Valvular heart disease (VHD) occurs as the result of valvular malfunction, which can greatly reduce patient’s quality of life and if left untreated may lead to death. Different treatment regiments are available for management of this defect, which can be helpful in reducing the symptoms. The global commitment to reduce VHD-related mortality rates has enhanced the need for new therapeutic approaches. During the past decade, development of innovative pharmacological and surgical approaches have dramatically improved the quality of life for VHD patients, yet the search for low cost, more effective, and less invasive approaches is ongoing. The gold standard approach for VHD management is to replace or repair the injured valvular tissue with natural or synthetic biomaterials. Application of these biomaterials for cardiac valve regeneration and repair holds a great promise for treatment of this type of heart disease. The focus of the present review is the current use of different types of biomaterials in treatment of valvular heart diseases. According to the American Heart Association’s 2019 report, cardiovascular diseases remain a major source of mortality and disease-related cost burden in the United States and worldwide . Some ofIn particular, VHD occurs as the result of valvular malfunction. Left untreated, valvular diseases can lead to stroke, heart failure and death due to sudden cardiac arrest (SCA). Different treatment regimens are available for management of VHD, including medications and lifestyle changes, as well as surgical and interventional procedures. Although most of these treatments can be helpful in reducing the symptoms, the gold standard approach is to repair or replace the injured valve tissue in order to restore full cardiac function. On the other hand, some impaired cardiac valves cannot be repaired (in 70% of cases) and need to be replaced by biomaterials . AlthougAs life expectancy and access to screening methods has improved across the world, the number of VHD cases has increased considerably in the past few years. Many people with valvular defects have no symptoms and in most cases, this condition remains constant throughout the person’s life. However, for other people, VHD slowly progresses and the symptoms become worse. Estimations suggest that the prevalence of VHD may increase up to 122% by the end of 2056, creating a significant socio-economic impact on the society . CurrentIn the last decade, along with the tremendous growth in biomaterials applications, there have been numerous successful implementation of biomaterials in the replacement and repair of body tissues, including cardiac valves. Biomaterials are simply defined as materials that either would interact with body’s tissues for medical purposes, as implanted medical devices or used to support, augment or replace injured tissues and/or organs or as drug carriers. The main characteristics of a biomaterial substance include bio-functionality, biocompatibility, bioactivity, sterilizability and bio-inertia.Various synthetic and natural biomaterials have been used for replacement and repair of damaged valvular tissues . These bHeart valve diseases are among the most common CVDs in the world, affecting nearly 2.5% of the US population . PotentiThere are two main classes of VHD—valvular stenosis and valvular insufficiency. Valvular stenosis occurs because of the stiffening and reduced elasticity of valve leaflets, which can lead to narrowing of the valve opening and subsequently, reduction of blood flow. Valvular insufficiency or regurgitation occurs as the result of incomplete closure of valve leaflets, leading to leakage or regurgitant flow development .According to American Heart Association (AHA)/American College of Cardiology (ACC) guidelines, VHD progression can be categorized according to disease stage as follow :Stage A: Patients who have the risk factors for development of VHD.Stage B: Asymptomatic patients with progressive VHD (mild to moderate severity).Stage C: Asymptomatic patients with severe VHD with either normal right or left ventricular systolic function (Stage C1) or decompensated ventricular function (Stage C2).Stage D: Symptomatic patients with severe VHD.VHD diagnosis might be challenging since patients may be asymptomatic or VHD might be accompanied by possible comorbidities. In this regard, precise patient evaluation in terms of family history and risk factors as well as careful physical examination (including intra- and extra-cardiac conditions and comorbidities) are mandatory.VHD conditions can be congenital or acquired and may involve any of the four valves of the heart, however, when the aortic and mitral valves are involved, patient’s condition is often more serious. Age is another determining risk factor in VHD, in a way that the risk of VHD increases from less than 1% in people in the age of 18–44, to more than 13% in people over 75 years old .Since the heart valve tissue cannot regenerate spontaneously, replacement , repair (via reconstructive surgery) or interventional catheterization are the current treatment options for management of VHD. Abnormal valves that are not repairable are replaced with bio-prosthetic  or mechanical (prosthetic) valves . ExtensiGenerally, cardiac valve biomaterials should be biocompatible with good hemodynamics, high mechanical stability and resistance to degradation and calcification. Despite recent advances in valvular replacement, mechanical and bio-prosthetic heart valves, both share the disadvantage of remodeling and growth following implantation, which is considered a major limitation in their application—especially in children with congenital valve disorders, since the transplanted heart valve should be able to simultaneously grow along with the patient’s heart. Tissue-engineered heart valves (TEHVs) are possible substitutes for bio-prosthetic and mechanical valves, with the ability of remodeling and acquiring patient’s normal valve structure.Understanding the mechanical properties of natural heart valves is essential for successful design and fabrication of prosthetic valves so they can more closely resemble native valve’s structure and function. Cardiac tissue is composed of different cell types including cardiomyocytes, fibroblasts, endothelial, and smooth muscle cells. Fibroblasts are the most frequent cell types in the myocardium, which are responsible for the extracellular matrix (ECM) components deposition . CardiacFour cardiac valves provide unidirectional forward blood flow during each cardiac cycle. Two types of cardiac valves exist: semilunar valves  with three identical leaflets or cusps and sigmoid or atrioventricular valves . The sigmoid valves have a more complex structure compared to semilunar valves due to their asymmetrical geometry and unequal leaflet size .All the four heart valves lie on the basal plane of the heart, made from dense collagen fibers, which help maintain their constant position relative to the movements of other parts of the heart. While the mitral and tricuspid valves are responsible for regulating the blood inflow to the heart, the aortic and pulmonary valves control the blood flow from the left and right ventricles into the aorta and pulmonary artery, respectively .Each valvular leaflet is made of three different layers including fibrosa, spongiosa, and the ventricularis with their distinct ECM composition. All these layers are composed of VICs with their surrounding ECM, covered with VECs. Fibrosa is the main load bearing and the thickest layer of the valve leaflet, which is made of type I collagen fibers that can endure high tensile forces. Ventricularis is made of dense collagen and radially aligned elastin fibers and is responsible for reducing the radial strain during valve opening and maximum forward blood flow. The spongiosa layer provides lubrication during leaflet bending and pressurization and is composed of collagen fibers, hydrated PGs, and GAGs. Hydrated PGs and GAGs are also involved in oxygen and nutrient elements diffusion through the valve tissue, as well as growth factor sequestration and controlled release .Heart valves undergo 30 million heart cycles a year, while operating under high dynamic and mechanical forces  . These fNatural valve leaflets represent a dynamic biological material with a heterogeneous anisotropic structure and complex mechanical behavior. They present the optimum structure and geometry, which minimizes the shear stress resistance while maximizing the blood flow. Some of the most important features of heart valves include dynamic motion, complex surface geometry, anisotropic deformation, thin leaflets, and remodeling . The preThe common aortic valve is a tricuspid valve responsible for maintaining the unidirectional blood flow from the left ventricle into the aorta. The leaflets does not have uniform thickness, their thickness increases toward free cusps margins . SimilarPHVs or mechanical heart valves fabricated from synthetic materials  have lifFatigue and wear stress are two other major problems associated with valve prostheses failure . GeneralThe main types of PHVs include ball in cage, tilting disc and bileaflet valves. The first successful prosthetic heart valve implantation  , titaniuElastomers  are commonly used in the biomedical field, mainly due to their ability to sustain deformation under stress conditions without being ruptured and resuming their original state upon removal of the stress. Elastomeric materials exist as natural and synthetic (including silicones and polyurethanes) forms . Polyure® (a thermoplastic PU) and were able to improve surface hydrophilicity up to 30%, as well as enhanced antibacterial activity and hemocompatibility.Surface modification is a useful strategy for manipulation of PU’s resistance to biodegradation, thrombogenesis and calcification. Bernacca et al. used heparin, taurine, 3-aminopropyltriethoxysilane and polyethylene oxide (PEO) to modify PEU and PEUE heart valves and to improved their fatigue resistance and durability . Many siFlexibility of PU heart valves is obtained by using low modulus materials, however, low modulus PUs show poor durability due to high strain accumulation . Since tPyrolytic carbon’s excellent features including its strength, clot forming prevention, and wear resistance as well as tissue- and blood-compatibility, make it an interesting biomaterial for fabricating PHVs . Low-temBlood-flow hemodynamics near the heart valve as well as the interactions of blood cells and platelets with valvular structures are among the most important determining factors for prosthetic valve’s success or failure. Since thrombosis and thromboembolism, are two major complications associated with PHVs, novel mechanical valves with improved hemodynamic characteristics are needed to be developed. The blood flow mechanics of each prosthetic heart valve design, will determine PHV’s performance. For example, in the ball in cage model, presence of a low-velocity recirculating blood flow with high shear stress downstream of the cage’s apex, which extends throughout the forward blood flow, has been identified. The turbulent shear stress in this region is high enough to activate platelets and trap them inside the recirculating blood flow, which in turn promotes platelet-platelet contacts and leads to thrombose formation at the apex region . As for In an interesting study by in vivo experiments in juvenile and adult ships, and used computational simulations to assess its stress-strain profile under physiological conditions. Three main geometrical factors were considered in the design of their prototypes including leaflet’s geometry, leaflets attachment and valve expansion geometries. A key parameter in geometrical consideration of their concept design was to fix the length of leaflet attachment, so that upon radial expansion, the valve’s height reduces. As a result, the valve shortens upon increasing the opening diameter, which fulfills valve coaptation without the need to increase leaflet’s surface. Expandable polytetrafluoroethylene (ePTFE) was