious and this restricts the use of kinase inhibitors to selective tumor types. Intriguingly, YAP/TAZ activation has emerged as a prominent survival strategy adapted by cancers that cause drug resistance to EGFR and its downstream MEK/MAPK inhibitors The mevalonate pathway is essential for the biosynthesis of isoprenoids, cholesterol and steroid hormones. Statins as well as other mevalonate pathway inhibitors like zoledronic acid and GGTI-298 that target farnesyl pyrophosphate synthase and geranylgeranyltransferase, respectively are identified as drugs that restrict the nuclear entry of YAP and TAZ Actin polymerization promotes YAP/TAZ nuclear localization and therefore, polymerization inhibitors like latrunculin A YAP/TAZ inhibitory phosphorylation is dynamic and the protein phosphatases PP1 and PP2A are shown to associate with YAP/TAZ and aid in their dephosphorylation and activation. Inhibiting these phosphatases using okadaic acid or calyculin A increases YAP/TAZ phosphorylation and shifts YAP/TAZ to the cytoplasm Cellular energy stress is closely linked with attenuation of YAP/TAZ activities Histone deacetylases (HDACs) are uniquely positioned to alter the transcription of target genes. Interestingly, HDAC inhibitors panobinostat, quisinostat, dacinostat, vorinostat and Trichostatin A transcriptionally repress the expression of YAP but not TAZ, and thereby reduce YAP-addicted tumorigenicity Many group I drugs can potentially be repurposed to treat YAP/TAZ- driven cancers Modalities that target either the TEAD family of transcription factors or YAP/TAZ are classified under this group Figure . The majGroup I drugs target the upstream YAP/TAZ-activating proteins like the EGFR, GPCR, Src, or Integrins. As there are so many upstream YAP/TAZ activators, group I drugs are vulnerable to oncogenic bypass where inhibition of one group I YAP/TAZ activator leads to selection of cancer cells that activate YAP/TAZ via another group I activator. Strategically, Group II drugs may address this issue by directly targeting YAP/TAZ or TEAD, the converging points for various pathways and also the effectors for oncogenic transcription. However, Group II targeting modalities are still at the exploratory stage and it remains to be seen whether it is feasible to develop a Group II modality that works in clinic. We also need to be mindful of the possible associated toxicities due to YAP/TAZ-TEAD inhibition Most of the reported Group II modalities are disruptors; they target YAP/TAZ or TEAD and prevent their binary interaction. However, in addition to disruptors, in the future, we predict the emergence two other classes of group II compounds that would act as TEAD stabilizers and destabilizers/degraders Figure .A small molecule benzoporphyrin drug named Verteporfin (VP) was shown to have the ability to bind to YAP and disrupt the YAP-TEAD interaction YAP and TAZ bind on the TEADs' surface; Inventiva Pharma has identified several compounds with benzisothiazole-dioxide scaffold that bind to the TEADs' surface and disrupt the YAP/TAZ-TEAD interaction. These compounds are currently in the lead optimization stage and have the potential to treat malignant pleural mesothelioma as well as lung and breast cancers that are driven by YAP/TAZ in vitro but they have poor cell-penetrating abilities YAP cyclic peptide (peptide 17) and cystine-dense peptide (TB1G1) are also disruptors of YAP/TAZ-TEAD interaction We identified a novel druggable pocket in the center of the TEADs' YAP/TAZ- binding domain Palmitate, by occupying the PBP, allosterically modulates YAP's interaction with TEAD Being predominantly unstructured, YAP and TAZ are difficult to target directly. However, TEADs offer two attractive ways for targeting, one is to directly block the YAP/TAZ-binding pocket on the TEADs' surface with small molecules or peptides, whilst the other is to leverage on the PBP and allosterically disrupt YAP/TAZ interaction or inhibit TEADs Figure . HoweverThe PBP could also be leveraged to allosterically enhance YAP/TAZ-TEAD stability or interaction. This prediction is subject to the identification of small molecules that functionally mimic the ligand palmitate Figure . Compounin situ unfolding and degraders reduce TEAD levels through proteasomal degradation. Reducing the levels of their interacting partners deprives YAP/TAZ of their ability to activate transcription.We identified a few chemical scaffolds that have the ability to occupy the PBP and destabilize TEAD (unpublished results). Addition of these compounds unfolds the TEADs' YAP/TAZ-binding domain and we call these compounds destabilizers Figure . DegradeAny TEAD-binding compounds  can only access unbound TEADs, as binding of YAP and TAZ blocks both the surface and the palmitate-binding pockets Figure . After aYAP/TAZ-mediated tumor development is due to the collective action of the repertoire of proteins that are expressed under their influence. However, some proteins are able to drive oncogenesis much better than others and they vary depending on the solid tumor and context. Therefore, drugs against these downstream YAP/TAZ targets including metabolic enzymes, kinases, ligands and proteins, such as BCL-xL, FOXM1 and TG2 are also used to combat YAP/TAZ-mediated oncogenicity  is shown to impart stemness and tumorigenic ability; inhibition of ALDH1A1 using A37 reverses this transformation In hepatocellular carcinoma, Axl kinase has been shown to be crucial for mediating several YAP-driven oncogenic functions like cell proliferation and invasion In a mouse model of prostate adenocarcinoma, the YAP-TEAD complex promotes the expression of the chemokine ligand CXCL5 that facilitates myeloid-derived suppressor cells (MDSC) infiltration and adenocarcinoma progression. Administering CXCL5 neutralizing antibody, or blocking CXCL5 receptor using the inhibitor SB255002, inhibits MDSC migration and tumor burden YAP mediates drug resistance to RAF- and MEK-targeted therapies in BRAF V600E cells, in part through the expression of the anti-apoptotic protein BCL- xL. BCL-xL inhibition using navitoclax sensitizes these cells to targeted therapies YAP-mediated proliferation through its target gene FOXM1 could be prevented in sarcoma cell lines and mouse models through the administration of thiostrepton that reduces FOXM1 levels Transglutaminase 2 (TG2) - the multifunctional transamidase is a YAP/TAZ target gene that is important for cancer stem cell survival and for maintaining integrin expression. TG2 inhibition using NC9 dramatically reduces tumorigenicity We are aware that many of these target proteins also act upstream and stimulate YAP/TAZ by forming a positive feedback but we would nevertheless consider them in this group and not as group I as their expression is influenced by the TEAD-binding motif and YAP/TAZ.Although attractive, toxicity issues and the identification of responsive patient population could be challenges in the successful implementation of the YAP/TAZ inhibitors in the clinic. YAP/TAZ inhibition might elicit toxicity Several drugs that act as YAP/TAZ inhibitors target multiple signaling pathways. Targeting multiple pathways could be a boon or a bane. Drug resistance is minimized in a multi-targeted approach as potential bypass mechanisms are also targeted. However, toxicity becomes an issue when the drug targets multiple important signaling pathways. For instance, raising cAMP through the use of PDE inhibitors activates a multitude of proteins like PKA, EPACs, ion channels and small GTPases. Similarly, GPCR modulators influence multiple pathways through signaling via G proteins, arrestins or GPCR kinases. To reduce toxic side effects, there are options available like selective targeting or biased signaling. Instead of hitting all the PDEs, the PDE enzyme that is the most potent activator of YAP/TAZ should be selectively targeted. Nonspecific PDE inhibitors cause more severe side effects than sub-type selective PDE inhibitors Another major challenge is the identification of patients responding to a YAP/TAZ inhibitor. YAP/TAZ expression is low in normal tissues and their levels are significantly elevated in cancers. Is YAP or TAZ positivity in tumors sufficient criteria to administer a YAP/TAZ inhibitor? YAP and TAZ might not be transcriptionally active or drivers in all tumors. Further, they could be expressing target genes that negatively regulate their activity As YAP and TAZ contribute to the acquisition of many hallmarks of cancer traits, targeting them is predicted to be more relevant for the management of several cancer types. It is still early to expect a newly developed drug against YAP/TAZ but it is nevertheless disconcerting to see that there are hardly any clinical trials that evaluate if known drugs could be repurposed as YAP/TAZ- inhibitors. Group I drugs are well suited to repurpose


