Heart failure (HF) is a global public health threat affecting 26 million individuals worldwide with an estimated prevalence increase of 46% by 2030. One of the main causes of HF and sudden death in children and adult is Dilated Cardiomyopathy (DCM). DCM is characterized by dilation and systolic dysfunction of one or both ventricles. It has an underlying genetic basis or can develop subsequent to various etiologies that cause myocardium inflammation (secondary causes). The morbidity and mortality rates of DCM remains high despite recent advancement to manage the disease. New insights have been dedicated to better understand the pathogenesis of DCM in respect to genetic and inflammatory basis by linking the two entities together. This cognizance in the field of cardiology might have an innovative approach to manage DCM through targeted treatment directed to the causative etiology. The following review summarizes the genetical and inflammatory causes underlying DCM and the pathways of the novel precision-medicine-based immunomodulatory strategies to salvage and prevent the associated heart failure linked to the disease. Dilated Cardiomyopathy (DCM) is a common cause of Heart Failure (HF) and is the primary indication for heart transplantation. DCM is characterized by progressive dilatation and impaired contraction of one or both ventricles. The incidence of DCM has been estimated to be one case per 250 individuals, with a prevalence of >0.4% in the general population which accounts for 36% of HF cases , 2. DCM The World Health Organization (WHO) defines DCM as a serious cardiac disorder in which structural or functional abnormalities of myocardium that leads to cardiac malfunction, substantial morbidity and mortality, and complications such as heart failure and arrhythmias. The European Society of Cardiology (ESC) classifies cardiomyopathy into familial or non-familial (non-genetic) forms while the American Heart Association (AHA) committee classifies cardiomyopathies into three categories: “hereditary,” “mixed,” and “acquired” , 6. In rThis review will briefly address the diagnosis, etiologies, and pharmacological and non-pharmacological management of DCM. The main focus will go to the emerging potential immunomodulator agents being developed to treat DCM. The current and future clinical practice through guided individualized treatment strategies bring promises to improve the patients' outcomes and reduce treatment costs.The signs and symptoms of DCM may be fulminant, acute, subacute or chronic, as they are related to the extent of left ventricular or biventricular systolic dysfunction. The diagnosis of DCM is evident by chamber dilation and reduced systolic function of one or both ventricles with an ejection fraction <50%. A thorough evaluation and wide array of non-invasive and invasive techniques are needed to ascertain DCM diagnosis. Non-invasive imaging techniques like electrocardiogram, echocardiogram, chest X-ray screens and cardiac magnetic resonance (CMR) imaging are used to detect and assess enlarged cardiac silhouette, chamber size dimensions, ventricular dysfunction, strain abnormalities, contrast enhancement, the presence of oedema and/or fibrosis, abnormalities ranging from isolated T-wave changes to adverse myocardial remodeling as featured in DCM cases , 10. ConIn patients with idiopathic DCM, genetic/familial reasons should be considered. Familial DCM diagnosis is ascertained when the proband has two or more first-degree relatives who experienced premature sudden cardiac death aged <35 or heart failure without a definitive cause or by three-generation history of DCM . Thus, gAdditional considerations should however be added to other subcategories of DCM, mainly inflammatory cardiomyopathy. Inflammatory DCM (DCMi) or inflammation of the myocardium is best regarded as any heightened humoral or cellular immune response in the heart with various symptoms such as chest pain, mild dyspnea, or acute cardiogenic shock , 13. ForBefore highlighting standard and personalized approaches to treat DCM (sections Targeted Treatments for DCM and Emerging Immunomodulator Therapeutic Strategies), we will first provide an overall picture on the environmental and genetic etiologies of the disease .The cellular changes that result in DCM begin first as an adaptational response but are then transformed into a detrimental cellular, and organ “malaise” as a consequence of accumulated uncontrolled molecular events. We hereby refer to the microenvironment as the environment that surrounds the myocyte. This includes the surrounding cells and their secreted proteins and growth factors in the myocardial interstitium: endocardial, fibroblast, blood cells. In DCM, the myocardial interstitium is constantly subjected to an increase in the extracellular matrix content and reduction in collagen linkage, resulting in faulty matrix and Left Ventricular (LV) dilation . StudiesIn contrast, the macro-environment refers to the overall body adaptation/response to extra-cardiac “insults” and is sensed through a hemodynamic and/or hormonal overload on the heart . ExampleDiabetes is a known risk factor for cardiovascular diseases , 17. DevDCM can result from autoimmune diseases such as systemic lupus erythematosus, systemic sclerosis, rheumatoid arthritis, Kawasaki disease–related myocarditis, lupus erythematosus, cardiac sarcoidosis, and giant cell myocarditis , 21. In Some of the toxins that can cause DCM are alcohol, cocaine, and cytostatics . Left veSeveral anti-neoplastic drugs are cardiotoxic like Anthracyclines , alkylating agents (Cyclophosphamide), antimicrotubular molecules  and antimetabolites . The function, and metabolic activity of the heart are drastically perturbated by these agents , 26. DoxCardiotropic viral infections induce cardiac dysfunction and may lead to DCM. The predominant viral cause seems to change with every decade  . In viraAs discussed above, TNF-α overexpression causes a series of cellular events that causes cardiomyocyte inflammation/necrosis. TNF-α and other cytokines such as interleukin-1 (IL-1), interleukin-6 level (IL-6), interleukin-10 (IL-10), and interleukin-18 (IL-18) are an essential part of the inflammatory process. Cytokines are produced by several immune cells like the innate macrophages, dendritic cells, natural killer cells and the adaptive T and B lymphocytes. Accumulating evidence suggest that patients with DCM suffer from a “cytokine storm.” The “cytokine storm” results from a sudden acute overexpression in circulating levels of IL-6, IL-1, IL-10, IL-18, TNF- α, and interferon. This cytokines overexpression results in influx of various immune cells such as macrophages, neutrophils, and T cells from the circulation into the site of infection with destructive effects in cardiovascular cells resulting to capillary damage and myocardial fibrosis leading to DCM –33. FurtLMNA or SCN5A, BAG3, FLNC, PLN, RBM20, and TTN. Identifying the heredity can be difficult due to the incomplete penetrance and variable expressivity of DCM and genetic variation. Thirty-five percent of