used to fabricate the leaflets of the prototype, which were sewed to a stent made from stainless steel , which are made partly or entirely from biological materials , show good hemodynamic characteristics without necessary lifetime anticoagulation treatments. Natural biomaterials in BPHVs generally consist of ECM components or decellularized tissues such as arterial wall, pericardium, heart valve or small intestinal sub-mucosa .BPHVs can be classified as autografts , homografts or allografts , and xenografts. The Ross procedure (Switch procedure) is the autograft replacement of faulty aortic valve with patient’s own pulmonary valve. The pulmonary valve is then replaced with a homograft cadaveric pulmonary valve. This procedure was first introduced in 1967 and has been performed on young patients and children since . This duDifferent steps have been taken in order to increase xenograft valve’s stability and biocompatibility including; soluble protein removal by washing or electrolysis, sodium periodate denaturation of structural glycoproteins and mucopolysaccharides, neutralization by ethylene glycol and finally, glutaraldehyde treatment for cross-linking the remaining free amino groups of amino acids. Glutaraldehyde treatment is the most effective step in preserving and reducing the antigenicity of xenograft tissues . DespiteGlutaraldehyde toxicity toward residual cells in xenograft valves is also associated with SVD, since dead resident cells cannot be removed from the tissue. These cells are not able to maintain calcium hemostasis and can initiate calcium nucleation leading to eventual SVD .Another issue that greatly affects BPHV’s durability is the expression of different antigenic epitopes  in xenograft valves. The α-Gal epitope is not presented in the human body but it is preserved in non-primate mammals. However, the anti-Gal antibody constitutes 1% of immunoglobulins in the human body and is responsible for anti-gal reactivity and early rejection of xenograft BPHVs . Glutarain vitro durability.More recently, the use of genetically modified animals expressing low levels of α-Gal epitopes have attracted researcher’s attention . In thisThree types of BPHV replacements exist: stented, stentless, and percutaneous . StentedPercutaneous or trans-catheter valve replacement is the most advanced alternative approach to open heart surgery for patients with high risk of complications. Transcatheter endovascular delivery of BPHVs requires the BPHV to be crimped, which reduces its dimensions to up to 3-fold without rupturing the leaflets. Throughout these years, different issues have been reported that can potentially limit the application of percutaneous valves including paravalvular leakage, vascular, and neurological complications as well as complete atrioventricular blockage. The development of first percutaneous valve dates back to 1965, which was an umbrella-shaped valve placed on a catheter that was implanted into a dog . An earlBased on a study published in 2009, aortic valve stent devices fabricated from stainless steel, cobalt chromium, nickel and titanium for percutaneous implantation, were characterized and evaluated by finite element analysis technique to assess the effect of biomaterial properties on stent performance under high blood pressure conditions. Their results indicated that titanium had the greatest impact on device performance, with maximum displacement and minimum stress levels .Current guidelines recommend using of MHVs for younger patients (<50 years of age) and BPHVs in patients over 70 years of age, and either type of these prosthetic valves can be used for patients in the range of 50–70 years old . The choChildren and young adults are not good candidates for mechanical heart valve replacement since they are at risk of complications due to long-term consumption of anti-coagulation medications and lack of implanted valve remodeling. On the other hand, they cannot fully benefit from advantages of BPHVs as well, due to early occurrence of SVD. Taken together, these patients are in need of suitable valvular prosthesis and extensive research in this area seems mandatory. α-Gal-free porcine pericardium obtained from transgenic pigs seems to be a promising biomaterial for increasing the durability of BPHVs, especially in younger patients. It should be noted that α-Gal is not the only antigenic epitope that can trigger immune responses in the recipient patients and evaluation of other xenogeneic antigenic epitopes might be essential for quality control assessment of BPHVs.The ideal approach in valve replacement is to provide a viable valve capable of self-regeneration and growth, with greater life span and better biocompatibility. Tissue engineering, which is the use of biomaterials and engineering in combination with cells, offers a new generation of cardiac valves aiming to overcome the shortcomings of existing biological and mechanical heart valves . To achiin vitro and in situ valve heart tissue engineering  can pre-determine TEHV’s performance . In geneleaflets .2) treatment are alternative approaches. Due to specific advantages and disadvantages of each technique, combinatorial treatments may be performed in order to achieve the best results. For example, physical approaches are more successful in maintaining intact ECM, while they are unable to eliminate tissue’s immunogenicity. Chemical approaches on the other hand are not ideal for removing cellular debris. Combining these two approaches can yield an intact ECM with no debris. Ramm and colleagues in 2019 studied decellularized porcine pulmonary heart valves (dpPHVs), implanted in sheep. They used nine different techniques for generation of these dpPHVs. They evaluated the amount of residual SDS as well as DNA, GAGs and hydroxyproline content of dpPHVs and observed that addition of trypsin to Triton X-100 in the decellularization process results in efficient removal of cellular debris, while preserving the ECM. Trypsin- and Triton X-100-treated pdPHV’s performance was comparable to allogeneic decellularized valves. For DNA and N-linked glycans removal, they observed that the combination of PNGase F and DNase I with Triton X-100 and SDS improved the efficacy. However, the combination of trypsin and Triton X-100 resulted in lowest immunogenicity  or the combination of both. Each technique consists of the following steps: cell lysis and removal, genetic material removal (for lowering the immunogenicity) and preserving the composition and structure of the ECM . Chemicagenicity . Among dgenicity . Anothergenicity .The issue of decellularized valve’s immunogenicity should also be addressed. Hyperacute, acute and chronic rejection may occur following xenogeneic decellularized tissue implantation due to presence of xenoantigens. The process of decellularization can increase tissue’s immunogenicity, itself. For example, cardiovascular ECM is reach in hyaluronan (HA) polymers . Anti-inNatural polymesr including collagen, elastin , polyhydOnce the scaffold is ready and seeded, the new construct is placed inside a bioreactor in order to get adapted to the physiological biochemical and mechanical conditions. This process prepares the TEHV for implantation into the patient’s body. Bioreactors may also be used to study cellular functionality, cell-cell and cell-ECM interactions as well as cellular responses to physiological conditions of the valve prior to implantation. Various bioreactor designs have been developed for this purpose including cell-stretching bioreactors , dynamicDespite numerous attempts over the past decades in the area of design and development of biomaterial-based cardiac valves, this task remains extremely challenging. This is partly due to the difficulty of replicating biomechanical features of native heart valves, since cardiac valves are not merely passive systems and undergo constant on-demand adjustment and remodeling. One of the main purposes of studying valve biomechanics is to understand the mechanisms by which the biomechanical forces are transmitted to valvular cells and the ECM. This can be achieved by using mathematical modeling and computer simulations. The level of complexity of valvular micro and macrostructure should be considered in material selection for prosthetic heart valves. In this regard, more research toward better understanding of valvular biomechanics via accurate simulations and mathematical modeling can lead to significant advancements in the performance of designed valves. This task requires a thorough understanding of the biomechanics of healthy and diseased valvular tissue, and with help of state-of-the-art techniques (such as nanotechnology), biomaterials with adjustable characteristics can be obtained.Both medical professionals and researchers strive to provide durable hemocompatible, anticoagulant-independent and thrombus-free heart valves with the ability of remodeling. While these attempts are not far from becoming the standard routine in clinical practice, novel biomaterials with adjustable properties and mechanized industrial processing techniques are currently under research, since biomaterial’s properties, cost and availability are among the most important determining factors in material selection for biomaterial-based valve prosthesis.Biomaterials have shown great potential in management of CVD. Biocompatibility and biodegradation rates of most common biomaterials have been widely studied by various research groups. The optimum biomaterial-based heart valve should possess combined advantages of MHVs and BPHVs. It seems that the future of biomaterials-based CVD management is headed toward TEHVs. However, the optimum combination of cells and biomaterials for promotion of tissue regeneration is yet to be identified.Another concern that needs to be addressed, is minimizing the immunogenicity of applied biomaterials or tissue constructs, as they may trigger immune responses which have negative impact on their efficacy and performance.Despite these challenges, research in the field of biomaterials and tissue engineering for CVD treatment has achieved significant progress. However, the gold standard approach would provide the ability of using biomaterial scaffolds in combination with suitable cell types with good functionality, biocompatibility, and durability, with the aim of providing partial or whole heart regenerational capacity. Achieving this goal will ultimately eliminate the need for heart transplant in patients with heart failure, manage disease states in which irreversible functional loss has occurred and result in improved patient’s quality of life.ZI, LT, and HD performed the main conceptual ideas and proof outline. BT, HD, and LG wrote the manuscript with support MR, MJ, and PZ. NZ, MJ, MM, and ZI designed the figures. LT supervised the manuscript and final approval of the version to be published. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The left bundle branch pacing (LBBP) makes the ventricular depolarization closer to the physiological state and shortens QRS duration. The purpose of this study is to explore the ventricular systolic mechanical synchronization after LBBP in comparison with traditional right ventricular pacing (RVP) using two‐dimensional strain echocardiography (2D‐STE).Thirty‐two patients who received LBBP (n = 16) or RVP (n = 16) from October 2018 to October 2019 and met the inclusion criteria were included in this retrospective study. Electrocardiogram (ECG) characteristics, pacing parameters, pacing sites, and safety events were assessed before and after implantation. Acquisition and analysis of ventricular systolic synchronization were implemented using 2D‐STE.P < .001). Both the maximum time differences (TD) and SDs of the 18‐segments systolic time to peak systolic strain were significantly shorter under LBBP than under RVP , indicating that LBBP could provide better left ventricular mechanical synchronization. Left and right ventricular pre‐ejection period difference was significantly longer in RVP group than in LBBP group , indicating left and right ventricular contraction synchronization in LBBP group being better than in RVP group.In RVP group, ECG showed left bundle branch block patterns. At LBBP, QRS morphology was in the form of right bundle branch block, and QRS durations were significantly shorter than that of the RVP QRS (109.38 ± 12.89 vs 149.38 \± 19.40 ms, LBBP is able to provide a physiologic ventricular activation pattern, which results in ventricular mechanical contraction synchronization. After penetrating through the membranous atrioventricular septum, the conductive fibers of the left bundle branches spread beneath the endocardium of ventricular septum in a relatively large dimension,22.1This study was performed in Beijing Friendship Hospital with patients who were diagnosed as II° atrioventricular block (AVB), III° AVB, or sick sinus syndrome, and indicated for pacing therapy according to 2013 ESC/EHRA Guidelines.The inclusion criteria were as follows: (a) age > 18 years; (b) II° AVB, III° AVB or I° AVB sick sinus syndrome with ventricular pacing ratio > 70%; (c) LVEF >50%; (d) New York Heart Association (NYHA) score of I or II; and (e) being able to visit the hospital during follow‐up. The exclusion criteria were as follows: (a) moderate to severe valvular diseases; (b) congestive heart failure; (c) acute or old myocardial infarction; (d) history of cardiomyopathy; (e) poor condition of the acoustic window because of emphysema or other reasons; or (f) severe liver, lung or kidney dysfunction.The protocol was approved by Beijing Friendship Hospital Institutional Review Board, and all patients had submitted written informed consent. From October 2018 to October 2019, 32 patients who received LBBP or RVP and met the criteria mentioned above were included.2.2Before the pacemaker implantation, the ventricular septal thickness was assessed by Echo. Twelve‐lead ECG and intracardiac electrograms were simultaneously displayed and recorded on a multichannel recorder.V5 or RV6 shortening abruptly with increasing output or remaining shortest and constant (<90 ms) at low and high outputs; (d) selective LBBP and non‐selective LBBP; or (e) recording retrograde His potential or anterograde LBB potential during pacing .LBBP: The delivery sheath  was inserted via the left subclavian vein or axillary vein and placed on the right side of the septum inferior to the septal leaflet of the tricuspid valves about 1 to 1.5 cm from HBP site toward right ventricular apex (RAO 30°). Then, the Select Secure pacing lead  was advanced through the sheath with its tip just beyond the distal part of the sheath for unipolar pacing and local activation potential recording. The sheath and the pacing lead touched the septum and pacing with an output of 5.0 V/0.4 ms was applied, which created ECG QRS morphology of “W” pattern with the notch closer to nadir in lead V1. The pacing lead was then screwed perpendicularly to LV septum  was positioned in the right ventricular apex  or the right side of ventricular septum . The lead positions in patients with LBBP and RVP were confirmed with the high‐quality fluoroscopic radiographs. All patients underwent the regular follow‐up postimplantation.2.3Conventional lead‐related parameters including stimulation threshold, impedance, and sensing amplitude were recorded right after implantation and 7 days later. Ventricular pacing rates of all patients were more than 70%. The atrioventricular delay was selected, which corrected bundle branch block and yielded narrower QRS duration. Lead‐related adverse events were not observed during follow‐up.2.4max), and the SDs of systolic times to peak systolic strain (PSS) of the 18 LV segments were calculated. The 6‐segment time differences (TDs) to PSS of the apex four‐chamber view, apex three‐chamber view, and apex two‐chamber view were also calculated, respectively. Both the LV function and synchronization status using 2D‐STE were assessed using the offline software TOMTEC . Septal‐to‐posterior wall motion delay (SPWMD) was also recorded  with S‐5 transducers 7 days after surgery. Acquisition and analysis of synchronization using 2D‐STE were performed by senior sonographers. Standard apex four‐chamber view, apex three‐chamber view, and apex two‐chamber view were clearly exposed and recorded as well as ECG, and four consecutive cardiac cycles with constant heart rate were collected. The 18‐segment systolic times to peak 2‐D longitudinal systolic strain were recorded for every patient. Then the maximum time difference of systolic times to peak 2‐D strain among the 18 LV segments , 27 were diagnosed with AVB, 6 with sick sinus syndrome, 3 with coronary diseases, 8 with hypertension, 11 with diabetes mellitus, and 2 with paroxysmal atrial fibrillation. No statistical differences were noted in baseline clinical characteristics between the two groups , but there was no significant difference in QRS duration between patients of LBBP group and RVP group at baseline.ECG was characterized with wide QRS complex and the pattern of LBBB)or delay during either RVAP or RVSP as shown in Figure There was no significant difference in sensing amplitude, pacing impedance, and capture threshold among LBBP and RVP Table . Pacing In patients with LBBP, fluoroscopy at implantation confirmed the location of the pacing lead in the left bundle branch area Figure , and pos3.3max) was significantly shorter in the LBBP group than in the RVP group ; while at baseline, 2D‐TDmax did not differ between the two groups . There was no statistical difference for 2D‐TDmax in the LBBP group when comparing with baseline . After pacemaker implantation, the 2D‐TDmax was significantly longer compared with baseline in the RVP . Similar results were obtained when comparing SD of 18‐segment systolic times to peak 2‐D strain between the two groups at baseline and after operation . There was no statistical difference for SD in the LBBP group when comparing with baseline . After pacemaker implantation, the SD was significantly longer compared with baseline in the RVP . . Comparing the TD between the anterior wall and inferior wall and the TD between septum and lateral wall, we can get similar statistical results . The maximum TD was that between the septal and lateral wall in the RVP group (127.31 ± 53.18 ms). No significant TD difference of the abovementioned ventricle segments was found between the RVP group and the LBBP group at baseline.  (Supplementary P < .05), and the result indicated that interventricular contractile synchronization was better in the LBBP group than in the RVP group  nor after pacemaker implantation  revealed significant differences between the RVP and LBBP groups . We fused the right and left ventricular depolarization of three patients in this article to make the LBBP QRS duration and morphology more closer to the normal QRS wave , and the result indicates left and right ventricular contraction synchronization was better in the LBBP patient than the RVP patient. In the LBBP case, the left and right ventricular pre‐ejection period were 116 ms and127 ms respectively, and Left and right ventricular pre‐ejection period difference was 11 ms(=127‐116 ms). In the RVP case, the left and right ventricular pre‐ejection period were 180 ms and131 ms respectively, and Left and right ventricular pre‐ejection period difference was 49 ms(=180‐131 ms).Supplementary Figure 3. The 78‐years‐old female patient with atrial fibrillation and III0 AVB had symptoms of heart failure including dyspnea and decreased activity tolerance. The patient underwent pacemaker implantation 10 years ago, and her ventricular pacing ratio was 100%. Because of ventricular lead malfunction (threshold>4.0v/1.0 ms) the patient was needed to implant a new ventricular lead. The former ventricular lead was in the right ventricular apex (Sup Figure max of the 18‐segment systolic time to peak systolic strain was 96 ms (Sup Figure Click here for additional data file.


To investigate the performance of a deep learning-based algorithm for fully automated quantification of left ventricular (LV) volumes and function in cardiac MRI. We retrospectively analysed MR examinations of 50 patients . The most common indications were known or suspected ischemic heart disease, cardiomyopathies or myocarditis. Fully automated analysis of LV volumes and function was performed using a deep learning-based algorithm. The analysis was subsequently corrected by a senior cardiovascular radiologist. Manual volumetric analysis was performed by two radiology trainees. Volumetric results were compared using Bland–Altman statistics and intra-class correlation coefficient. The frequency of clinically relevant differences was analysed using re-classification rates. The fully automated volumetric analysis was completed in a median of 8 s. With expert review and corrections, the analysis required a median of 110 s. Median time required for manual analysis was 3.5 min for a cardiovascular imaging fellow and 9 min for a radiology resident . The correlation between fully automated results and expert-corrected results was very strong with intra-class correlation coefficients of 0.998 for end-diastolic volume, 0.997 for end-systolic volume, 0.899 for stroke volume, 0.972 for ejection fraction and 0.991 for myocardial mass . Clinically meaningful differences between fully automated and expert corrected results occurred in 18% of cases, comparable to the rate between the two manual readers (20%). Deep learning-based fully automated analysis of LV volumes and function is feasible, time-efficient and highly accurate. Clinically relevant corrections are required in a minority of cases.The online version of this article (10.1007/s10554-020-01935-0) contains supplementary material, which is available to authorized users. The quantification of LV ejection fraction (EF) as a measure of global systolic LV function is clinically important in a wide spectrum of cardiac conditions. LV EF is a strong prognostic parameter in acute coronary syndrome , 2, acutCardiac magnetic resonance (CMR) imaging is established as the clinical gold standard for the evaluation of left ventricular (LV) volumes, ejection fraction and myocardial mass , 7. In oMore recently, the dramatic evolution in artificial intelligence—specifically deep learning—has enabled the development of fully automated algorithms for volumetric analysis of CMR datasets. Initials studies indicate substantial time-saving and reduced observer bias compared to manual or semi-automated contouring , 9–14. SThe study was approved by the responsible institutional review board, informed consent was waived. The study was designed as a retrospective single centre cohort study. The study population consisted of 50 adult patients who underwent a CMR examination at 1.5 T in 2018. We selected suitable patients through a retrospective search of our radiology information system. We excluded children (n = 8), patients examined at 3 T (n = 8), patients with severe congenital heart disease (n = 4), large left ventricular aneurysms (n = 2) and datasets with severe artefacts (n = 15).fit, Siemens Healthineers). The cardiac MRI protocol was tailored to the clinical indication following national and international recommendations. All protocols included steady-state free precession cine sequences in 4-chamber view, 2-chamber view, left ventricular outflow tract view and as short axis stack perpendicular to the long axis of the LV. For the short-axis cine images, in-plane resolution was 1.9 × 1.9 mm, slice thickness was 8 mm with an inter-slice gap of 2 mm. TR was 42 ms, TE 1.1 ms and flip angle 72°. Parallel acquisition (GRAPPA) was used with an acceleration factor of 2. The short-axis image stack typically consisted of 10 slices. FOV size was typically 360 mm. Retrospective ECG-gating was used with 25 phases calculated over the cardiac cycle.All MRI examinations were performed on a 1.5 T MRI scanner . In brief, the network architecture is inspired by Unet architecture that is widely used for medical image segmentation. The architecture is adapted to maximize performance