The sensitivity and specificity of the routine detection of acute myocardial infarction (AMI) in early diagnosis are not high, which can not meet the clinical needs. Copeptin combined with hypersensitive cardiac troponin T (hs-cTnT) is a new detection scheme, and its value in the early diagnosis of acute myocardial infarction is still unclear. Accordingly, the aim of this study is to evaluate the diagnostic value of copeptin combined with hypersensitive troponin T detection in early acute myocardial infarction.This is a prospective, randomized; double-blind diagnostic trial to investigate the diagnostic value of copeptin combined with hypersensitive troponin T detection in early acute myocardial infarction. Approved by the clinical research ethics of our hospital. Patients were randomly divided into one of 2 test protocols: (A) copeptin combined with hs-cTnT group and (B) cardiac troponin I (cTnI) group. Patients, doctors, nurses, inspectors, and data-gathering assistants were blinded to group allocation. We will focus on the sensitivity comparison of the 2 detection methods at different time periods and the sensitivity and specificity comparison of the two detection methods. Data were analyzed using the statistical software package SPSS version 25.0 .The purpose of this study is to evaluate the diagnostic value of copeptin combined with hypersensitive cardiac troponin T detection in early acute myocardial infarction. The results of this study will establish clinical evidence for the detection of high sensitivity cardiac troponin T in the early diagnosis of acute myocardial infarction.Private information from individuals will not be published. This systematic review also does not involve endangering participant rights. Ethical approval was not required. The results may be published in a peer-reviewed journal or disseminated at relevant conferences.DOI 10.17605/OSF.IO/6TE5Z. Rapid and accurate early diagnosis of AMI is the key to reduce mortality and improve prognosis of patients.Acute myocardial infarction (AMI) is an acute coronary syndrome in which blocked coronary artery causes insufficient blood supply to the heart muscle and impairs heart function, has the characteristics of rapid progression and high mortality, Although cardiac troponin (cTn) has become a recognized indicator for the diagnosis of AMI, the blood concentration reflecting myocardial necrosis cannot be detected within 1 hour after the onset of AMI symptoms, and the level of troponin begins to rise 3 to 6 hours after the occurrence of myocardial injury, appearing the “troponin blindness stage”, since cTn lacks sensitivity in the early stages of myocardial injury, it is particularly important to add a marker for rapid diagnostic AMI. Copeptin is a newly discovered marker of myocardial necrosis. Clinical studies have confirmed that copeptin begin to rise in early AMI, earlier than troponin, breaking the “troponin blindness stage” and making up for defects in early atypical changes in electrocardiogram. Early diagnosis and prognosis evaluation of AMI can be carried out quickly.In the previous clinical diagnosis, AMI was mainly diagnosed based on medical history, physical examination, electrocardiogram, echocardiography and other examinations, but all of these examinations had certain defects and their accuracy was not high, while myocardial necrosis markers such as C reactive protein (CRP), myoglobin (Mb), creatine kinase isoenzyme (CK-MB) have poor sensitivity and specificity in the early stage of the disease. The sensitivity of hypersensitive cardiac troponin (hs-cTn) is higher than that of traditional troponin. At present, the diagnostic value of hs-cTn combined with copeptin in early detection of AMI is not clear. The aim of this study is to investigate the early diagnostic value of hs-cTnT combined with copeptin in early detection of AMI.Some studies have pointed out that although the level of copeptin in AMI patients is significantly increased, because of the lack of specificity, it should not be considered as a single biomarker for the diagnosis of suspected AMI patients.22.1 And we followed the Consolidated Standards of Reporting Trials (CONSORT) guidelines for reporting randomized trials and provided a CONSORT flow diagram  (Registration number: DOI 10.17605/OSF.IO/6TE5Z). Prior to the trial, written informed consent will be obtained from all patients. Personal information about potential participants and registered participants will be collected, Shared, and kept in a separate repository to protect confidentiality before, during, and after the trial.2.3,10Estimation of sample contents for both test and control groups will be obtained based on anticipated sensitivity according to Buderer formula:N = anticipated sensitivity; α = size of the critical region (1 – α is the confidence level); Z1-α/2 = standard normal deviate corresponding to the specified size of the critical region (α), and L = absolute precision desired on either side  of sensitivity or specificity. According to the sensitivity of the test group to be 90% and that of the control group to be 75%, the sensitivity of the control group to be 0.8, α=0.05, Z1-α/2 = 1.96, L = 0.1, it is calculated that at least 43 persons are required to be included on the test group and 90 persons on the control group. At last, 90 persons are selected from the test group and the control group respectively.Where n = required sample size; S2.4; Regardless of gender, age ≥18; Be to the hospital within 2 hours after onset of chest pain; Be all received AMI therapy for the first time and had no old myocardial infarction; Voluntary participants with informed consent of patients and their families.Inclusion criteria: Clinical examination meets the diagnostic criteria of AMIExclusion criteria:1.Patients with severe arrhythmia;2.Patients with congenital heart disease and heart valve organic lesions;3.Patients with malignant tumors examined;4.Patients with heart, liver and kidney dysfunction;5.Unable to understand the research programme or unwilling participants.2.5Patients were randomly divided into one of 2 test protocols:1.Copeptin combined with hs-cTnT group,2.cTnI group.Randomization was performed without any stratification. Randomization listings were prepared with a probability of 1:1 and after that, randomized numbers were printed according to the results of the randomization. After the patient had given consent, the members of the inpatient clinical research center divided the patients into 2 groups according to the parity of the assigned numbers, the odd number was the test group, and the even number was the control group. Patients, doctors, inspectors, nurses and research assistants collecting data were blinded to group allocation.2.61.After admission, 5 ml cubital venous blood was collected from all patients at 0 hours, 4 hours and 6 hours, respectively. According to the digital markers assigned at admission, the blood was centrifuged at 3000 r/minutes for 10 minutes, and the plasma was collected and stored at -70°C for testing.2.; (3) copeptin detection: Using enzyme linked immunosorbent assay (ELISA), the kit was produced by