DCM cases have a family history, inherited in Autosomal Dominant manner (AD), in some cases autosomal recessive or X-linked inheritance traits  pathway. To confirm that, TNF-α was used as a treatment and resulted in a dose- and time-dependent decrease in mRNA levels of dystrophin and titin . Other sMNA encodes Lamin A/C, an envelope protein that acts as a support element to intermediate filaments and regulates gene expression by stabilizing the inner nuclear membrane , a nuclear phosphoprotein mainly expressed in the cardiac myocytes have been emerging as one of the latest causes of familial DCM cases despite being first linked to arrhythmogenic cardiomyopathies , 46. TheWith all the etiologies being exposed, the following sections will first provide a current summary of the ongoing and proposed clinical trials that use conventional treatment and etiology-driven therapeutic treatments.Conventional medications are the first line drug treatment that have been studied in large clinical scale trails and shown survival improvement and reduction in hospital admission. Conventional treatment is based on the classification of the patients as per “measured” clinical criteria. The New York Heart Association (NYHA) classified DCM patients into five groups based on their heart failure. Class I: patients with cardiac disease but without resulting limitations of physical activity, and ordinary physical activity does not cause undue fatigue, palpitation, dyspnea, or anginal pain. Class II: patients with cardiac disease resulting in slight limitation of physical activity, are comfortable at rest and ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal pain. Class III: patients with cardiac disease resulting in marked limitation of physical activity, are comfortable at rest, and less-than- ordinary physical activity causes fatigue, palpitation, dyspnea, or anginal pain. Class IV: patients with cardiac disease resulting in inability to endure physical activity without discomfort. Symptoms of cardiac insufficiency or of the anginal syndrome may be present even at rest. If any physical is undertaken, discomfort is increased. Overall, the treatment of each class varies between the use of Angiotensin Converting Enzyme Inhibitors (ACEIs) –51, AngiIn general, with conventional therapies, ~25% of DCM patients with recent onset symptoms of HF will have spontaneous improvement, but patients with symptoms lasting >3 months who show severe clinical presentations generally have less chance of recovery, thus treatments will be recommended to optimize heart function, reduce the risk of worsening disease, prevent complications, and/or reduce symptoms caused by heart failure. Non-pharmacological treatment is strongly recommended for etiologies that can be controlled such as avoiding exposure to toxins . In alcoholic cardiomyopathy (aCM), abstinence from alcohol has shown to improve the LVEF in patients. A study conducted for 82 months on 101 aCM patients showed a noticeable improvement in LVEF function  for 42% of them . Also, fThe second approach is targeting the defect gene mutations at the molecular level directly by affecting the structure and function of the encoded proteins. Currently, an allosteric modulator was developed to directly bind in the same region on myosin, increasing actin affinity and cross-bridge formation, as well as enhancing sarcomere force production. This modulator is well-studied in patient with reduced LVEF from heart failure, which can benefit DCM patients since they have reduced LVEF. CK-1827452 also known as Omecamtiv mecarbil (INN) accelerates the transition of actin-myosin complex from weakly to strongly bound and increases the number of myosin heads engaged with the thin filament. These effects are independent of calcium transients because CK-1827452-treated cardiomyocytes with isoproterenol augment contraction, whereas β-adrenergic inhibition does not diminish contractility  ATOMIC . AdditioSpecific inhibitors to the pathogenic effects bestowed by the pathogenic mutations are postulated to be beneficial in treating DCM. Pre-clinical trials using novel small molecules did yield encouraging results. The LMNA mouse model was treated with ARRY-371797, an oral medication that inhibits the p38 MAP kinase: LV dilation was prevented, and EF substantially improved. To investigate the benefits of ARRY-371797 in DCM patients with LMNA mutations, patients with LMNA mutations, a clinical trial is currently ongoing to evaluate its effectiveness based on changes in the 6 min-walk tests over a 24 weeks-time period (NCT03439514). With the increasing focus on the role of RBM20 as a master regulator of alternative splicing, recent data suggest that in patients with reduced RBM20 activity, all-trans retinoic acid (ATRA) could be used to restore RBM20 levels and efficiently curb down the deleterious effects of loss of function mutations in this gene .in vitro and in vivo  preclinical studies and this led to the support of its advancement into clinical investigations (A novel myosin activator is Danicamtiv (formerly known as MYK-491). It is a new targeted myosin activator under development for the treatment of DCM. It accelerates and activate myosin contractility directly by increasing cross-bridge formation with no effects on the calcium transient. This has the potential to improve the hemodynamic profile of patients with systolic heart failure while avoiding the energetic consequences of adrenergic agonists and phosphodiesterase inhibitors. It was characterized in igations .Antiviral therapy treatment is suggested for viral causes of DCM and currently there are many trials ongoing to understand their beneficial effects at distinct phases. In summary, patients with enterovirus are treated with Interferon beta, Parvovirus B19 with immunoglobulins and Telbivudine and Human Herpesvirus Type 6-Positive Patients with Ganciclovir and this will be further explained below in details  83)..83).Immunoglobulins reduces oxidative stress by preventing the development of proinflammatory cytokines; thus, they have both antiviral and anti-inflammatory properties . IntraveTelbivudine, an analog of thymidine is an antiviral nucleoside that has immunomodulatory-antiapoptotic properties. The PreTopic Study assessed the effect of Telbivudine on B19V-positive patients . PatientAnti-viral treatment with type I interferons was shown to be a suitable choice for viral positive cardiomyopathies. A non-randomized study showed administration of INF-ß results in improved survival by reducing the virus induced injury to the myocardium. The study showed that patients who received IFN-ß had higher virus elimination rates, improved quality of life and fewer adverse cardiac associated occurrences .P = 0.001) (Treatment guidelines specific to inflammatory causes of DCM are scare. Extensive multicenter studies need to be conducted to prove the effectiveness of the treatment options . Current= 0.001) . A large= 0.001) . Other r= 0.001) .The assumption that disease associated auto antibodies (AAB) play a role in DCM pathogenesis, entail