on CMR images in clinical settings (fast and low memory requirement). The network had been trained on 5000 healthy subjects from UK Biobank dataset combined with pathological cases collected from clinical collaborators. Manual annotation of the training set included the LV endocardium, LV epicardium, and RV endocardium.The short-axis cine stack was manually selected, and the deep learning-based algorithm was started with one mouse click. No other manual pre-processing or user interaction occurred. The fully automated algorithm automatically identified the end-diastolic and end-systolic phases and performed complete contouring of the endocardial contour in both diastole and systole. The epicardial contour for calculation of LV mass was automatically delineated in diastole only. The papillary muscles were detected and not included with the LV volume. Time required for fully automated volumetric analysis was recorded.After recording the results and contours of the fully automated analysis, the selection of cardiac phases, selection of slice inclusion and the contours were subsequently checked and corrected by an expert  as necessary. The number and type of corrections were registered categorised in correction of cardiac phase (choice of end-systolic or end-diastolic phase), correction of slice inclusion  and fine corrections of contours. The time required for all checks and corrections was recorded and added to the time required for fully automated analysis, to determine the time required for expert-corrected automated analysis.Manual volumetric analysis was performed on a randomly selected subset of 25 cases by a radiology resident  and a board certified radiologist currently performing a fellowship in cardiovascular radiology  using manual contouring tools within the same software . The analysis was performed on the short axis cine stack. The 4-chamber cine sequence was displayed for reference with a reference line indicating the position of the short axis slice to determine the most basal and apical slices to be included into the left ventricle. First, the end-systolic and end-diastolic phases were visually determined followed by manual delineation of the epi- and endocardial contours in end-diastole and the endocardial contours in end-systole. Both readers had been instructed in the use of the software. The cardiovascular imaging fellow had significant experience in performing volumetric analysis with this software (approximately 50 cases), whereas the radiology resident had limited experience (approximately 10 cases). Readers generally used a threshold-based tool for segmentation of the endocardial border and a multi-point tool for segmentation of the epicardial border but were free to use whichever tools in the software they found most efficient and accurate. Readers were instructed to exclude papillary muscles from left ventricular volume. The time needed for manual analysis was recorded.Analysis of electronic patient data was performed to assemble demographic information as well as indications and results of the CMR examinations.Statistical analysis was performed with Prism  and SPSS Statistics . Continuous values were presented as median and interquartile range, since normal distribution could not be assumed. Categorical data were displayed as absolute frequencies and proportions. Pairwise comparison of numerical results between volumetric methods was made using Wilcoxon matched pairs test. Inter-method agreement was assessed using Bland-Altmann statistics and intra-class correlation coefficient for absolute agreement with a two-way mixed model. To account for multiple testing, P-values < 0.005 were considered to indicate statistical significance. Intra-class correlation coefficients were considered significantly different if 95% confidence intervals did not overlap.To evaluate the frequency of clinically important differences between fully automated and expert-corrected results, we further categorized LV ejection fraction into five categories inspired by the recommendations of the American College of Cardiology for the measure reporting in outpatient setting: hyperdynamic (> 70%), normal (50–70%), mild dysfunction (40–49%), moderate dysfunction (30–39%), severe dysfunction (< 30%) . Differe2 with a range of 18.3 to 43.3 kg/m2. The most common primary indications for CMR examinations were known or suspected ischemic heart disease , known or suspected cardiomyopathy  and known or suspected myocarditis . The most frequent indication in women was cardiomyopathy , while ischemic heart disease was the leading indication in men .An overview of patient characteristics and CMR indications is given in Table The results of the CMR examinations are summarized in Table In all cases the fully automated algorithm operated without processing failures and the LV was appropriately detected on most slices. In 20% of all data sets n = 10), the expert fully agreed with the fully automated algorithm and no corrections were necessary. An example is shown in Fig. 0, the exResults of fully automated and expert corrected analyses are summarized in Table The correlation between fully automated results and expert-corrected results was very strong with correlation coefficients of 0.998  for end-diastolic volume, 0.997 (0.995–0.999) for end-systolic volume, 0.899 0.733–0.953) for stroke volume, 0.972 (0.923–0.987) for ejection fraction and 0.991 (0.985–0.995) for myocardial mass . In 8 of these 9 cases, expert corrections placed the patient in a better functional category, most commonly (n = 4) moderate dysfunction (EF 30–39%) instead of severe dysfunction (< 30%). A remarkably similar re-classification rate  was observed between the two manual readers.Median end-diastolic volume and ejection fraction were 130.9 ml/59.1% in patients with no pathological findings at cardiac MR, 162.0 ml/47.8% in patients with ischemic heart disease and 244.2 ml/28.8% in patients with cardiomyopathies (Supplementary Table 2). Relative limits of agreement for end-diastolic volume and end-systolic volume were similar across all subgroups. However, for stroke volume and ejection fraction they were wider in ischemic heart disease and cardiomyopathies than in patients without pathological findings at cardiac MR (Supplementary Table 3). Intra-class correlation coefficients did not show significant differences between subgroups.The fully automated volumetric analysis required a median of 8.4 s to complete (interquartile range 8.2–8.6 s). The expert-corrected analysis was completed in a median of 110 s (IQ range 66–126 s). This includes performing the fully automated analysis, checking correct identification of end-systole and end-diastole, checking correct slice inclusion and accurate contouring and making any necessary corrections. The time required for manual volumetric analysis was approximately 3.5 min for a cardiovascular imaging fellow  and approximately 9 min for a radiology resident .In this paper, we investigated the performance of a deep learning-based algorithm for fully automated quantification of LV volumes and function in cardiac MRI. We observed that the fully automated analysis was performed successfully in all patients in less than 10 s. The correlation between fully automated and expert-corrected results was very strong—stronger than between the manual analysis of two radiology trainees. Minor corrections were made in most (80%) cases. However, even with these corrections the expert corrected automated analysis took less than 2 min on average—significantly less than the manual analysis, which on average took 3.5 or 9 min, depending on level of experience.Several previous publications focus on the technical aspects of developing and validating deep learning-based algorithms for fully automated volumetric analysis of cardiac MRI , 16–19. Bernard and colleagues recently provided an in-depth review of deep-learning techniques for automatic cardiac MRI segmentation . They suAn important use case for fully automated volumetric analysis are large population-based cohort studies incorporating cardiac MRI examinations. The UK Biobank is on its way to acquire 100,000 cardiac MRI examinations by 2020 , 14.There is scarce data on the performance and utility of such algorithms in clinical routine. One recent study investigated a similar algorithm by a different vendor in 300 cases randomly selected cases from routine clinical care . Their sOur results agree with this previous publication in that both studies indicated that the relative differences are somewhat larger for LV stroke volume and ejection fraction than for end-diastolic volume, end-systolic volume and myocardial mass. This is likely mostly a mathematical effect: Stroke volume and ejection fraction are not measured directly but calculated from end-diastolic and end-systolic volume such that measurement errors add up if errors occur in opposite directions. We furthermore demonstrated that agreement between fully automated and expert-corrected results for stroke volume and ejection fraction was lower in ischemic heart disease and cardiomyopathies than in patients without pathological findings at cardiac MR. In part, this may be attributed to the lower ejection fraction in these patients, which means that the same absolute deviations amount to wider relative limits of agreement. In part, however, this may also be an expression of how the algorithm was developed, namely initially trained on a large volume of—mostly normal—cardiac MRIs from the population-based UK Biobank cohort, although the algorithm was later also trained on a large volume of pathological cases.To establish a precise reference standard for our analysis, meticulous corrections to the fully automated contours were made by an expert in our study in as many as 80% of cases. However, many of these corrections were minor and may not be clinically meaningful. To address this issue, we performed a secondary analysis of the re-classification rate based on pre-specified categories of LV function. We found that expert corrections made a clinically meaningful difference in 18% of cases, very similar to the re-classification rate between the two manual readers (20% in our study). This suggests that only a minority of cases may require corrections in clinical routine. However, we do not recommend using the algorithm without supervision. Rather, the results of fully automated volumetric analysis should be checked and corrected, if necessary, by a human reader. As with other applications of artificial intelligence, the role of humans imaging experts shifts from performing mechanical tasks to critically reflecting the results of algorithms and developing a professional relationship between physicians, patients and machine-generated data .Several limitations of our study are worth noting. This was a retrospective analysis describing our initial experience in a limited number of cases. In particular, the number of patients in each subgroup was relatively small, such that the results of the subgroup analysis should be considered hypothesis-generating. An obvious limitation of our investigation is that we examined the performance of a specific deep learning-based fully automated algorithm. The results cannot be directly transferred to the algorithms of other vendors or even later version of the same algorithm. However, we believe that our results may provide some insights into strengths and typical limitations of deep learning-based approaches to fully automated volumetric CMR analysis that may benefit the further development of the technique.In conclusion, deep learning-based fully automated analysis of left ventricular volumes and function is feasible, extremely fast and shows respectable performance without any manual corrections. Even with manual corrections—which are required for precise results in most patients—this approach remains time-efficient compared to manual analysis.Supplementary file1 (DOCX 36 kb)Supplementary file2 (DOCX 33 kb)Supplementary file3 (DOCX 38 kb)Below is the link to the electronic supplementary material.