phoenix pharmaceuticals in the United States, and the copeptin value <14 pmol/L as the diagnostic cut-off point.,13cTnI detection: Immunofluorescence assay was used, the kit was produced by Roche in Germany, cTnI value <0.05ng/ml was used as the diagnostic cut-off point; (2) hs-cTnT detection: Electrochemical luminescence method was used on roche Cobas 601 automatic chemiluminescence instrument. The kit was Roche fifth generation trotropoin reagent, and hs-cTnT value ≤14 ng/L as the diagnostic cut-off point3.All patients underwent coronary angiography as the gold standard for diagnostic validation: CAG was performed by an experienced interventional cardiologist using the standard Judkins method, with at least 3 multi-position exposures per vessel.2.7All data will be collected separately by 2 assistants, and all data will be stored and kept separately. The access to the database will be restricted to the researchers in this study team.2.8Z test. P < .05 was statistically significant.SPSS 25.0 was used for statistical analysis of the data and normality test of the measurement data. The normal distribution data were expressed as 3 accurate diagnosis of AMI in chest pain patients in the early stage is of great clinical value in improving the prognosis of patients and reducing their mortality.Since chest pain and other symptoms account for about 5% to 10% of the total number of emergency patients, Hs-cTnT has high sensitivity to myocardial injury and strong specificity, can appear in the early stage of AMI, and can exist in the blood stream for a long period of time. It is the most favorable marker for early diagnosis and prognosis evaluation of AMI. The hypersensitive troponin will rise abnormally when there is damage of cardiomyocytes and the sensitivity is high, serum level of hypersensitive troponin T is positively correlated with the degree of myocardial injury in acute myocardial infarction.Troponin T is a regulatory protein for myocardial tissue contraction and a biochemical marker of myocardial injury and necrosis. It is usually detected from the blood 4 to 6 hours after chest pain occurs. Traditional cTnT detection methods have lower sensitivity and affect the early diagnosis of AMI, while hs-cTnT have higher sensitivity than traditional detection methods. The plasma copeptin level peaks immediately after AMI, and decreases gradually within 6 hours, with the largest change range within 0 to 3 hours. However, the copeptin specificity is low, and it can increase in acute or chronic stress state, such as respiratory tract infection, chronic obstructive pulmonary disease, heart failure, critical illness and so on, which has certain influence on the early diagnosis of AMI. The combination of copeptin and hs-cTnT detection is expected to improve specificity and accuracy in early diagnosis of acute myocardial infarction.Copeptin, a part of the original C-terminal of arginine vasopressin (AVP), is positively correlated with AVP in the normal population and patients with cardiopulmonary and vascular diseases, and is an acute endogenous stress marker. Its stability in vivo is stronger than AVP, and it is easy to measure. Therefore, copeptin can replace AVP as a clinical early-warning marker of cardiovascular disease.,22 Therefore, we used cTnI as a control group to evaluate the clinical value of copeptin combined hs-cTnT in the diagnosis of early acute myocardial infarction.Cardiac troponin I remains the preferred cardiac marker for AMI diagnosis, according to guidelines published by the European Society of Cardiology (ESC), the American College of Cardiology (ACC), and the American Heart Association (AHA).This study may have the following limitations: because this is a single central regional experimental study, the inclusion of the population may be relatively single, there is a certain bias; factors such as age may have a certain impact on the results.Data collection: Yan Yang and Qiuju FangLiterature retrieval: Songtao GaoSupervision: Songtao Gao and Qiuju FangSoftware operating: Qiuju FangFunding support: Jing YangWriting – original draft: Yan Yang and Songtao GaoWriting – review & editing: Yan Yang and Jing Yang


Culture, defined as shared behavior or information within a community acquired through some form of social learning from conspecifics, is now suggested to act as a second inheritance system. Cultural processes are important in a wide variety of vertebrate species. Birdsong provides a classic example of cultural processes: cultural transmission, where changes in a shared song are learned from surrounding conspecifics, and cultural evolution, where the patterns of songs change through time. This form of cultural transmission of information has features that are different in speed and form from genetic transmission. More recently, culture, vocal traditions, and an extreme form of song evolution have been documented in cetaceans. Humpback whale song “revolutions,” where the single population-wide shared song type is rapidly replaced by a new, novel song type introduced from a neighboring population, represents an extraordinary example of ocean basin-wide cultural transmission rivaled in its geographic extent only by humans. In this review, we examine the cultural evolutions and revolutions present in some birdsong and whale song, respectively. By taking a comparative approach to these cultural processes, we review the existing evidence to understand the similarities and differences for their patterns of expression and the underlying drivers, including anthropogenic influences, which may shape them. Finally, we encourage future studies to explore the role of innovation vs. production errors in song evolution, the fitness information present in song, and how human-induced changes in population sizes, trajectories, and migratory connections facilitating cultural transmission may be driving song revolutions. Individual sound units can be stretched and split into 2 units, new themes can be added, and older themes deleted from the song . The prosong revolution” to clearly distinguish it from the common and much slower process of song evolution as described above , but this similarity depends on the geographical distance and variable interactions among populations . Song shed above . The comZonotrichia albicolis) song spread across Canada in a west to east direction replacing the existing song; the spread was similar in the extent of change, but much slower in that the change took some decades  within a sensitive period in early life (when nestling or fledgling), after which the song is unchanging e.g., . This paMale great tits defend a territory in the breeding season and pair with a (non-singing) female. The role of song in territory defense is well-established . Males sbilingual” in the sense that they sing both local dialects. Playback experiments have shown the salience of local dialects to males  in humpbacks vs. a few kilometers for corn buntings – this is unremarkable given the differences between species in patterns of movement . However, the associated population size differences  may have relevance for population genetics. Active singing space, i.e., the number of other individuals in the communication network centered around a singing male, may be a better way to consider the geographical scale of change. Humpback song transmits for tens of kilometers see  and coulrate = 1 or 0.1%) facilitated the gradual song evolution observed in the wild . In such a scenario, song changes are unlikely to radiate out from a center akin to corn buntings, as male humpbacks do not hold territories, rather they roam freely  on the breeding grounds. Song changes are hypothesized to be passed along a chain of singers or to radiate out from a single singer regardless of his position on the breeding grounds. It is unclear which male(s) within the population “lead” song changes, if this is a collective process, or if the directional change observed in song units follows an innate template