that removing such antibodies will result in improving the patients' cardiac parameters. Few studies have been conducted and some are still underway. There was an improvement in the pulmonary capillary output pressure, cardiac index, pulmonary resistance, reduction in AAB levels when immunoadsorption therapy was done for 5–7 cycles on 9 patients with DCM and increased anti-beta adrenergic receptor AAB levels . The resSubstantial emerging anti-inflammatory agents are entering early phase clinical evaluation . These sUp until now, Etanercept and Pentoxifylline are the most studied agents, but there is a lack of recent studies of their effectiveness. The use of Etanercept, a TNF-α antagonist lowered the levels of biologically active TNF in patients with moderate heart failure. The treatment was safe and well-tolerated for 3 months; it led to a significant dose-dependent improvement in left ventricular (LV) ejection fraction and LV remodeling . Other sAs such, biological treatments that block the IL-1 pathway are potential agents to treat myocarditis such as the IL-Ra (IL-1 receptor antagonist) anakinra, and canakinumab.The IL-Ra antagonist (Anakinra) blocks the acute inflammatory response accompanied with ST-segment elevation in acute myocardial infarction. A study on Anakinra receiving patients showed a lower incidence of heart failure . In receCanakinumab which is an anti–IL-1β monoclonal antibody has demonstrated reduction of highly sensitive c reactive proteins and 1β, and IL-6 in patients with CAD . However, its possible benefits in DCM need to be studied further .Mesenchymal stromal cells cardioprotective and immunomodulatory properties have been well-established and have been shown myocarditis improvement in experimental models of CVB3-induced myocarditis, autoimmune-induced DCMi and chronic Chagas cardiomyopathy , 105. InThere is a necessity to better understand DCM pathogenies and etiologies to tailor the treatment for patients. Many immuno-based therapies are currently available, but refinement of these novel drugs need to be done to better understand the clinical efficacy in patients. Large cohort studies and advanced animal model experimentation need to be carried out prior conducting clinical trials to validate the significance of these etiology-based treatments. A challenge to apply specific tailored therapies would be the stratification of patients based on the causative factors. Effective stratification of patient into virus positive, negative, and inflammatory causes using EMB and imaging methods will allow for causative agent identification that can be used in the diagnosis, prognosis, and initiation of immuno-modulators agents. Thus, more clinical research needs to be conducted to prove the effectiveness of stratification, pharmacological use of immuno-modulators and the significance of it in hospital settings.AK, FM, and GN have made significant contributions to writing this manuscript. 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.


KoRV infection has become a permanent part of koalas in northern Australia. With KoRV presence and abundance linked to more severe chlamydial disease and neoplasia in these koalas, understanding how KoRV exists throughout an increasingly fragmented koala population is a key first step in designing conservation and management strategies. The koala population in northern Australia has become increasingly fragmented due to natural and human-made barriers and interventions. This situation has created a unique opportunity to study both endogenous and exogenous koala retrovirus (KoRV). To determine the impact that population isolation has had on KoRV diversity in Queensland, 272 koalas from six fragmented koala populations were profiled for their KoRV provirus across two natural biogeographical barriers , one humans-made geographical barrier (the city of Brisbane), and two translocation events . Analysis revealed that all koalas tested were KoRV-A positive, with 90 to 96% of the detected KoRV provirus from each koala representing a single, likely endogenous, KoRV-A strain. The next most abundant proviral sequence was a defective variant of the dominant KoRV-A strain, accounting for 3 to 10% of detected provirus. The remaining KoRV provirus represented expected exogenous strains of KoRV and included geographically localized patterns of KoRV-B, -C, -D, -F, -G, and -I. These results indicate that lineage diversification of exogenous KoRV is actively ongoing. In addition, comparison of KoRV provirus within known dam-sire-joey family groups from the koala sanctuary revealed that joeys consistently had KoRV proviral patterns more similar to their dams than their sires in KoRV-B, -C, and -D provirus composition. Collectively, this study highlights both the consistency of endogenous KoRV and the diversity of exogenous KoRV across the fragmented koala populations in northern Australia.IMPORTANCE KoRV infection has become a permanent part of koalas in northern Australia. With KoRV presence and abundance linked to more severe chlamydial disease and neoplasia in these koalas, understanding how KoRV exists throughout an increasingly fragmented koala population is a key first step in designing conservation and management strategies. This survey of KoRV provirus in Queensland koalas indicates that endogenous KoRV provirus is ubiquitous and consistent throughout the state, while exogenous KoRV provirus is diverse and distinct in fragmented koala populations. Understanding the prevalence and impact of both endogenous and exogenous KoRV will be needed to ensure a future for all koala populations. Phascolarctos cinereus)  is found both endogenously and exogenously in koalas (inereus) , 2. It iinereus) , 4 and hinereus) . Examinainereus) . In parainereus) –10. Withnereus) ––14. ThisDespite not knowing when KoRV entered the Queensland koala population, there are several Queensland features that have led to koala population fragmentation that do have known dates. Starting on a geological scale, there are two major biogeographical barriers that are believed to have impacted koala populations . The St.This study compares the diversity of KoRV provirus detected in 272 koalas from six distinct Queensland koala populations, spanning two natural biogeographical barriers, one isolated island population and one long-term captive koala colony. The goal was to determine the impact, if any, these short- or long-term separation events/barriers have had on KoRV diversity across Queensland. Interestingly, KoRV provirus profiling revealed that endogenous KoRV was virtually identical and by far the most dominant KoRV strain across the entire state, with only minor contributions of different exogenous KoRV strains contributing a unique KoRV pattern to each fragmented koala population. Additionally, the long-term captive koala colony contained the most KoRV diversity within Queensland, allowing for a comparison of KoRV provirus profiles within dam-sire-joey family units. This detailed family comparison revealed that exogenous KoRV patterns detected in joeys were much more