To develop a three-dimensional (3D) high-resolution free-breathing magnetization transfer ratio (MTR) sequence for contrast-free assessment of myocardial infarct and coronary vein anatomy.Two datasets with and without off-resonance magnetization transfer preparation were sequentially acquired to compute MTR. 2D image navigators enabled beat-to-beat translational and bin-to-bin non-rigid motion correction. Two different imaging sequences were explored. MTR scar localization was compared against 3D late gadolinium enhancement (LGE) in a porcine model of myocardial infarction. MTR variability across the left ventricle and vessel sharpness in the coronary veins were evaluated in healthy human subjects.A decrease in MTR was observed in areas with LGE in all pigs (non-infarct: 25.1 ± 1.7% vs infarct: 16.8 ± 1.9%). The average infarct volume overlap on MTR and LGE was 62.5 ± 19.2%. In humans, mean MTR in myocardium was between 37 and 40%. Spatial variability was between 15 and 20% of the mean value. 3D whole heart MT-prepared datasets enabled coronary vein visualization with up to 8% improved vessel sharpness for non-rigid compared to translational motion correction.MTR and LGE showed agreement in infarct detection and localization in a swine model. Free-breathing 3D MTR maps are feasible in humans but high spatial variability was observed. Further clinical studies are warranted.The online version of this article (10.1007/s10334-020-00833-9) contains supplementary material, which is available to authorized users. MRI plays an important role for non-invasive assessment of myocardial fibrosis in patients with ischemic and non-ischemic cardiomyopathies. Myocardial scar assessment has been shown to have important prognostic value –3. FurthLate gadolinium enhancement (LGE) MRI is the gold standard for the assessment of myocardial fibrosis . LGE shoMagnetization transfer (MT) is an endogenous MR contrast mechanism, which does not require the injection of a contrast agent. MT has shown to be sensitive to structural changes associated with myocardial fibrosis, such as the increase in collagen content –11. MT wT2 preparation is known to be useful in coronary angiography  was appk-space data were incorporated in a motion-corrected generalized matrix description (GMD) .The bSSFP module yielded higher CNR than SPGR  for bSSFP vs. SPGR, respectively. SPGR led to reduced MTR variability between segments compared to bSSFP , as seen in Fig. Representative MTR maps and myocardial segment mean values across all subjects using SPGR and bSSFP are shown in Fig. p < 0.01) and MTR = 41.0 ± 2.4 , for bSSFP and SPGR, respectively. Liver MTR measurements showed similar spatial variability compared to myocardium, with MTR = 32.3 ± 2.9  and MTR = 29.6 ± 3.5 , for bSSFP and SPGR, respectively. One reason for this similarity may be that the liver and the heart experience similar extent of respiratory motion.MTR values in pectoral muscle showed significantly reduced spatial variability compared to myocardium: MTR = 43.8 ± 1.7  and the PCV . Three examples from representative subjects are shown in Fig. The use of translational motion correction allowed good depiction of the PCV and GCV. The non-rigid motion correction improved visualization of the entire cardiac anatomy with respect to the translational motion correction. This was observed in an increase in vessel sharpness in the GCV  integrity , 42, i.eAt least two competing processes that may increase or decrease the size of the bound pool are at play in cardiac remodelling after MI, namely, the growth of the extracellular matrix and the death of protein-rich cardiomyocytes, respectively. The presence of connective tissue or oedema within the fibrotic scar may also increase the size of the free pool. Our results in 6-week-old (post MI) scar showed that MTR was significantly decreased, suggesting that the proposed MT preparation might be more sensitive to myocyte death rather than the known increase in collagen content associated with chronic infarct .This interpretation would greatly benefit from data at various stages of the cardiac remodelling process to assess the specificity and utility of the technique in clinical practice. In an experimental mouse model, Vandsburger et al. reported increasing MT effects after induced MI from day 7 to 21 with a cine CEST technique . To the The conflation of bound pool size, free pool size, exchange rate and all the relaxation rates into a single parameter, i.e. the MTR, may hinder the applicability of the technique within clinical settings, where oftentimes the aetiology of the scar may be unknown or multi-pronged. In these cases, a quantitative approach using a multi-parameter MT model could be more appropriate.The number of off-line post-processing steps and setup parameters may slow down widespread clinical adoption; however, more automated or end-product frameworks that apply many of these same techniques are currently being developed by the present research group and others.The small number of pigs used in this study was a limitation; however, the results showed consistency across all three cases. Other limitations included the relatively long scan time and anisotropic resolution in the human subjects. The anisotropic resolution affected image quality, specifically when reformatting to orientations other than coronal. The resolution was compromised to maintain a short scan time (< 10 min) that was clinically appealing. Future work might benefit from isotropic resolution paired with an accelerated acquisition framework.We have developed a non-contrast high-resolution 3D sequence that allows calculation of magnetization transfer ratio (MTR) maps for the assessment of myocardial scar and visualization of cardiac veins across the whole heart. Good agreement was found between MTR and LGE in a small cohort of pigs with 6-week-old scar. Further studies are warranted to fully characterize the potential of MT for imaging of myocardial fibrosis.Supplementary file1 (DOCX 1552 kb)Below is the link to the electronic supplementary material.


In 2010, the concept of “heart failure pandemic” was proposed, and it has been recognized as a global social/economic issue. In particular, the number of elderly patients with heart failure has increased with the rapid aging of society and a decrease in the number of children in Japan. A rapid increase in the number of heart failure patients increases stress and social disease-related/medical economic burdens on individuals and their families. The prognosis of patients with chronic heart failure is unfavorable, and the quality of life markedly reduces. To improve the prognosis of elderly patients with heart failure and reduce the readmission rate, the innovation of a medical-care-providing system for heart failure is required. In addition to the provision of medical practice based on a potent heart failure disease control program, manifold strategies, such as lifestyle improvements, self-care practice, cardiac rehabilitation, and environmental intervention, are essential. It is necessary to innovate hospital-based medical practice to a regional-care-system-based medical care system. In addition, to efficiently promote future heart failure strategies, an investigational study with disease registration must be conducted. Recently a new basic act on countermeasures to cardiovascular diseases has been established which may help the reform for this purpose.An increase in the number of patients with heart failure is an international health-related problem. In advanced countries, the number of such patients has rapidly increased since the beginning of the 21 In males, it rapidly increases from 75 to 80 years of age, reaching approximately 6% at 90 years of age. The rapid aging of society is a common phenomenon in the world, and an increase in the incidence of heart failure is a global issue (7). Internationally, about 26 million adults are living with heart failure (6). The same trend is emerging in Asia as well (9). In Japan, the rapid aging of society is the most advanced in the world, and the morbidity rate of heart failure has also rapidly increased. Currently, there may be approximately 1,000,000 patients with chronic heart failure in Japan, although there are no accurate epidemiological data (10). The number of patients who will newly develop heart failure in 2025 is estimated to be 370,000. Although the total population will decrease from 126 to 110 million persons in 2035, the number of heart failure patients is estimated to reach 1,300,000 (11).As indicated by the Rotterdam study, the morbidity rate of heart failure increases with aging (12).Geriatric heart failure is characterized by frequent readmission related to acute exacerbation. A cohort study (JCARE-CARD study) in Japan showed that the readmission rates within six months after discharge and after one year in patients with heart failure were 27% and 35%, respectively, and were similar to those reported in Europe and the United States (15).“Heart failure pandemic” is a warning that represents the coming of a critical social status related to a rapid society-aging-related increase in the number of heart failure patients, social burdens, and extraordinary health expenditure The profile of patients with heart failure has markedly changed recently . Heart f(16). It is lower than in patients with breast cancer or prostatic cancer, and therefore, heart failure must be regarded as a progressive, fatal disease. Despite advances in medicine, the pathogenesis of heart failure and the mechanism of progression to a severe status remain to be clarified. No causal therapy has been established. For this reason, advance care planning (ACP) or palliative care must be considered in patients with heart failure.Patients with heart failure are repeatedly readmitted, and they have several comorbid disorders; therefore, the condition varies, being complex. Concerning the prognosis, the five-year survival rate is less than 50% (12). Acute-phase coronary reperfusion therapy for acute myocardial infarction, which had been often fatal, has improved the lifesaving rate (17). Emergent coronary intervention for acute myocardial infarction can be performed in more than 90% of cardiovascular emergent wards in Japan (18). However, even when lifesaving is achieved, heart dysfunction remains as a sequela in many patients. Subsequently, the process of cardiac remodeling gradually deteriorates the heart function even in the absence of symptoms, leading to heart failure. Subsequently, long-term therapeutic intervention is required, but admission and discharge are repeated every time heart failure exacerbates, resulting in a fatal outcome . According to the JCARE-CARD study, HFpEF accounted for 26% of 1,692 patients with heart failure, excluding those with valvular disease. In the elderly patients, the rate of HFpEF was higher than in those with heart failure related to contractile dysfunction. As a disease that causes HFpEF, hypertension accounts for 44%, suggesting that the rapid aging of society and hypertension contribute to an increase in the incidence of HFpEF in Japan (12). The prognosis of patients with HFpEF is unfavorable compared with the prognosis of those with heart failure related to contractile dysfunction, but no effective treatment method has been established.In the majority of elderly patients with heart failure, contractile dysfunction is absent: heart failure with preserved ejection fraction (HFpEF) (25). A frailty cycle consists of physical, mental, and social fragility. It refers to a condition in which various aging-related functional changes or a reduction in reserve increases frailty to health damage. It must be considered that frailty may be prevented/reduced by adequate support/intervention. Etiological factors for frailty in elderly persons vary: malnutrition, physical hypofunction, sarcopenia-related muscle weakness, a decrease in the opportunity of social interactions, and chronic diseases, including heart failure (29). Frailty treatment and heart failure management may be the two sides of the same coin.Fried et al. proposed the entity of frailty in 2000 (33). Each patient has several disorders. Polypharmacy for such disorders makes the state of the patient more complex in some cases (35). The major cause of readmission of elderly patients with heart failure is the inappropriateness of self-care for daily life. The difficulty in achieving behavior change in such patients is another serious problem in the management of the disease. Moreover, the behavior of the medical staff for such patients should be flexible, depending on individual patient as compared with younger patients. In addition to heart failure management, diagnosis and guidance beyond the extent of specialty based on the general condition are necessary (36).In addition, geriatric heart failure is characterized by the presence of comorbid disorders in most patients: dementia, cerebral infarction, chronic kidney disease, diabetes mellitus, peripheral vascular occlusion, chronic obstructive pulmonary disease, cancer, depression, and bone and joint diseases “Heart failure pandemic” also refers to a state in which a rapid society-aging-related increase in the number of heart failure patients with such complex backgrounds cannot be covered by the current medical basis.