of how songs should evolve , reproductive success, and movements (to name a few). The following list of questions in key topics needs to be addressed:Innovation. Do some or all males innovate? To what extent does innovation occur? Are all innovations copied? How do males choose which male (or innovation!) to copy?Song and mating. Do songs (or parts of songs) convey fitness information? And if so, what aspects do females use in mate choice? Is novelty part of the answer?Source of variation. Is song evolution primarily caused by production errors?Anthropogenic influences. Are human-induced changes in population size and distribution critical factors driving revolution, innovation, and local dialects?To test these questions, meticulous individual-level data are needed for some , while other broader-scale questions  can be addressed by population surveillance. For example, the study of cultural evolution of savannah sparrow song over three decades showed a change in some song elements but not others, and variants of some parts of the song were associated with reproductive success . In termThere is one final piece to the cultural puzzle we have not considered here: human culture. Cultural evolution, language evolution, horizontal transmission of fads, and the like all provide a rich expansion for the comparative approach we have taken here . The sprEG and PM conceived of the study, drafted the manuscript, critically revised it, and provided approval for publication of the final version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Recognizing specific heart sound patterns is important for the diagnosis of structural heart diseases. However, the correct recognition of heart murmur depends largely on clinical experience. Accurately identifying abnormal heart sound patterns is challenging for young and inexperienced clinicians. This study is aimed at the development of a novel algorithm that can automatically recognize systolic murmurs in patients with ventricular septal defects (VSDs). Heart sounds from 51 subjects with VSDs and 25 subjects without a significant heart malformation were obtained in this study. Subsequently, the soundtracks were divided into different training and testing sets to establish the recognition system and evaluate the performance. The automatic murmur recognition system was based on a novel temporal attentive pooling-convolutional recurrent neural network (TAP-CRNN) model. On analyzing the performance using the test data that comprised 178 VSD heart sounds and 60 normal heart sounds, a sensitivity rate of 96.0% was obtained along with a specificity of 96.7%. When analyzing the heart sounds recorded in the second aortic and tricuspid areas, both the sensitivity and specificity were 100%. We demonstrated that the proposed TAP-CRNN system can accurately recognize the systolic murmurs of VSD patients, showing promising potential for the development of software for classifying the heart murmurs of several other structural heart diseases. The clinical presentation of a VSD is correlated with the size of the defect5. Mild VSDs are usually asymptomatic and commonly occur spontaneously within close proximity6. Patients with medium defects often suffer from dyspnea. Patients with severe VSDs exhibit cyanosis, dyspnea, syncope, or heart failure and require adequate surgeries unless the defects spontaneously decrease9. VSDs can also be classified according to the morphology and anatomical location of the defect. They can also be classified into four anatomical types: type I , type II , type III , and type IV (muscular or trabecular)12. The perimembranous type is the most common (~ 80%), followed by the muscular (15–20%), inlet (~ 5%), and outlet (~ 5%) types.Ventricular septal defect (VSD), a type of congenital heart disease (CHD) caused by developmental defects of the interventricular septum, is the most common type of heart malformation present at birth. It occurs in approximately 2–6 of every 1000 live births and accounts for approximately 30% of all CHDs in children/adolescents13. Patients with a VSD are known to commonly experience holosystolic murmurs, owing to the turbulence of the blood flow between the left and right ventricles15. Murmur recognition with auscultation is conventionally used for the screening and diagnosis of VSD16. However, the accuracy of this method largely depends on clinical experience and is a challenge for most young and inexperienced clinicians17. Therefore, the development of tools to automatically recognize heart-sound patterns can help physicians diagnose heart disease.Similar to many other heart malformations, heart murmurs can be heard in patients with VSD19. For example, many algorithms that claim to automatically recognize and classify medical images have been developed using deep learning22. Recent efforts have shown significant advances using artificial neural networks (ANNs) or deep neural networks (DNNs) to detect and classify heart sounds25. Convolutional neural networks (CNNs) have also been used to identify heart murmurs26. The aim of this study was to develop a novel algorithm that can automatically recognize the systolic murmurs of VSD patients using a novel temporal attentive pooling–convolutional recurrent neural network (TAP-CRNN) model27.Artificial intelligence has recently been widely used in computer-aided diagnosisHeart sounds from 76 subjects, including 51 VSD patients and 25 patients without significant heart malformations, were included in this study. Table Two repeated heart sound recordings were obtained at each of the five standard auscultation spaces. For some subjects whose recordings did not qualify, owing to the presence of noise, more than two recordings were obtained within the same auscultation space to confirm the quality of the soundtracks. A total of 776 heart soundtracks were recorded from 76 subjects, including 525 soundtracks from VSD patients and 251 soundtracks from normal subjects. The number of soundtracks in the training and test sets is shown in Table The TAP-CRNN model was used to recognize systolic murmurs in the current study. The structure of TAP-CRNN is described in Fig. 28 was used as the optimizer. For the train–test split task, the entire set of data were divided into 70%  and 30%  for training the murmur recognition models and testing their performances, respectively. For this task, the sensitivity and specificity scores were 88% and 85% for CNN, 92% and 93% for CRNN, and 97% and 98% for TAP-CRNN, respectively. In supplementary Tables The performance of the algorithm for systolic murmur recognition was analyzed for two different tasks, namely, a train–test split and K-fold cross-validation. Table The capability of the TAP-CRNN model for recognizing the systolic murmurs at the five standard auscultation sites was also analyzed Table –8. Both 29. Murmurs can be classified based on their timing, duration, intensity, pitch, and shape. Specific murmur patterns may occur as a result of many types of structural heart diseases14. For example, holosystolic murmurs, which are characterized by uniform intensity during the systolic period, usually appear in patients with mitral regurgitation (MR), tricuspid regurgitation (TR), or VSD32. Murmurs that occur during the systolic period with a crescendo-decrescendo shape are called systolic ejection murmurs and are often heard in patients with aortic stenosis (AS), pulmonic stenosis (PS), and atrial septal defect (ASD)30. Experienced cardiologists may successfully distinguish these specific heart sound patterns during routine auscultation, and this capability is important in disease diagnosis. However, it is always a challenge for young and inexperienced physicians to make a correct diagnosis based on auscultation33. Therefore, the development of tools that can automatically classify specific murmur types is necessary and clinically significant35.A murmur is a sound generated by the turbulent blood flow in the heart. Under normal conditions, the