related to their dam’s KoRV profile than their sire’s KoRV profile, further strengthening a proposed link in dam-to-joey exogenous KoRV transmission.n = 30), scat samples from Peak Downs Highway (n = 39), and blood samples from koala populations at Moreton Bay (n = 62), Hidden Vale (n = 20), Gold Coast (n = 39), and Lone Pine Koala Sanctuary (n = 82). Previous study has determined that KoRV proviral profiles generated from multiple sample types can be combined for analysis , with the five KoRV-D clades having distinct distributions around the state . KoRV-B Principal coordinate analysis (PCoA) of total KoRV proviral profiles continued to highlight the differences exogenous KoRV contributed to each study region, with total koala profiles clustering distinctly by study area . UnexpecLone Pine Koala Sanctuary has an active breeding program, resulting in many well-documented family units (dam-sire-joey) at the time of this study. The high prevalence of multiple KoRV subtypes detected at the sanctuary, together with 18 complete family units represented in the sanctuary sample collection, allowed for direct comparison of KoRV proviral patterns between joeys and their parents. A list of the koala family units analyzed can be found in Table S2. PCoA analysis compared both the presence and abundance of KoRV strains detected within each dam, sire, and joey family unit and calculated a distance metric to represent how similar or different the profiles were. The first component of this metric, representing the largest component of the distance between samples, is diagrammed in Comparisons revealed that joeys most often had proviral patterns more similar to their dams than their sires in overall total KoRV profiles  and koalas in the vicinity of Peak Downs Highway, Queensland (n = 39), respectively. Blood samples from Hidden Vale koalas (n = 20) and Moreton Bay koalas (n = 62) were collected as part of an ongoing population-wide health management program  and have been previously reported (n = 39) and Lone Pine Koala Sanctuary koalas were collected as part of routine veterinary care . All samples were DNA extracted using the QIAamp DNA minikit (Qiagen) by following the manufacturer’s protocol for each sample type.Tissue and scat samples were opportunistically collected from St. Bees Island koalas  were generated with the primers env22.F (TCGTCGGCAGCGTCAGATGTGTATAAGAGACAGGCTTCTCATCTCAAACCCG-CGCC) and env514.R (GTCTCGTGGGCTCGGAGATGTGTATAAGAGACAGGGGTTGCCAGTAGGCGGTTCC) according to previous studies (KoRV  studies , 11, 24.env sequences (generated from references KoRV sequence reads were filtered for length and primer trimmed with cutadapt  before fA maximum likelihood phylogenetic tree was generated using KoRV OTU DNA sequences aligned with mafft  before MTo compare the KoRV OTU profiles between koalas, the QIIME 1.9.1 software package  was usedMW122516–MW122721.Sequences of the OTU generated in this study can be found under the GenBank accession numbers


Whilst the risk factors for type 1 myocardial infarction due to atherosclerotic plaque rupture and thrombosis are established, our understanding of the factors that predispose to type 2 myocardial infarction during acute illness is still emerging. Our aim was to evaluate and compare the risk factors for type 1 and type 2 myocardial infarction.P < 0.05 for all). Whilst women accounted for a greater proportion of patients with type 2 as compared to type 1 myocardial infarction, after adjustment for other risk factors, sex was not a predictor of type 2 myocardial events . The strongest predictor of type 2 myocardial infarction was a prior history of type 2 events .We conducted a secondary analysis of a multi-centre randomized trial population of 48 282 consecutive patients attending hospital with suspected acute coronary syndrome. The diagnosis of myocardial infarction during the index presentation and all subsequent reattendances was adjudicated according to the Universal Definition of Myocardial Infarction. Cox regression was used to identify predictors of future type 1 and type 2 myocardial infarction during a 1-year follow-up period. Within 1 year, 1331 patients had a subsequent myocardial infarction, with 924 and 407 adjudicated as type 1 and type 2 myocardial infarction, respectively. Risk factors for type 1 and type 2 myocardial infarction were similar, with age, hyperlipidaemia, diabetes, abnormal renal function, and known coronary disease predictors for both (Risk factors for coronary disease that are associated with type 1 myocardial infarction are also important predictors of type 2 events during acute illness. Treatment of these risk factors may reduce future risk of both type 1 and type 2 myocardial infarction.  O’Donoghue et al., Myocardial infarction is a clinical diagnosis based on the presence of symptoms or signs of myocardial ischaemia in conjunction with acute myocardial injury, as indicated by a rise or fall in cardiac biomarker concentrations., Graphical Abstract).The risk factors for type 1 myocardial infarction have been well characterized in a number of large trials., , Our knowledge of the risk factors and patient characteristics that predispose to type 2 myocardial infarction during acute illness is limited.STAT high-sensitive troponin I assay; Abbott Park, IL, USA). This assay has an inter-assay coefficient of variation of <10% at 4.7 ng/L, the limit of detection of 1.2 and 1.9 ng/L, and a sex-specific 99th centile thresholds of 16 and 34 ng/L for women and men, respectively., , Between June 2013 and March 2016, a total of 48 282 consecutive patients with suspected acute coronary syndrome who attended one of the 10 secondary and tertiary care hospitals in Scotland were enrolled in the High-Sensitivity Troponin in the Evaluation of patients with Acute Coronary Syndrome (High-STEACS) trial.2. A detailed summary of the adjudication procedures is provided in the All diagnoses in patients with hs-cTnI concentrations above the sex-specific 99th centile were adjudicated using the hs-cTnI assay and classified according to the Fourth Universal Definition of Myocardial Infarction.