(37). However, differences from healthy life expectancy in males and females are about 9 and 12 years, respectively; nursing/support is required for these periods (38). Nursing is an extremely serious social burden. The primary factors that require nursing include stroke, dementia, an advanced age, and bone and joint diseases in Japan. Heart disease and stroke account for more than 20% of patients requiring nursing. Frailty-based elderly-specific characteristics termed “geriatric syndrome” consist of physiological aging and morbid aging.Japan is one of the top countries in the world showing a very long average life span (39). The rate of persons who live with their children was approximately 70% in 1980, but it decreased to 39.0% in 2015. One-person households or those consisting of a husband and wife accounted for <30% in 1980, but the percentage increased to 56.9% in 2015. Heart failure under such circumstances makes it difficult to select a care facility due to a reduction in the activity level, increase in the burdens for nursing, and delay in decision-making. In addition, there are various problems, including poverty and social support systems (40). Concerning heart failure, there are only a few special consulting services, differing from cancer. Thus, the limitation of information also promotes social isolation (42). In many underpopulated areas, the rapid aging of society led to the breakdown of regional communities. As the duration of heart failure is prolonged, problems become more serious and protracted.The concept of geriatric syndrome is medically and socially important. Recently, the number of families consisting of elderly persons alone and that of elderly persons who live alone have increased, and burdens for nursing in our society are increasing. As of 2016, households involving persons aged ≥65 years account for 48.4% of all households (43). One of the reasons is an increase in the number of elderly persons. A situation in which the working-age population and the number of children decreases while the need for medical care increases has been reached. Recently, effective, costly treatment methods have been innovated. Extremely expensive treatment instruments, such as devices for cardiac resynchronization therapy with defibrillation, catheters for percutaneous aortic valve replacement, stents for vascular treatment, and implantable heart assist devices, are used for heart failure treatment, although this is not frequently discussed in comparison with anticancer drugs. Health expenditure on cardiovascular treatment exceeds 6 trillion yen ($50 billion) per year, which is approximately 1.5 times higher than that for cancer (43). In addition to the high cost of equipment/devices for treatment, admission-related health care costs raise a financial issue on heart failure treatment with repeated readmission. In Japan, the average admission period in patients with heart failure is ≥2 weeks, and expenditure required for a session of heart failure admission per person is estimated to exceed one million yen ($10 thousand) (45).Currently, the total annual health expenditure in Japan exceeds 40 trillion yen ($330 billion) and is still increasing Advances in medical practice, which contribute to patient saving, life prolongation, and an improvement in the QOL, should be welcomed, but the indication of treatment must always be carefully examined, considering medical and financial resources, which are not infinite.In general, elderly heart failure patients have multiple problems in their heart. Therefore, their medication often includes antihypertensive drugs, statins, β-blockers, renin-angiotensin system blockers, diuretics, direct oral anticoagulants, antiarrhythmic agents, and others. Some of the new drugs for cardiovascular diseases are quite expensive, and elderly patients with heart failure tend to receive many drugs due to comorbidities. Expensive medical charge for outpatients with heart failure could promote decreased adherence to the medication after discharge and result in further deterioration of health economics.(46). More appropriate and active acute care of heart failure should be associated with better prognosis, especially in elderly patients. Other important medical progresses to improve or prevent heart failure are less invasive measures to treat structural heart disease and other devices to treat heart failure and arrhythmias.The most important solution for heart failure pandemic should be primary prevention, as discussed later. Fortunately, the incidence of heart failure can be reduced through the management of atherosclerosis and hypertension. In the future, it may be necessary to advance acute-phase and recovery-expected patient care and establish a heart failure treatment system for better support for the elderly (47). In July 2017, a proposal on a medical system to be arranged was announced by the Ministry of Health, Labor, and Welfare (48). In this proposal, it is emphasized that a new regional medical cooperation system covering the maintenance phase should be established in addition to an acute-phase system to improve the prognosis over a long period from the acute phase and maintain the QOL . Rehabilitation for cardiovascular diseases should be started immediately after the onset of heart failure or myocardial infarction and is continued during admission. It aims for early ambulation after admission, functional recovery, and prevention of frailty. Further functional recovery and readmission prevention are targeted through continued outpatient rehabilitation. In addition, for patients who find it difficult to visit a hospital, continuation of rehabilitation at home is recommended (52).In Japan, rehabilitation has been discussed, considering stroke and orthopedic diseases. In particular, physical therapy has been regarded as playing a central role. However, the goal of rehabilitation for cardiovascular diseases, such as heart failure and myocardial infarction, is to achieve physical function maintenance/improvement by physical therapy and perform comprehensive disease control involving lifestyle/compliance/nutritional guidance, mental care, and social life support for recurrence prevention or prognosis improvement (53). Furthermore, the ExTraMATCH study indicated that exercise therapy improved survival and readmission avoidance rates (54). Provoking factors for readmission in patients with heart failure include environmental factors that can be prevented in addition to medical factors. Multi-occupational intervention, as described in the next section, during outpatient cardiac rehabilitation contributes to more effective disease control (55). The J-HOMECARE study showed that such a disease control program reduced depression or anxiety, improving the QOL and preventing readmission related to heart failure exacerbation (56). Therefore, cardiac rehabilitation may be the most effective disease control program including multilateral and comprehensive lifestyle/nutritional guidance, counseling, and patient education in addition to exercise therapy.Exercise tolerance is a prognostic factor for heart failure. Exercise therapy improves exercise tolerance, health-associated QOL, and long-term outcome through manifold effects. Belardinelli et al. reported that exercise therapy decreased the relative risk of cardiac death by 63% in patients with chronic heart failure (59) ((60). Concerning physicians, in addition to cardiologists, cardiac surgeons, gastroenterologists, ophthalmologists, dentists, and orthopedists may be involved in accordance with patients’ conditions. In particular, psychiatrists, Liaison nurses, and clinical psychologists must participate in the mental and psychological intervention. Such intervention may improve drug compliance, motor ability, lifestyle, and self-monitoring, preventing weakness, and, thus, facilitating readmission avoidance (60).For treatment after the onset of heart failure, the involvement of various occupations is required (59) : nurses In addition, even in outpatient care or medical care by home doctors after discharge, multidisciplinary management leads to admission avoidance and shortening of the admission period through the assessment of lifestyle-related background factors, drug compliance, diet, and early detection of slight heart failure exacerbation. Such team-based involvement should be started immediately after admission, and continued during outpatient care, regional care by practitioners, or home care. For this purpose, patient notebooks, combination paths, and checklists are used as communication tools.(62). A study investigated 600 medical institutions in the United States, and indicated the following heart failure-related readmission-preventing factors: 1. cooperation with regional physicians, 2. strategy-sharing with other hospitals, 3. adjustment of drug therapy plans by nurses on discharge, 4. preparation of an outpatient consultation plan after discharge, 5. provision of information on discharge to home doctors, and 6. sharing of laboratory data on discharge with patients (63).In Europe and the United States, it has long been recognized that such a comprehensive disease control program by a multidisciplinary team prevents readmission related to heart failure, improving the prognosis (64).Recently, the importance of such an attempt has also been recognized in Japan. In Tottori University, admission care involving the multidisciplinary education of inpatients with heart failure, conferences, optimization of treatment, and rehabilitation through intervention by a multidisciplinary heart failure team markedly decreased the heart failure-related admission and mortality rates in comparison with the period during which standard treatment had been performed (59). In modern times, with the rapid aging of society, there are many patients who live alone or care for elderly husbands or wives, and the place of living has been shifting from the home to various facilities: homes for the aged, housings of the aged with various services, rehabilitation facilities for the elderly, special nursing homes for the aged, and group homes. Various service-providing organizations, such as home-visit rehabilitation/nursing offices (care managers) and in-home nursing offices (home-helpers), are involved. In particular, the Government of Japan has promoted community-based integrated care system (Patients with heart failure live at home for the longest time after discharge e system . It is a(65). In the future, regional heart failure management by home doctors, assistance, and standardization may be necessary (66). In this situation, the role of hospitals will change. When treating elderly patients with heart failure, it is necessary to prevent weakness and target home return rather than cure. Careful prescriptions and dementia-supposed ward management must be considered for prevention of unnecessary prolongation of admission period.In a community-based integrated care system, practitioners and in-home doctors, as regional home doctors, primarily support elderly patients with heart failure Concerning hospital-clinic cooperation, it is necessary to aim at horizontal-type cooperation characterized by an equal relationship between home doctors and hospitals, from hospital-based vertical-type cooperation. Hospital-clinic cooperation has been promoted to smoothly conduct referral from core hospitals to home doctors, reverse referral, and hospital transfer. However, for the future cooperative management of rapidly increasing elderly patients with heart failure, it is necessary to share information on individual patients more closely. Multi-job, inter-institutional information sharing through heart failure regional cooperative conferences involving a hospital team and home doctors is ideal. For the prevention of post-discharge recurrence and early detection of deterioration, close communications with visiting nurses are also necessary.