blood flow in a vascular bed is smooth and silent. However, blood flow can be turbulent and produce extra noise when the heart has a structural defect37. Previous studies have used a CNN to classify pathological heart sounds39. A recurrent neural network is another model frequently used in computer-aided diagnosis41. In this study, we combined CNN and RNN models (forming a CRNN model) to recognize the systolic murmurs from VSD patients. We used a convolutional unit to extract invariant spatial–temporal representations and the recurrent unit to capture long temporal-context information for systolic murmur recognition. In addition, the TAP mechanism was also applied in the CRNN model to assign an importance weight for each frame within the murmur regions. Finally, the overall model is called TAP-CRNN. From our experimental results, the TAP-CRNN model demonstrated an accuracy of 96% for distinguishing systolic murmurs from normal heart sounds, outperforming both CNN and CRNN without TAP.In recent years, CNNs have been widely used in computer-aided diagnosis42.For heart sounds recorded in the tricuspid and second aortic areas (Erb’s point), both the sensitivity and specificity reached 100% when the TAP-CRNN model was used. A high accuracy in these two areas is reasonable because the murmurs caused by the blood flow between the right and left ventricles can be most clearly heard in the tricuspid area or the lower left sternal border, which overlies the defectThe intensity of the murmur is inversely proportional to the size of the VSD. The ability of the algorithm to recognize the murmurs caused by a moderate or large VSD was also tested in the current study. In the test set, 63 soundtracks from 6 patients with moderate/large VSDs were included. When using the TAP-CRNN model, the murmurs of these soundtracks from moderate/large VSDs can be accurately recognized, except for two soundtracks recorded in the mitral area. Although the results obtained by TAP-CRNN are encouraging, we will further test the performance using a larger dataset of heart sound in the future.45. A larger heart sound database is currently being established to comprehensively collect heart sounds from patients with all types of structural heart diseases. An advanced version of the proposed TAP-CRNN algorithm that can recognize the specific murmur types in such diseases is also under development.This study has several limitations. As a major limitation, this study focused on the specific heart sound patterns of VSD, while not considering other types of structural heart diseases. Although heart murmurs can be heard in many other congenital and valvular heart diseases, such as atrial septal defects, patent ductus arteriosus, mitral regurgitation, and aortic regurgitation, patients with these diseases were not included in this study. Harmless heart murmurs, which occasionally occur in normal subjects, were also not includedWe demonstrated that a TAP-CRNN model can accurately recognize the systolic murmur of VSD patients. As compared to CNN and CRNN without TAP, the proposed TAP-CRNN achieves higher sensitivity and specificity scores for systolic murmurs detections in patients with VSDs. The results suggest that by incorporating the attention mechanism, the CRNN-based model can more accurately detect murmur signals. We also noted that sounds recorded from the second aortic and the tricuspid areas can facilitate more accurate murmur detection results as compared to other auscultation sites. The experimental results from the present study confirmed that the proposed TAP-CRNN serves as a promising model for the development of software to classify the heart murmurs of many other types of structural heart diseases.In this section, we introduce our data source, algorithm, and analysis method.The sound dataset used in this study included heart sounds recorded from subjects at the National Taiwan University Hospital (NTUH) using an iMediPlus electronic stethoscope. This study was approved by the research ethics committee of NTUH, and informed consent was obtained from all subjects or, if subjects are under 18, from a parent and/or legal guardian in accordance with the Declaration of Helsinki. It is also confirmed that all methods were carried out in accordance with relevant guidelines and regulations.46.Sounds from patients diagnosed with VSD were categorized as the VSD group and sounds from patients without a significant heart malformation were categorized as a normal group. Auscultation was applied for each subject by a cardiologist with 30 years of experience to confirm whether a pathological systolic murmur occurred in patients with VSD. Normal subjects with innocent murmurs were not included in this study. Echocardiography was conducted on all subjects to confirm the disease diagnosis47. The sounds were recorded by trained study nurses under the supervision of an experienced cardiologist. The soundtracks were saved as WAV files.For each subject, two repeated heart sound recordings lasting 10 s each were made at each of the following sites: the aortic area , the pulmonic area , the secondary aortic area/Erb’s point , the tricuspid area , and the mitral area/apex The soundtracks collected were divided into training and test sets. Notably, the training and test sets are two mutually exclusive sets without an overlap.N is the number of frames of X. Each frame is represented by a 257-dimensional log-power spectral feature vector. The collection of frames in X forms a spectrogram, which is generally used to visualize the characteristics of temporal signals varying over time . By contrast, local attention focuses on small regions . The idea of global attention is to consider all outputs of the convolutional layer and the temporal summarization of the output of the recurrent layer. For global attention of the TAP, we employ a simple concatenated layer to construct the global attentive vector c(n) by combining the information from the output of the convolutional layer In this study, a short-time fast Fourier transformation was used to transform the phonocardiogram (PCG) signal into a time–frequency representation , where ime Fig. . In thismentclass2pt{minimThe global attentive vector In addition to the global attention, the local attention is used to further refine the feature extraction and is calculated in the following manner:s of the dense layers, such as in the following:After obtaining the attentive context s and the output of the first hidden layer is described as follows:, and F(.) is the activation function. After obtaining the output of the first hidden layer, the relationship between the current and next hidden layer can be expressed as follows:L is the total number of layers of neurons in the output layer. Thus, the relationship for the classification layer or the output layer can be described as follows:G(.) is the softmax function, and o is the final output of TAP-CRNN.The dense layers are constructed using fully connected units. The relationship between feature The importance coefficients provided by the global and local attention were regarded as a frame-based event presence likelihood (EPL), i.e., The sex distribution, mean age, mean height, and mean weight of the subjects were calculated. An independent sample t-test and a chi-square test were conducted to compare the differences between the VSD and normal groups in terms of continuous and categorical variables, respectively.53. A diagnosis using echocardiography was applied as the gold standard for these calculations54. The equations are as follows:Tp indicates a true positive, Tn indicates a true negative, Fp indicates a false positive, and Fn indicates a false negative.The soundtracks used in the test set were applied to test the recognition performance. The accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for the distinction of the systolic murmur of VSD patients from the normal heart sounds of healthy volunteers were calculatedSupplementary Information.