χ 2, Kruskal–Wallis, or one-way analysis of variance tests as appropriate. Multivariable Cox proportional hazard models were used to determine the predictors of type 1 or type 2 myocardial infarction accounting for the competing risk of all-cause mortality. Adjusted hazard ratios (aHRs) are reported with 95% confidence intervals (CIs) and P-values for the individual outcomes of type 1 or type 2 myocardial infarction. Baseline clinical variables for the models were selected based on their clinical relevance and included age, sex, previous history of coronary artery disease, previous history of cerebrovascular disease, diabetes mellitus, hyperlipidaemia, creatinine concentration, and coronary revascularization history., , , , P-values >0.05 were considered satisfactory to meet the proportional hazards assumption. Statistical analysis was performed in R (version 3.5.1).Baseline characteristics were summarized for the whole population, and in those with and without myocardial infarction during follow-up. Continuous variables are presented as mean (standard deviation) or median [interquartile range (IQR)], as appropriate. Categorical variables are presented as absolute numbers (%). Group-wise comparisons were performed using Supplementary material online, Table S4).This study was conducted in accordance with the Declaration of Helsinki and approved by the Scotland A Research Ethical Committee. All data were collected prospectively from the electronic patient records, deidentified, and linked within secure NHS Safe Havens (K = 0.8) and subsequent diagnoses (K = 0.7). During follow-up, there were 924 patients with an adjudicated diagnosis of type 1 myocardial infarction, 407 with type 2 myocardial infarction, and 1169 and 77 patients adjudicated as acute or chronic myocardial injury, respectively.In 48 282 patients with 1 year of follow-up, 2839 patients reattended the emergency department with suspected acute coronary syndrome and were found to have a hs-cTnI concentration above the 99th centile. It was possible to adjudicate the index and subsequent diagnosis in 88% and 92% of patients, respectively, with moderate agreement between adjudicators for the index . However, compared to those with type 1 myocardial infarction, those with type 2 myocardial infarction were marginally older [median age 77 (IQR 69–83) vs. 74 (IQR 62–83)] and were more likely to have abnormal renal function (44% vs. 39%).Patients with either type 1 or type 2 myocardial infarction had a similar prevalence of known coronary disease (56% vs. 58%), cerebrovascular disease (12% vs. 13%), hyperlipidaemia (63% vs. 67%), and diabetes mellitus (22% vs. 21%) (Table S1). There was no difference in age, sex, prior history of coronary disease, cerebrovascular disease, hyperlipidaemia, or diabetes mellitus between different causes of type 2 myocardial infarction  of patients. Tachyarrhythmia (50%), hypoxia (22%), hypotension (12%), and anaemia (11%) were the most common causes, with coronary causes (<2%) and hypertension (2%) less frequent . Risk factors for type 1 myocardial infarction were increased age  and a prior history of coronary artery disease , diabetes mellitus , or increased creatinine concentration  . Similarly, type 2 myocardial infarction was more likely in those with increased age , or a prior history of coronary artery disease , hyperlipidaemia , diabetes mellitus , or increased creatinine concentration . Sex was not a significant predictor of type 1  or type 2  myocardial infarction.In a multivariable model, the factors associated with increased susceptibility for future type 1 or type 2 myocardial infarction were similar . Similarly, patients with a prior type 2 myocardial infarction were at increased risk of a future type 2 event . Future type 2 events occurred in 7% (75/1121) of patients with a prior type 2 event, as compared to 2% (83/4981) of those with a prior type 1 myocardial infarction .A prior diagnosis of type 1 or type 2 myocardial infarction was the strongest predictor of future type 1 or type 2 events, respectively. Patients with a prior type 1 myocardial infarction had the highest risk of a future type 1 myocardial infarction event  with a subsequent type 1 event occurring in 8% (409/4981) of those with a prior type 1 myocardial infarction, as compared to 3% (39/1121) of those with a prior type 2 event (Table 1).Patients with a future type 1 or 2 myocardial infarction during follow-up were on similar preventative medication including aspirin (71% vs. 65%), lipid-lowering therapy (76% vs. 73%), beta-blockers (65% vs. 64%), and angiotensin-converting enzyme inhibitors . Our findings are consistent with prior studies of consecutive patients with myocardial infarction where investigators demonstrated that >50% of patients undergoing coronary angiography had evidence of obstructive coronary disease., , Although the underlying conditions responsible for myocardial oxygen supply or demand imbalance are heterogeneous, our analysis is the first to demonstrate that a number of common cardiovascular risk factors are associated with susceptibility to type 2 myocardial infarction. We demonstrate that several risk factors usually associated with coronary disease and atherothrombotic type 1 myocardial infarction, including hyperlipidaemia, diabetes mellitus, and a prior history of coronary artery disease, are also important predictors of future type 2 myocardial infarction . Furthermore, coronary artery disease in those with type 2 myocardial infarction could explain why the incidence of future cardiac death is broadly comparable to patients with type 1 events., Our observation that traditional cardiovascular risk factors were common and shared predictors of future type 1 or type 2 myocardial infarction suggests that the presence of coronary artery disease, or risk factors for the progression of atherosclerosis, confers increased susceptibility to type 2 events. Whilst the risk of supply or demand imbalance leading to type 2 myocardial infarction is primarily driven by the severity of acute physiological stress, the threshold at which ischaemia occurs may be related to the extent of flow limitation from atherosclerotic coronary disease. In contrast to a patient with obstructive coronary artery disease and attenuated flow reserve, a patient with no coronary disease may have a higher ischaemic threshold, and a similar physiological stress may not lead to cardiac consequences., , , Currently, there is no consensus on how patients with type 2 myocardial infarction should be managed. In contrast to type 1 myocardial infarction where ∼60% patients undergo coronary angiography and 80% are prescribed preventative pharmacotherapies at discharge, in those with type 2 myocardial infarction, <20% of patients undergo coronary angiography and >40% are discharged without antiplatelet or lipid-lowering therapies.Whether the systematic use of preventative therapies or treatments for coronary artery disease, or its risk factors, can reduce the risk of type 2 myocardial infarction is uncertain. Indeed, widespread use of antiplatelet medication could be harmful in type 2 myocardial infarction, including, for example, where acute supply or demand imbalance has been triggered by bleeding.Despite the paucity of trials in type 2 myocardial infarction, exploratory analyses from trials in other populations have shown that the treatment of risk factors for coronary artery disease may reduce the risk of type 2 myocardial infarction. The ODYSSEY OUTCOMES trial recently observed that alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor used in the treatment of hypercholesterolaemia, could reduce both future type 1 and type 2 myocardial infarction by 13% and 22%, respectively, as compared to placebo.Our observation that type 2 myocardial infarction begets type 2 myocardial infarction could be a consequence of the lower rates of coronary angiography, revascularization, and pharmacotherapy prescriptions in these patients., , , et al. In our study, we also evaluated whether sex was associated with