(58). Various telemedicine devices that are being developed may be useful for collecting patient information, and home doctors who comprehensively utilize them are desirable (67). Patients may repeatedly move from a hospital to their home, from their home to their child’s family, and to a nursing facility. It is difficult to continue care by activities in a single area alone. Therefore, information-sharing tools covering a broader extent are required, and it is necessary to improve/support the degree of recognition for the establishment of a new system by society as a whole.For regional patient information sharing, it may be necessary to standardize charts using the cloud under accurate security control and arrange patient paths/notebooks on heart failure (69). In particular, Japanese people’s view of life and death markedly differs from that of Europeans and Americans; the entity of ACP has not commonly been accepted (70). Currently, the number of physicians and institutions responsible for terminal care for chronic cardiovascular diseases is limited. In addition, the course of heart failure varies among individual patients, which makes it complex. In some cases, acute care is repeatedly performed, and the course is not uniform. Because of the complexity and individuality of the clinical course of heart failure, the concept of terminal-palliative care would be different from that of other diseases, such as malignant diseases or senility deaths. It is recommended to start ACP from the early stage of heart failure. Although this concept may not adapt to Japanese culture, we should promote society-wide discussion on this issue to protect patients’ dignity.Geriatric heart failure leads to death. How patients live in the terminal phase of a refractory disease is an important issue . CurrentFurthermore, in clinical practice, there are methodological difficulties in palliative care for heart failure patients in whom repeated dyspnea or systemic weakness leads to a fatal outcome.Comprehensive strategies, as described above, are necessary to reduce elderly persons’ disease burdens associated with lifestyle-related diseases and prolong health expectancy . HoweverAcute-phase interventional treatment markedly improves the prognosis of patients with acute heart disease. The education of the Japanese people to promote emergency consultations, the regional establishment of an emergency transport system, arrangement of medical institution networks, and introduction of early interventional treatment through the utilization of telemedicine in medically underpopulated areas are effective. Once a disease develops, QOL improvement and secondary prevention by manifold intervention and regional integrated care, as described above, may be necessary in addition to appropriate treatment.(50). Data regarding the cost-effectiveness of cardiac rehabilitation in Japan are not available, although a retrospective multicenter cohort study is currently underway. Also, the economic impact and cost-effectiveness of integrated healthcare for heart failure has not been reported. Because of differences in health care and the medical expense payment system in each country, effectiveness and social impact of medical system reform should be considered and investigated in each country from multiple aspects.The economic impact of the implementation of the above-mentioned integrated healthcare system is not clear. There are a limited number of literatures regarding cost and cost-effectiveness of exercise training. Two studies indicated exercise-based rehabilitation to be a potentially cost-effective use of resources in terms of gain in quality-adjusted life year In addition, to promote these medical services, the actual status of lifestyle-related diseases, including heart failure, must be evaluated. A survey regarding the actual status and patient registration are required. To achieve such a comprehensive strategy, the national and local government’s support is necessary. In 2018, a national basic law on the countermeasures against cardiovascular diseases for this purpose has been established as a big advance in this field.With the coming of the “heart failure pandemic” era, geriatric heart failure control must be promptly established. Information sharing, social recognition of problems, new social system establishment, and support from the government are necessary. If there is no paradigm shift regarding medical systems, current medical systems in Japan may not continue to exist eventually. It is obligatory for all health care professionals and Japanese people to overcome the serious situation with wisdom.In addition, “heart failure pandemic” will also surge in Asian countries, where the rapid aging of society is progressing, as indicated for Japan. To overcome this problem from a global viewpoint, information sharing and cooperation against the common enemy are necessary.NoneThis work was supported by Research Grants from the Japan Agency for Medical Research and Development (AMED) grant number 16ek0210058h0001 and the Ministry of Health, Labor and Welfare, Government of Japan grant number 18062589.Mitsuaki Isobe is one of the Associate Editors of JMA Journal and on the journal's Editorial Staff. He was not involved in the editorial evaluation or decision to accept this article for publication at all.


BackgroundLeft ventricular (LV) dysfunction in patients with aortic valve stenosis (AVS) is seen in two scenarios: in neonates and in elderly patients. Neonatal AVS may present as a congestive cardiac failure (CCF), while older children rarely present with CCF if they have not been diagnosed early. Only a few reports of LV dysfunction with AVS have been described in the literature. However, there is a paucity of data regarding the safety and effectiveness of balloon aortic valvuloplasty (BAV) in children with AVS with LV dysfunction. Therefore, the aim of this study was to evaluate outcomes to establish the safety and effectiveness of BAV in children with AVS and LV dysfunction in improving LV function and survival.MethodsA total of 160 BAVs were performed from 2004 to 2017; of these, 41 (25.6%) patients had LV dysfunction. We reviewed these cases, and data were obtained on clinical features, echocardiographic parameters including LV ejection fraction (LVEF) and LV dimensions, LV posterior wall, interventricular septal thickness, pressure gradient across the valve, aortic valve morphology and annulus and aortic insufficiency (AI), and angiographic parameters such as aortic and LV pressures, AI and annulus size, and balloon size. Echocardiography was done before the procedure, one day after intervention, at three months, at six months, and on regular follow-up. Mortality during and after the procedure and at follow-up was reported.ResultsChildren who had undergone BAV for AVS and LV dysfunction within the age range of six to 192 months showed a significant reduction in peak-to-peak pressure gradient (PPG) from 73.5 ± 30 mmHg to 26.7 ± 6.7 mmHg and improvement in LVEF from 32.8 ± 11% to 54.3 ± 12.7% after 24 hours. Instantaneous gradient on echocardiography after three months showed PPG was 29.8 ± 7.7 mmHg and mean LVEF was 63 ± 8.6%. Mean LV end-diastolic pressure was 20.8 ± 4.7 mmHg and decreased to 13 ± 2.4 mmHg. Four patients died, all of whom had severe LV dysfunction - one died during the procedure and three died within six to 20 hours after successful BAV. On average follow-up of 6.4 ± 3.8 years, with a range of three months to 13 years, there was no mortality, pressure gradient increased to 40 ± 16.3 mmHg , and three had BAV after one, four, and six years, respectively. There was an increase in AI from mild to moderate in five patients, but they did not require any intervention. Four patients had aortic valve replacement (AVR) with two patients having an increase in pressure gradient and AI after eight and 13 years, respectively. One patient had AI (+3) after BAV had AVR after three years, and one patient who had a very thick and dysplastic aortic valve with LVEF of 20% and pulmonary hypertension (PH) had AVR after six months.ConclusionPatients with AVS who develop LV dysfunction deteriorate and die soon without treatment. Our data suggest that BAV in children with aortic stenosis and LV dysfunction is safe and effective in the normalization of LV function. Aortic valve stenosis (AVS) accounts for 3% to 7% of all congenital heart diseases . Left veFrom 2004 to 2017, 160 children ages 15 days to 16 years had BAV at the Pediatric Cardiology Department of the National Institute of Cardiovascular Diseases in Karachi, Pakistan. Of these, 41 (25.6%) patients had LV dysfunction. For this retrospective study, we reviewed the record of these patients, ages six months to 192 months. Infants younger than six months with AVS and LV dysfunction were excluded to rule out the continuum of critical AVS. Weight ranged from 4.5 to 50 kilograms. Patients were categorized as severe, moderate, and mild LV dysfunction against criteria of LVEF ≤35%, 36% to 45%, and 45 to 55%, respectively. After approval from the ethical review committee, data were obtained based on their clinical features, echocardiographic, and angiographic parameters. All patients were symptomatic with a history of poor feeding, syncopal attacks, dyspnea on exertion, chest pain, and hypotensive with blood pressure less than one-third percentile. Chest X-rays had a cardiothoracic ratio of 0.68 (0.6-0.75), chest X-ray posterior-anterior view showing cardiomegaly is presented in Figure All echocardiographs were performed by pediatric cardiologists. Echocardiographic parameters were noted as morphology  of the aortic valve, aortic valve annulus (AVA), aortic insufficiency (AI) (if any), LV function, LV dimensions, LV posterior wall, and interventricular septal thickness. Instantaneous pressure gradient peak and mean were recorded by continuous-wave Doppler tracing in multiple planes, including apical five-chamber, apical three-chamber, right parasternal, subxiphoid long axis, and suprasternal views, and maximum gradients were considered, as shown in Figure The severity of AI was classified as none, trivial, mild, moderate, and severe or graded from 0 to IV . AngiogrBefore changing the balloon size, the AI was checked by aortogram. Following angiography, a further intervention was not performed if an AI of plus 1 or greater was detected or if the balloon/annulus ratio was 1. After the procedure, PPG and LV end-diastolic pressure (LVEDP) were also measured. A reduction of the PPG of at least 50% or a residual gradient of less than 25 mmHg were defined as satisfactory results.Collected data were entered and analyzed using IBM Statistical Package for the Software Sciences Statistics for Windows, Version 21.0. . Appropriate mean ± SD or median (interquartile range) were calculated. An appropriate t-test or Mann-Whitney U test was applied. The cutoff p-value for statistical significance was ≤ 0.05.Forty-one patients with LV dysfunction were included. Ages ranged from six to 192 months, and weight ranged from 4.5 to 50 kg. Male patients and female patients were 61% and 39%, respectively. A history of poor feeding was found in 26.8%, exertional dyspnea in 53.7%, syncopal attack in 12.2%, and chest pain in 7.3% . LVEF was 32.8 ± 11%  with severe, moderate, and mild LV dysfunction of 58.5%, 29.3%, and 12.2%, respectively. Pre-dilatation AI of grade 0 was found in 80.5% and grade 1 in 19.5% of patients  with a p-value of <0.001 in all patients. LVEDP also decreased from mean 20.8 ± 4.7 mmHg to 13 ± 2.4 mmHg. After successful BAV, approximately 9.7% of patients had an AI of grade 3 to 4. All patients had a femoral artery assessed, and none of the patients developed vascular complications. In our study, in-hospital mortality was found in four (9.8%) patients, all of whom had severe LV dysfunction. One six-month-old patient (2.4%) who died during the procedure had an EF of 20% and intractable heart failure. Three patients (7.3%) died six to 20 hours after successful BAV; two had mild AI, and one had no AI. All were stable and they died suddenly. In our study, 14 patients (34.1%) had rhythm disturbance (premature ventricular contractions) with no sustained ventricular tachycardia noted, and two patients (4.9%) developed bradycardia (temporarily), which resolved at the end of the procedure  after 24 hours (p < 0.001) and to mean LVEF 63% ± 8.6  after three months . Three patients had BAV after one, four, and six years, respectively. There was an increase in AI from mild to moderate in five patients, but they did not require any intervention. Four patients had aortic valve replacement (AVR) with two patients having an increase in gradient and AI after eight and 15 years, respectively. One patient had AI (+3) after BAV had AVR after three years, and one patient who had a very thick and dysplastic aortic valve with LVEF of 20% and pulmonary hypertension (PH) had AVR after six months.In patients with AVS, diastolic dysfunction is common due to hypertrophied noncompliant LV; however, systolic dysfunction beyond the neonatal period and early infancy is not common. LV dysfunction in this condition may be due to subendocardial contractile dysfunction caused by long-standing high wall stress or diffuse myocardial fibrosis, scarring, apoptosis, or it could be a “pseudo LV dysfunction” . Severe pressure overload in AVS resulting in LV systolic dysfunction is an undesirable consequence . In our Our study was a single-center retrospective study of prospectively collected data and had all the inherent limitations of a retrospective design. Secondly, follow-up data were based on voluntarily follow-up patient visits on a given date, and the duration of follow-ups was not the same for all patients.Patients with AVS who develop LV dysfunction deteriorate very soon, if they do not receive early intervention, resulting in poor outcomes. Data suggest that transcatheter BAV in children with aortic stenosis and LV dysfunction are associated with a significant improvement in LV function and a reduction in PPG. BAV can be a better alternative to the surgical correction of AVS.