Moderate positive correlation between the G3 and z-score of the left ventricular diameter  and moderate negative correlation between the G3 and the left ventricular ejection fraction in cardiac magnetic resonance (CMR EF)  were found. According to the multiple linear regression analysis, CMR EF and VES were independent predictors for G3 elevation. Conclusion: Galectin-3 plasma concentration is elevated and correlates with the chosen left ventricular dysfunction parameters in adolescents suffering from ventricular arrhythmia. Further investigation is necessary to establish if elevated G3 is a useful biomarker for screening young individuals with ventricular arrhythmia who are at risk of structural cardiovascular pathology.Galectin-3 (G3) is a biomarker known as an inflammatory state exponent. The aim of this paper was to analyze the G3 in adolescents with ventricular arrhythmia (VES) in order to evaluate its impact on myocardial tissue preservation. The study group (SG) consisted of 25 VES adolescents. The control group (CG) was 21 healthy children. G3 was assessed in the SG and CG. In the SG electrocardiography, Holter monitoring, echocardiography and CMR were performed. The G3 in SG was 13.45 ± 11.4 ng/mL and in CG 7.2 ± 2.0 ng/mL,  Galectin-3 is a protein produced by many tissues and is involved in a variety of processes, such as inflammatory reaction, apoptosis, fibrosis, or heart remodeling. This biomarker is considered as a novel, useful tool in many clinical situations, and among them in the area of cardiology .Galectin-3 plasma concentration is elevated in patients with persistent atrial fibrillation, and it is useful for the prediction of atrial fibrillation recurrence after catheter ablation ,3,4,5,6.The prevalence of ventricular arrythmia in young populations is extremely common. It is present in 16–50% of children, but the number of extra beats usually does not exceed 50 per day in each individual . A screeThe aim of this study was to analyze the galectine-3 plasma concentration in adolescents with ventricular arrhythmia in order to evaluate its impact on myocardial tissue preservation. The study group consisted of 25 consecutive children, aged 11–17 years, mean 14.7 years, diagnosed with ventricular arrhythmia. The lower limit for the diagnosis of ventricular arrhythmia was 100 extra ventricular beats per 24 h and/or complex arrhythmia detection. Complex arrhythmia was defined as it was described previously in the literature [The control group consisted of 21 healthy children aged 11–17 years, mean 14.6 years, matched to the study group according to the age and body size.The study was approved by the Bioethical Committee of the Medical University (No. 98/2020).Plasma collections for galectin-3 concentration assessments were performed in all consecutive patients from the study group and in children from the control group. A sample of 2.7 mL of peripheral venous blood was drawn into EDTA-containing tubes, centrifuged immediately, and stored at −80 degreases Celsius. Frozen samples from the trial sites were stored for the analysis. Analysis of galectin-3 concentration was performed using an enzyme-linked immunosorbent assay (ELISA) developed by BioVendor Research and Diagnostic Products . The lower limit of detection for this assay is 0.29 ng/mL, which does not cross-react with collagens, other members of the galectin family or common heart failure medications.Standard, resting 12-lead electrocardiograms were obtained. The morphology of ventricular extra beats was assessed, if present. Furthermore, arrhythmia was evaluated using 24 h Holter monitoring, where the number and complexity of arrhythmia were assessed.Adolescents in the study group were examined by an experienced pediatric cardiologist using a standardized protocol with an EPIQ ultrasound system (Philips). Procedure was performed with the patient being in the left lateral decubitus position with a phased-array transducer S5-1. Routine measurements of the left ventricular diameter (LVDd) and right ventricular outflow tract diameter (RVOTd) in parasternal long (PLAX) and short axis (PSAX), as well as left ventricular ejection fraction (LV EF) using the Teicholz method, were performed according to clinical practice and international guidelines . AdditioCMR scanning was performed with the use of a 3 Tesla Philips Achieva MR system  as described earlier in the literature . In partp < 0.05 was taken as being statistically significant.The Kolmogorov–Smirnov test was used to verify a normal distribution. In case of normal distribution data was presented as mean ± SD, whether with not normal distribution it was presented as median and range. Comparison between the controls and the study group was determined by using the Mann–Whitney U test. Correlations were determined according to the Spearman rank order correlation. Multiple linear regression analysis was made in order to assess galectin-3 plasma concentration on the basis of arrythmia number and ejection fraction calculated in the cardiac magnetic resonance. A receiver operating characteristic (ROC) curve was generated to determine the sensitivity and specificity of arrhythmia burden to detect increased galectin-3 plasma concentration. The statistical analysis was not performed if the number of patients was less than 10. A None of the patients suffered from any chronic diseases. The demographical data of the study and control group are summarized in Arrhythmia was detected in seven patients in the resting ECG. In six of them, ectopic beats had a morphology suggesting right ventricular outflow tract origin. In one patient, ectopic beat morphology suggested posterior wall origin of the arrhythmia. In the rest of the children, arrhythmia was registered in 24 hours Holter monitoring after initial diagnosis of irregular rhythm in physical examination. In the 24 hours Holter monitoring, the median number of beats was 5944 beats  and accounted for 7% (range: 0–46%) of arrhythmia burden. Fourteen patients were diagnosed with complex arrhythmia.p < 0.001) compared to its level in children in the control group, for whom the value was 7.2 ± 2.0 ng/mL (p > 0.05) in children with complex arrhythmia (16.8 ± 14.2 ng/mL) compared to the protein level in patients without complex arrhythmia (9.1 ± 2.2 ng/mL) and in the control group  was achieved, as shown in We analyzed ROC curves for arrhythmia burden to detect its cut-off value for increased galectin-3 plasma concentration. The elevated plasma concentration of galectin-3 was fixed at above 10.71 ng/mL  and was increased in eleven patients of the study group. According to the results of the ROC analysis, a statistically significant correlation (area under the curve (AUC) 0.73, SE 0.1, Echocardiography was performed in all patients and CMR in 15 patients. All echocardiographic data are summarized in Significant pathology of the circulatory system was diagnosed following the echocardiography and/or cardiac magnetic resonance in four patients, as presented in 2 in CMR), and EF was as low as 55% in echocardiography and 51% when analyzed in CMR. A 16-year-old girl was diagnosed with arrhythmogenic ventricular cardiomyopathy on the basis of the following criteria: non-sustained ventricular tachycardia of left bundle-branch morphology with superior axis, inverted T waves in right precordial leads, enlarged right ventricular outflow tract (RVOT PSAX 22 mm/m2) in echocardiography, and right ventricular end-diastolic volume in CMR (108 mL/m2). In this case, the arrhythmia burden was 11% and the galectin level was 19.1 ng/mL.In a 14-year-old boy diagnosed with dilated cardiomyopathy, an extremely high percentage of arrhythmia burden (41.6%) was detected. Galectin-3 plasma concentration was 25.2 ng/mL. In that patient, left ventricular diastolic diameter was increased   . Moderatp = 0.032) was detected  = 7.29; p = 0.004.) The arrhythmia number is a slightly stronger predictor of galectin-3 plasma level than the left ventricular ejection fraction  between the arrhythmia number and galectin-3 plasma level, which confirms the hypothesis that dyssynchronous contractile activity due to ventricular arrhythmia is the ground for myocardial degeneration. Unfortunately, the sensitivity (73%) and specificity (71%) of optimal cut of point are relatively low. Nevertheless, the data in the literature suggest that in some clinical situations, the value of galectin-3 measurement may be improved by analysis with other biomarkers such as NT-proBNP [In our study, ROC analysis reveals statistically significant correlation  difference of galectin-3 plasma concentration in the study and control group was still observed  and arrhythmogenic right ventricular radiomyopathy (ARVC)) from our cohort, a statistically significant (observed . There aThe evidence for our assumptions does not yet exist in the literature. Nevertheless, in adults, a correlation between ventricular arrhythmia burden and left ventricular systolic dysfunction has been reported ,22,23,24Currently, galectin-3 is a valuable marker for the diagnosis of heart failure that precisely predicts increased risk for mortality during mid-term follow-up. In the clinical course of heart failure, plasma concentration elevates over time, and the increase is independently associated with a poorer clinical outcome ,25,26. FFinally, although the ejection fraction correlates moderately with the galectin level in both echocardiography and cardiac magnetic resonance, we did not achieve statistical significance in the case of echocardiography. There are several reasons that may explain this difference. Firstly, the methodologies of ejection fraction assessment in cardiac magnetic resonance and echocardiography are different. In cardiac magnetic resonance ejection, fraction analysis is based on volume changes, while in echocardiography, it is performed after simple measurement of the diameter followed by a mathematical calculation based on the premise that the left ventricular shape is elliptic. During the echocardiographic study, every small alteration of the measurement is powered by the formula for the ejection fraction calculation, which creates a higher variability of the results, so that statistical significance may be accomplished only in a relatively large cohort of patients.On the basis of our findings, we conclude that galectin-3 can be a useful tool in the screening of adolescents with ventricular arrhythmia. However, further trials are necessary to establish the extent to which it may be applied in everyday clinical practice.Some limitations could also bias our results; e.g., stimulation of the cardiac beta-adrenoreceptors can affect the number and complexity of arrhythmia as well as galectin-3 plasma concentration . In suchGalectin-3 plasma concentration is elevated and correlates with the chosen left ventricular function parameters in adolescents suffering from ventricular arrhythmia. Further investigation is necessary to establish if elevated galectin-3 plasma concentration is a useful biomarker for screening young individuals with ventricular arrhythmia who are at risk of structural cardiovascular system pathology.