the risk of myocardial infarction. Male sex is an established risk factor for type 1 myocardial infarction,K = 0.7–0.8) and potential for diagnostic misclassification, especially in patients without serial troponin testing. Finally, our study was limited to a single healthcare system, and the prevalence of type 2 myocardial infarction is highly dependent on the approach to patient selection for troponin testing.Our study has several limitations. First, we recognize that our study population is limited to patients attending a secondary or tertiary care hospital with suspected acute coronary syndrome, and the prevalence of subsequent myocardial infarction is therefore higher than would be anticipated in the general population. As the incidence of type 2 myocardial infarction in the general population is low, we conducted this analysis in a higher-risk population to enable a fully adjusted multivariable analysis. Nevertheless, we believe that our population is relevant to address this question since all patients enrolled in our study were hospitalized for an acute illness, which is a prerequisite for type 2 myocardial infarction. Second, we did not have access to information on all cardiovascular risk factors, notably smoking status, and hypertension, nor did we have access to lipid profiles or blood pressure readings to evaluate the role of risk prediction tools such as the Framingham risk score. Further studies in a population undergoing screening for cardiovascular risk factors are needed to confirm our findings. Third, although all diagnoses in patients with troponin concentrations above the 99th centile were adjudicated according to the Universal Definition, there was moderate agreement between adjudicators . R.W. and A.B. are supported by Clinical Research Training Fellowship (MR/V007017/1 and MR/V007254/1) from the UK Medical Research Council and by a Research Excellence Award (RE/18/5/34216) from the British Heart Foundation. D.M.K. was supported by Health Data Research UK, which receives its funding from HDR UK Ltd (HDR-5012) funded by the UK Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Welsh Government), Public Health Agency (Northern Ireland), British Heart Foundation, and the Wellcome Trust. Abbott Laboratories provided cardiac troponin assay reagents, calibrators, and controls without charge. N.L.M. is supported by the Butler BHF Senior Clinical Research Fellowship (FS/16/14/32023), a Programme Grant (RG/20/10/34966), and a Research Excellence Award (RE/18/5/34216) from the British Heart Foundation. A.R.C. receives support from a Starter Grant for Clinical Lecturers by the Academy of Medical Sciences (SGL021/1075).Conflict of interest: N.L.M. has received honoraria from Abbott Diagnostics, Roche Diagnostics, Siemens Healthineers, and LumiraDx, and the University of Edinburgh has received research grants from Abbott Diagnostics and Siemens Healthineers. All other authors declared no conflict of interest.The trial makes use of multiple routine electronic healthcare data sources that are linked, deidentified, and held in our national safe haven, which is accessible by approved individuals who have undertaken the necessary governance training. Summary data and the analysis code can be made available upon request to the corresponding author.ehab581_Supplementary_DataClick here for additional data file.


Myocardial strain analysis by 2D speckle tracking echocardiography could determine the left ventricular function. Our purpose is to investigate the global longitudinal strain (GLS) changes during the course of fulminant myocarditis (FM) and evaluate their correlation with cardiac magnetic resonance (CMR).Patients with clinical diagnosis of FM from June 30, 2017 to June 30, 2019 were screened prospectively. 18 survived patients (mean age 34 ± 18 years) who had two scans of transthoracic echocardiography and underwent CMR were included.P = .013) and with extracellular volume fraction , but not global native T2 relaxation time  and not with late gadolinium enhancement mass . In comparison, GLS at admission were not correlated with CMR parameters of fibrosis and oedema in the healed stage.All patients had severely impaired left ventricular ejection fraction and GLS value at admission that improved significantly before discharge. The patients in the healed stage revealed elevated global native T1 and T2 relaxation time and extracellular volume fraction as well, which were 1408.3 ± 88.3ms, 46.56 ± 5.23ms, and 0.35 ± 0.09, respectively. GLS from the second transthoracic echocardiography in the healed stage correlated significantly with global native T1 relaxation time (r =-0.574, GLS by 2D-STE may emerge as a new tool to monitor inflammatory myocardial injuries during the course of FM. FM in the acute healed stage has the presence of both chronic fibrosis and oedema which are correlated with GLS, but GLS at admission can’t predict the early recovery of myocardial inflammation. However, the outcome could not be predicted with certainty in the early stage of hospitalization.–9 Searching tools to assist diagnosis, monitor disease activity and evaluate prognosis of FM has been one of the most active areas of investigation in myocarditis.Fulminant myocarditis (FM) has been described in clinical settings as a clinical syndrome with rapid deterioration of hemodynamic status or heart function. FM patients often have dramatic presentation and a large proportion of them may die from cardiogenic shock or sudden death in the acute phase as reported. In comparison, FM is not a histological or an immunohistological diagnosis.,12 The amount of infiltrating cells in biopsy specimen is not equivalent of FM and has no diagnostic and prognostic relevance. Moreover, EMB is rarely performed clinically due to the limited ability in most centres, or the procedural risk particularly in FM. Tissue characterization by cardiac magnetic resonance (CMR) is becoming a routine and mostly used non-invasive imaging tool to confirm myocarditis recently. The magnitude of necrosis and/or oedema by late gadolinium enhancement (LGE) and T1/T2 mapping on CMR can provide incremental prognostic information in AM.–17 However, CMR is limited during the early stage of FM, particularly when circulatory supports are used. Thus, it is not a good candidate to detect inflammatory myocardial injuries in the early stage of FM and monitor their activity during the course of FM.Histological evidence of inflammatory cell infiltrates by endomyocardial biopsy (EMB) is the gold criteria to diagnose myocarditis.–20 Therefore, we propose that strain by 2D-STE may be used as an additional tool to assist diagnosis and provide prognostic information in FM.Echocardiography is one of the routine examinations and can be performed on bedside as needed during the course of FM. Conventional echocadiography provides limited information other than left ventricular (LV) function. 