Mechanical unloading of the left ventricle reduces infarct size after acute myocardial infarction by reducing cardiac work. Left ventricular veno-occlusive unloading reduces cardiac work and may reduce ischemia and reperfusion injury. In a porcine model of myocardial ischemia–reperfusion injury we randomized 18 pigs to either control or veno-occlusive unloading using a balloon engaged from the femoral vein into the inferior caval vein and inflated at onset of ischemia. Evans blue and 2,3,5-triphenyltetrazolium chloride were used to determine the myocardial area at risk and infarct size, respectively. Pressure–volume loops were recorded to calculate cardiac work, left ventricular (LV) volumes and ejection fraction. Veno-occlusive unloading reduced infarct size compared with controls . Unloading increased myocardial salvage , while the area at risk was similar . LV ejection fraction was preserved in the unloaded group, while the control group showed a reduced LV ejection fraction. Veno-occlusive unloading reduced myocardial infarct size and preserved LV ejection fraction in an experimental acute ischemia–reperfusion model. This proof-of-concept study demonstrated the potential of veno-occlusive unloading as an adjunctive cardioprotective therapy in patients undergoing revascularization for acute myocardial infarction. Myocardial infarct size is a major determinant of prognosis. For every 5% increase in infarct size, 1-year all-cause mortality and hospitalizations for heart failure increases by 20%2. Although cardioprotective interventions by pharmacological and mechanical conditioning strategies have demonstrated infarct size reduction in experimental as well as proof-of-concept clinical studies, the translation into a clinical benefit has been challenging7. Hence, continued development of alternative adjunctive cardioprotective therapies to improve outcome following acute myocardial infarction are needed.Rapid reperfusion by primary percutaneous coronary intervention is the single most important approach to reduce infarct size in patients with acute myocardial infarction8. When preload and afterload are reduced, stroke work and thereby myocardial oxygen consumption decrease. Total mechanical unloading of the heart by implantation of a left ventricular (LV) mechanical assist device has been shown to reduce myocardial infarct size in experimental models of ischemia-reperfusion12. Further, a recent clinical multicenter trial demonstrated feasibility of LV unloading using the ‘Impella CP’ device in anterior ST-elevation myocardial infarction13. Insertion of the device caused a 30-min delay until reperfusion, and the trial showed no effect of unloading on mean infarct size after 30 days. In addition, implementation of this invasive approach is challenging in clinical practice. We hypothesized that veno-occlusive unloading of the left ventricle by balloon inflation in the inferior caval vein would be feasible and reduce cardiac work.Preload, afterload, myocardial contractility, and heart rate are the major determinants of cardiac output14.In the present study we sought to investigate the cardioprotective potential of veno-occlusive unloading by balloon occlusion of the inferior caval vein in a closed chest porcine model of ischemia–reperfusion injuryOne pig in the intervention and one pig in the control group died during reperfusion. Thus, sixteen animals completed the entire study and only results from those 16 pigs are reported.Hemodynamics and body temperature at baseline, during ischemia and after reperfusion in the control versus veno-occlusive unloading group are shown in Table Comparison between control and intervention group showed no statistically significant differences in the hemodynamic variables or body temperature between the control and intervention group.In the control group, LV ejection fraction was reduced during reperfusion  and cardiac work  while the correlation did not reach statistical significance in the intervention group . The null hypothesis that the two regression lines are identical was rejected with a p-value = 0.03 indicating that for a given area at risk, infarct size was lower with than without veno-occlusion , and fentanyl (12.5 µg/kg/h). To keep the core temperature constant between 37 and 38 °C during the entire experiment a convective temperature management system was used . We used ultrasound-guided modified Seldinger-technique to position sheaths in the femoral artery and vein for arterial blood pressure monitoring and blood sampling, respectively. Sheaths were introduced into the common carotid arteries and common jugular vein for percutaneous coronary intervention, LV pressure–volume measurements and introduction of a Swan-Ganz catheter. Prior to intravascular instrumentation, 10.000 IU heparin and 300 mg amiodarone were administered intravenously. Real-time pressure–volume loops were obtained using the ADVantage™ system  with an admittance catheter29. The cardiac output was calibrated by thermodilution using the Swan-Ganz catheter. Data were continuously recorded using a multichannel acquisition system and Labchart software .We included 18 Danish domestic pigs of female gender weighing 40 kg. All pigs were sedated with intramuscular tiletamine (2.5 mg/kg) and zolazepam (2.5 mg/10 kg) before transport to the surgical facilities. On arrival at the surgical facilities, the pigs were anaesthetized with an initial dose of intravenous propofol (3.3 mg/kg), intubated and mechanically ventilated using a 60% O2 were continuously recorded.Veno-occlusive unloading was done using a balloon engaged from the femoral vein into the inferior caval vein just below the right atrium. The unloading was calibrated by temporarily inflating the balloon with X-ray contrast to reach an approximately 25% reduction in stroke work according to the on-line pressure volume measurements. The veno-occlusive calibration procedure was done in all pigs. The pigs were subsequently randomized to control or unloading. Afterwards, X-ray coronary angiography was performed and a 2.0–3.0 mm wide angioplasty balloon  was placed in the left anterior descending artery (LAD) past the second diagonal branch and inflated for 60 min. Only in those pigs randomized to unloading, the veno-occlusive unloading, as determined from the calibration procedure, was initiated immediately after occlusion of the LAD in the intervention group and maintained during reperfusion. Invasive blood pressures, heart rate, blood oximetry and end-tidal CO30. A scale for reference was shown for calibration.After four hours of reperfusion, a midline sternotomy was performed and the LAD was sutured at the site of the previous occlusion according to visual inspection of side branches and guided by prior obtained X-ray images. To determine the myocardial area at risk, 10% Evans Blue dye was then injected directly into the left ventricle and allowed to circulate for 30 s. Then ventricular fibrillation was induced using a 9-V DC battery and the heart was harvested, sectioned into 8 mm cross-sections and photographed to determine myocardial area at risk. The slices were then immersion stained with 1% of 2,3,5-triphenyltetrazolium chloride (TTC)  for 5 min and photographed again to determine the infarct size31. All methods were carried out in accordance with relevant guidelines and regulations according to current European legislation (Directive 2010/63/EU).The experimental protocol was approved by The Animal Experiments Inspectorate in Denmark (J.nr. 2014-15-2934-01013). The study was carried out in compliance with the ARRIVE guidelinesThe digitized myocardial tissue images were processed using the open-source GNU Image Manipulation Program version 2.10.12. The area at risk was measured from the Evans Blue staining for each slice and the infarct size was measured from the TTC staining. Myocardial salvage index was then calculated as: ((area at risk − infarct area)/area at risk) × 100. The analysis was performed by two independent researchers blinded to the treatment status and the average of the two observers’ measurements was used.The following measurements were obtained from the pressure–volume data: stroke work, cardiac work per minute calculated as stroke work times heart rate, stroke volume, LV end-diastolic and end-systolic volumes, LV ejection fraction and cardiac output. These measurements were recorded by selecting 10 cardiac cycles at three different time points: at baseline, after 30 min of ischemia, and 30 min into reperfusion. Data were recorded and analyzed by two independent researchers on separate occasions. The mean of the two analyses provided the final result.10. An experimental failure rate of 10% was expected, so 18 experiments were performed in total. Results are presented as mean ± SD. Residuals were evaluated and determined to be approximately normally distributed. The infarct size, myocardial salvage index and area at risk were compared between the control and intervention group using an unpaired t-test. The hemodynamic variables derived from the pressure–volume measurements were compared using repeated measurement two-way ANOVA by groups (control versus intervention) and according to time points . Tukey post-hoc testing was used to correct for multiple comparisons.A required sample size (n = 16) was calculated to detect an increase in myocardial salvage index ≥ 25% by unloading with 95% power. This predicted reduction was based on the results from a previous study showing the effect of mechanical unloading on myocardial salvageMyocardial salvage correlations and the relation between final infarct size and area at risk were investigated by linear regression analysis. Statistical analysis of the data was performed using GraphPad Prism version 8.2.1. A p-value of < 0.05 was considered significant.