Objective: Analysis and presentation of the capabilities of the new ultrasound technique —the index of volume remodeling (IRV), which allows comprehensive assessing of pathological remodeling of the heart as an integrated functional anatomical system. Materials and methods: For this study 316 patients with acquired mitral valve disease (MVD) were examined prior to and following mitral valve replacement with bileaflet, disc-, and bioprostheses. Key parameters of the heart were measured in classical echocardiographic projections . The patients were examined 1–2 days prior to and following the surgery—before discharge, 6 months later, 1 year later, and then annually within next 5 years. The examination data were collected in one- and two-dimensional modes by using Philips EpiQ-7, iE33, HDI, Siemens Acuson, and HP Sonos 2500 diagnostic ultrasound machines equipped with 2.5 and 3.5 MHz transthoracic sensors. Results: A comprehensive study of structural geometric remodeling parameters of heart cavities in the context of acquired MVD allowed identifying new patterns in changes of the heart chambers geometry. These changes are reflected in the IRV, a digital indicator of the severity of cardiac pathological remodeling. Analysis of the dynamics of post-operative vs. pre-operative IRV-based remodeling data also showed that the index is highly sensible to the hemodynamic features of through-flows in various designs of prostheses. The IRV has a pronounced prognostic power and allows predicting the long-term outcome of surgical treatment with an accuracy of 82.35%. Conclusions: The IRV predictive accuracy formed the basis of the original classification of types of cardiac remodeling, which can assist both in determining the optimal timing for surgery, and in conjunction with other clinical diagnostic data, in predicting the long-term outcome of heart geometry restoration depending on the type of surgical correction. The IRV can be used in evaluation of the heart geometry for any cardiac pathology. It makes the approach to the analysis of pathological remodeling of the heart understandable, consistent, and universal, and also opens up opportunities for further expanding the diagnostic capabilities of radiology in cardiac surgery at all stages of the diagnostic process. Acquired heart defects represent a significant social problem as they affect people of socially active age and can lead not only to permanent disability, but also to death of patients, especially in case of ill-timed and inadequate treatment.While conservative treatment methods have clear clinical performance criteria, the timing of surgical correction has no fully defined criteria and is left to the discretion of the treating cardiologist or a patient’s decision ,2,3.Presently the flags for determining the timing of surgical intervention are heart rhythm disturbances and clinical manifestations, which do not always reflect the severity of intracardiac hemodynamic impairment. Often patients do not feel rhythm disturbances or do not pay due attention to them. Arrhythmia in such case is diagnosed accidentally. Often patients notice heart failure symptoms only when they begin to significantly limit their social activity. The need for surgery is often associated with a noticeable decrease in the effectiveness of drug therapy and negative dynamics of a patient’s clinical condition. At this stage of the disease, impaired intracardiac hemodynamics often leads to resistant or almost irreversible pathological remodeling of the cardiac chambers. The surgical correction performed at this stage improves the heart geometry and the patient’s state of health, but the clinical manifestations of the disease and intracardiac hemodynamics impairment persist. They continue to disturb the patient and do not allow him to fully return to his social activity. Results of surgical correction at this stage of the heart disease development do not always meet patient’s expectations in terms of improved well-being.Among surgical methods of treating MVD prosthetics remains the most widespread and frequently used type of surgical correction, despite great success in the development of valve-sparing reconstructive techniques. The timeliness of surgical correction determines the long-term results of treatment. The high technology surgery can reduce mortality by 3.5–5.0% during mitral valve replacement and in the early post-operative stages ,5,6,7.Postoperative patient survival largely depends on the initial state of intracardiac hemodynamics and severity of heart geometry changes  that occurs in response to the damaging effect of hemodynamic impairment.316 patients with acquired MVD were examined between 2004 to 2017 at the Bakulev National Medical Research Center of Cardiovascular Surgery . Ethical Code at the A.N. Bakulev Research Centre: 19 October 2012, Directive No. 470 On Establishment of Local Ethical Committee. The selection criteria were the presence of anatomical and hemodynamic signs of acquired organic mitral valve pathology. A concomitant aortic valve defect was a factor of exclusion. The MVD was diagnosed based on the clinical picture of the disease, history, and results of clinical and instrumental examination. The average age of the patients was 50.3 + 18.5 years. 178 (66.6%) patients were female (average age- 57.4 + 12.8 years), 138 (33.4%) patients were male (average age- 51.6 + 15.8 years). The research sought to study changes in the heart chambers geometry caused by initial pathology of mitral valve and hemodynamic characteristics of the mitral prosthesis. The study focused on assessing the predictive power of the new ultrasound technique for measuring heart geometry changes in patients with MVD.For this analysis, patients were grouped according to the type of initial pathology of mitral valve:Group 1—patients with mitral valve stenosis and 1st or 2nd degree of mitral regurgitationGroup 2—patients with mitral valve stenosis and 3rd or 4th degree of mitral regurgitation Group 3—patients with isolated organic mitral valve insufficiency.According to the type of mitral valve implant, patients were also grouped as follows:Group 1—patients with bileaflet prosthesesGroup 2—patients with disc prosthesesGroup 3—patients with bioprosthesesThe examination data was collected in one- and two-dimensional modes by using Philips EpiQ-7 , Philips-iE33 , Philips HDI , Siemens Acuson , and HP Sonos 2500  diagnostic ultrasound machines equipped with 2.5 and 3.5 MHz transthoracic sensors.According to statistics, 80.2% of patients in Russia with acquired MVD undergo mitral valve replacement . Thus thOrganic mitral valve pathology impairs intracardiac hemodynamics predominantly in the left heart chambers ,4,5. FirMRI and echocardiographic images  illustraThe concept of our research is based on the fact that the imbalance of heart cavities volumes in patients with acquired MVD is an integral part of the pathogenesis of the disease.Analysis of changes of the heart cavities volume, or pathological remodeling of heart geometry, is possible only with respect to indicators reflecting the normal ratio of the heart chambers volumes. We have encountered no information about such indicators in the literature, therefore the ratio index of cardiac cavities was determined in the control group of 20 healthy people  aged 28 to 52 years. The average normal ratio index of the left heart cavities was stated at 4.0 (varying from 2.0 to 5.8), of the right heart cavities – at 1.7 (varying from 1.2 to 2.8). The ratio index, or the index of volume remodeling (IRV) was calculated according to the formula:VV (d)—(volume of ventricle) ventricular volume in diastole (d): the end-diastolic volume (EDV) of the right or left ventricle calculated according to the Simpson method,VA (S × L): VA—(volume of atrium) is calculated as the product of the planimetric area of the left or right atrium (S) and the width of the corresponding cavity measured at the middle third (L).The MRI verification