2D speckle tracking echocardiography (2D STE) is an evolving method to determine the LV global and regional function quantitatively and is more sensitive than conventional echocardiographic parameters. Recent studies showed that strain imaging by 2D-STE is correlated well with cell infiltration in tissue specimen obtained by EMB and oedema detected by CMR in AM.This study included 18 survived patients with clinical diagnosis of FM by typical clinical characteristics, elevated necrosis biomarkers and positive “Lake-Louise” CMR criteria. Sequential echocardiographic images were performed and strains by 2D STE were analysed at admission and before discharge. CMR imaging was performed before discharge. The correlations of strains during the course with tissue characteristics by CMR were assessed. We aimed to analyse whether strain imaging by 2D STE can monitor myocardial injuries during the course of FM and evaluate its usefulness in FM.22.1 were prospectively screened. Coronary angiography was performed in patients older than 25 years to rule out acute myocardial infarction and concomitant coronary artery disease. Other exclusion criteria were: severe valve diseases, subjects < 15 years of age, previous heart disease history having rapid onset of symptoms of acute heart failure within less than two days and a flu-like prodrome;(2)having severe hemodynamic compromise that needed high doses of vasopressors (≥5 μg/kg/min of dopamine or dobutamine);(3)mechanical circulatory supports, such as intra-aortic balloon pumps and/ or venoarterial extracorporeal membrane oxygenation, were used in the early phase.Twelve patients who didn’t met the criteria were considered as non-fulminant myocarditis and were excluded from the study.We subsequently excluded the following patients:(1)2 patients who died;(2);2 patients who didn’t take CMRs before discharge or didn’t meet positive “Lake-Louise” criteria of myocarditis(3)1 patient who underwent CMRs in more than 48 hours apart from the second echocardiography scans;(4)4 patients with poor echocardiographic images or the presence of arrhythmias that interfered with strain analysis.Thus, the final study population was consisted of 18 patients. Figure  that includesAll 18 patients received treatment which is referred to as “Life-Support-Based Comprehensive Treatment Regimen (LSBCTR)”(i)mechanical life support ,(ii)immunomodulation therapy using sufficient doses of glucocorticoids and immunoglobulins, and(iii)application of neuraminidase inhibitors.All procedures were in accordance with the ethical standards of the responsible committee on human experimentation  and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients included in the study. And this study was approved by the Research Ethics Committee of Tongji Hospital.2.2A Vivid E9 ultrasound scanner  was used for TTE scans. Sequential TTEs were taken at a frequency of 1 scan per 1 to 2 days from the admission till the day when the LV ejection fraction (EF) recovered to >50% before discharge. Two scans were used for the data analysis, one at admission when the lowest LV function was recorded (day 1 or 2 of admission) and the second one before discharge when the patients’ hemodynamic statuses were stable and LV function almost was recovered (LVEF > 50%). Figure  Briefly, three cardiac cycles of each apical view were recorded at frame rate ≥60 frames/s. Duration of systole was defined in the five-chamber apical view by marking the aortic valve opening and closure from the continuous wave Doppler curve. An experienced investigator who was unaware of the patients’ clinical information and CMR data conducted the strain analysis off-line by using EchoPAC software . The LV borderline was manually traced in each apical plane, and motion tracking was performed automatically by the software. Segmental peak systolic longitudinal strain values were averaged to achieve global GLS according to AHA 17-segment LV model.LV and left atrial dimensions and LV wall thickness were measured using standard methods. LV EF was measured by the modified biplane Simpson's method. Global longitudinal strains (GLS) were obtained by 2D STE. 2D greyscale images of standard four-chamber, two-chamber and three chamber views with optimized focus on the LV were used for myocardial strain analysis as described previously.2.3CMR was performed before discharge, same as the second TTE. The time interval between CMR and the second TTE scan was within 48 hours Fig. . Cine images were obtained using steady state free precession sequence during breath hold in short axis and three long axis planes. The parameters were as follows: FOV, 360 × 360 mm2; TR/TE/flip angle, 37.7 ms/1.4 ms/55°; slice thickness, 8 mm; voxel size, 1.9 × 1.9 × 8.0 mm; bandwidth, 965 Hz/pixel. Black blood T2-weighted short tau inversion recovery MRI was performed in short axis plane covering the whole left ventricle (LV) using TR of 2 RR intervals; TE: 41ms; slice thickness, 8mm; FOV: 360 × 360 mm2. Native and post-contrast T1 mapping were performed using a MOLLI sequence with 5(3)3 and 4(1)3(1)2 acquisition scheme, respectively. The acquisition parameters were TR/TE/flip angle, 3.8 ms/1.2ms/35°; voxel size, 1.4 × 1.4 × 5.0 mm. T2 mapping was performed before contrast injection using a multi-echo fast spin-echo sequence with the following parameters: acquisition matrix = 206 × 256; TE = 0, 24, 55 ms; TR = 208 ms; FA = 12°; pixel size = 1.9 × 1.9 × 5 mm2; and slice thickness = 5 mm. Both T1 and T2 mapping were acquired in basal, mid-ventricular, and apical short-axis slices. Finally, LGE images were obtained by a 2D phase-sensitive inversion-recovery (PSIR) gradient-echo pulse sequence .All patients were scanned on a 3-T Magnetic Resonance Imaging (MRI) scanner  with a 18-channel body matrix coil. The diagnosis of myocarditis was made by “Lake Louise criteria”.All CMR images were assessed offline by 2 independent readers, experienced in cardiovascular MRI (with 2–4 years of experience) and blinded to clinical and echocardiographic information, using a dedicated CMR software cvi42 . The hematocrit-corrected extracellular volume fraction (ECV) and global mean values were measured on pre- and post-contrast T1 mapping images. Hematocrit samples were taken on the same day of cardiac MRI scans. Global LV native T1, T2, and ECV values were used for further analysis. Myocardial edema and non-ischemic LGE lesions were qualitatively assessed by consensus from the 2 observers. For each patient, the endo- and epicardial contours of all short axis LGE images were manually delineated, then LGE mass was obtained by using a signal intensity threshold of ≥5SD above the mean signal of the remote reference myocardium.2.4t test or Mann-Whitney U test according to its distribution. For paired comparisons, paired t test or paired sample Wilcoxon rank test were performed for continuous variables, depending on the normality of the variables. Univariate linear regression was used to determine the effect of continuous strain variables on fibrosis and oedema detected by LGE and T1/T2 mapping by CMR before discharge. Covariate was selected by clinical perspective and applied in the multivariate linear regression model. All analysis was performed using SPSS version 19.0 