of the left atrium volume figures, obtained by the proposed method, showed that the calculation error, in comparison with other methods implanted in the program of the ultrasound system, ranges from 5 to 9.3 %. The IRV deviation value in digital terms shows severity of heart geometry changes resulting from the impaired intracardiac hemodynamics; it reflects the severity of the pathological remodeling. The IRV is an ultrasound technique which allows to comprehensively evaluate the geometry of the heart as a single functional anatomical system that can respond not only to pathological factors, but also to their elimination.Analysis of the IRV in 316 patients with organic MVD showed that only 3.5% of patients have normal ratio of the heart cavities volumes, a small number that can be neglected to preserve the structure of our research. The pre-operative IRV random distribution curve (conforming Rayleigh law) showed that in 96.5% of patients the index was significantly less than 2.0; and for the majority of patients the IRV was 0.6 ± 0.3 .Post-operative long-term IRV dynamics  showed that the heart cavities volume ratio returned to normal in only 8.5% of cases. Such a small percentage does not allow comparing postoperative IRV dynamics with normal ratio index. The postoperative IRV chart shows that in 54.4% of cases the IRV becomes equal to one (1.0), with the rest of data showing uniform distribution around this value . As a rePost-operative remodeling was considered as positive if the IRV increased as compared with initial value; and negative if the IRV decreased. Analysis of the IRV dynamics of the heart geometry restoration over the course of 5 years shows varying degree of positive remodeling in all patients; remodeling occurs in line with a single algorithm in both the left and right chambers. The chart  shows thObtained data indicate that the heart geometry integrally responds to changes in intracardiac hemodynamics.The ROC curve analysis  of the IThe area under the ROC curve was 0.793 ± 0.052 , indicating a good quality model. According to the obtained data and analysis we identified three scenarios of long-term post-operative remodeling:Scenario 1: The IRV is restored to ≥1  . The cause of this negative remodeling is mostly post-operative complications and rhythm disturbances, especially atrial fibrillation, which is a predictor of worsening post-operative prognosis ,4. Post-The above-presented scenarios formed the basis of the original prognostic classification of types of pathological remodeling:Type I (mild remodeling)— favorable prognosis (IRV ≥ 0.8–2.0); see Type II (moderate remodeling)—moderately favorable prognosis (IRV 0.8–0.5); see Type III (severe remodeling)—poor prognosis (IRV ≤ 0.5); see Type III includes patients with the most severe, chronic pathological heart remodeling. Surgical correction of MVD contributed to a certain improvement of the intracardiac hemodynamics and clinical condition of these patients. However, cardiac resistance, especially of atria, did not allow heart geometry to restore significantly. The IRV in such patients remained at ≤0.5 even 5 years later after the surgery.This classification is averaged and does not exclude upward or downward IRV dynamics in each scenario, depending on the effect of concomitant diseases and rhythm disturbances, which require a separate study, especially in the long term after the surgery. However, the offset variation in each scenario is limited within the range of 17–25%.An analysis of the IRV values depending on the nature and severity of the initial pathology showed that the greatest prospect for heart geometry restoration is observed in patients with isolated organic mitral valve insufficiency  and patients with mitral valve stenosis and 1st or 2nd degree of mitral regurgitation (Group 1). The largest share of Type I remodeling was observed in patients of these groups; it almost doubled within 5 years following the surgery .Type III remodeling was initially observed in 58.8% of patients from Group 2. The share of this remodeling type decreased to 14.2% (down 44.6%) 5 years after surgery, however it remained the biggest as compared to Groups 1 (3.3%) and 3 (1.2%); this illustrates resistance of heart chambers, especially of left atria, in the process of restoration.We conclude that surgical interventions performed at stages of Type I and II pathological remodeling have the most favorable prognosis. At these stages it is still possible to restore the geometry of the heart chambers to normal or to Type I in more than 70% of cases.The remodeling classification was used in the retrospective analysis of the post-operative IRV dynamics (over the course of 5 years) in order to estimate the effect of hemodynamic features of various types of prostheses on the heart chambers geometry.The analysis of correlations between the IRV and hemodynamic features of different artificial heart valves showed that design of prosthesis has certain influence on the quality and speed of left heart chambers geometry restoration see .The patients of the study group had a valve replacement surgery with the following types of implants:disc (MIKS)bileaflet biological .The best results in restoring the geometry of the heart were found in patients of Group 3 . This is due to the design of these prostheses, ensuring a laminar, almost native blood flow. The design of mechanical prostheses with locking elements, crossing the passage opening, disrupts the laminar blood flow. In bileaflet prostheses the through-flow is turbulent, but central, while in disc prostheses it is turbulent and eccentric. The study showed that such a structuring of the through-flow required a period of adaptation in Group 2. In the early postoperative period, adaptation led to almost a two-fold decrease in Type I remodeling in this group (from 41.9% to 19.1%). However, the distribution of remodeling types in Group 1 (bileaflet prostheses) and Group 2 (disc prostheses) leveled out following adaptation of heart chambers to hemodynamics of disc prostheses in the long-term post-operative period. Our research offers a new ultrasound technique that can be used for a comprehensive assessment of the geometry of the heart as an integrated functional anatomical system. The results of this study are presented in the classification of patterns of heart remodeling identified in the course of the research. The IRV-based analysis of the correlations between the initial mitral valve pathology and type of prosthesis showed that the IRV has a pronounced prognostic power.The IRV of heart chambers provides an instrument for presenting the degree of cardiac geometry deviation in digital view. As a result the information on the dynamics of remodeling of structural and geometric parameters of the heart becomes universal for monitoring the patient’s postoperative state of health by any clinicians. We suggest that the IRV method, as an ultrasound technique, allows us to rate the severity of pathological remodeling and should assist surgeons in determining the optimal timing for surgery as well as predicting the long-term outcome. This research was not aimed to study the correlation between the IRV and rhythm disturbances or other comorbid conditions. These aspects require a separate large-scale study, which gives us an interesting direction for future research.Finally, we shall note that the pathological remodeling of heart occurs not only in case of MVD, but also in other valvular and cardiac pathologies. In these cases the IRV technique may also be used in researching remodeling patterns, providing a fresh look at the traditional approaches to determining the timing and type of treatment, including surgical, and predicting its long-term outcome. The IRV method has been included into the main echocardiographic protocol at the A.N. Bakulev National Medical Research Center of Cardiovascular Surgery, Moscow, since 2017. The IRV method is patented as of 15 August 2018 (Patent number 2664155).