software . Statistical tests were two-tailed and a P-value of less than 0.05 was considered statistically significant.Data are expressed as mean ± SD for continuous variables or numbers (percentages) for categorical variables. Continuous variables between groups were analysed by Student 2.5To investigate inter- and intra-personal measurement reproducibility, measurements were performed off-line in all subjects by 2 independent investigators. The intra-personal agreement was measured 7 days later by the same investigator. The interclass correlation coefficients were calculated; the point estimates and the 95% confidence intervals were reported.33.1Patients clinical characteristics were presented in Table 3.2P < .001). Parallel to the recovery of LVEF, GLS values were increased significantly from 9.6 ± 4.7% at admission to 17.2 ± 3.1% before discharge (P < .001). The representative images of the longitudinal strains before discharge presented as ‘bull's eye’ in two patients were shown in Figure Echocardiographic parameters at admission and before discharge were shown in Table 3.3CMRs were performed before discharge, at day 11 ± 4 of admission. Table 3.4r = -0.58, P = .011)   and not with LGE mass  as well  Table  and withr = 0.546, P = .019) and T1   but not T1/T2 mapping and ECV.We next compared CMR parameters with baseline GLS values. We found that there was no correlation between GLS at admission and CMR parameters before discharge, including global native T1 and T2 mapping, ECV as well as LGE Table . GLS at 3.5There were good intra-observer and inter-observer correlation for strain measurement. Interclass correlation coefficients was 0.90 (95% CI 0.85–0.93) for inter-observer agreement and 0.94 (95% CI 0.90–0.97) for intra-observer agreement.4The present study represents an assessment of myocardial deformation changes by speckle tracking echocardiography and an evaluation of myocardial oedema and/or fibrosis by CMR in survived FM patients. Particularly, the myocardial strains during acute and early recovery stages of FM were compared with tissue characteristics by CMR. The major findings of the study were that(1)FM patients who survived the acute phase had recovery of cardiac function in a short term,(2)FM patients in the early recovery stage had different tissue patterns with varied amount of oedema and fibrosis,(3)GLS can be a great indicator to monitor the course of myocardial inflammation in FM, and(4)the initial lower GLS does not reflect poor in-hospital recovery of cardiac function in FM.–4 Recently, a group from Japan reported much higher survival rate of 83.3% was with mechanical circulatory supports. A multi-centre study led by our group reported even lower in-hospital mortality of 3.7% with a LSBCTR. From the point of LV function, a study showed that the patients with FM had more severely impaired LVEF at admission and had steep improvement during hospitalization compared with non-fulminant myocarditis. Our study consisted of 18 survived patients with FM who all used LSBCTR and had clinical recovery in average 12 hospitalization days. They all had very severe LV dysfunction at admission with dramatically lower levels of EF and GLS but presented with rapid improvement before discharge. This finding provides new evidences that FM patients can have short term recovery of cardiac function once they survive the acute phase after appropriate treatments. These patients are being followed up in our centre to evaluate their long-term outcome.The in-hospital outcome of FM is poor with mostly reported survival rates of between 46% to 75.5%.,29,30 While the criteria provides good overall diagnostic performance, novel CMR mapping techniques as T1 and T2 mapping, and ECV were reported to have additional values in patients with suspected myocarditis. LGE is known to reflect focal necrosis/fibrosis, usually indicating irreversible or persistent myocardial injury. Elevated T1 mapping and ECV represent both acute inflammation/oedema and irreversible myocardial fibrosis, with T1 more sensitive to acute inflammation.,31,32 T2 mapping has the best value to differentiate acute from chronic myocarditis, representing mainly acute inflammation or reversible oedema.,16,30 CMR in this study was performed before discharge and therefore reflected tissue characteristics in the early recovery stage of FM. The results showed that all patients had focal LGE in a non-ischemic pattern and had elevated T1/T2 mapping and ECV as well. It indicates that myocardial inflammation may be still ongoing other than chronic fibrosis in this stage. However, the extent of fibrosis and oedema varied greatly in individual patients. Some patients had mainly fibrosis and others had predominantly oedema. Follow-up study is needed to investigate the effects of these different tissue patterns on the long-term outcome of FM.The Consensus Criteria for CMR in Myocardial Inflammation (“Lake Louise Criteria”) published in 2009 proposed 3 diagnostic targets-edema, hyperemia, and necrosis, which derived respectively from signal intensity assessment in T2-weighted, early gadolinium enhancement (EGE) and LGE CMR images. Studies in AM had demonstrated that there was significant correlation between strains by 2D-STE and oedema by CMR.,20 The other study demonstrated a positive correlation between amplitude of strain and delayed enhancement on CMR in patients with AM. To investigate the utility of myocardial strain in FM, we did the correlation analysis between CMR parameters and GLS from the same recovery stage of FM first. Our study showed that GLS was correlated significantly with CMR ECV but not with LGE and T2, which was different from the previous report in AM. The reason why the finding from FM is different from that of AM may because of the proportion of fibrosis and oedema. Strain is actually a measure of regional myocardial deformation and either fibrosis/necrosis or oedema will affect strain measurement. In the AM, oedema was the mainly changes of the myocardium. In early recovery stage of FM, fibrosis/necrosis and oedema were both pronounced as shown in our study. They two together contribute to the reduction of myocardial deformation or strain, but not fibrosis/necrosis or oedema alone. In addition, the different degree of inflammatory myocardial injuries may also cause the difference correlation of GLS and CMR in AM and FM. CMR parameters in the early phase of FM were not obtained in the study, and the correlation of GLS with CMR in the acute phase was not known. In summary, the good correlation of GLS with fibrosis and oedema detected by CMR and the portability of TTE make 2D STE a useful tool to monitor myocardial inflammatory injuries in the clinical management of FM.Compared with CMR, the portability of TTE makes it a great imaging tool in the management of FM. However, traditional echocardiography provides least information other than LV function in myocarditis. In contrast, strain analysis by 2D STE is more sensitive in evaluating LV function in AM. Another report also found that the initial LV EF was the only independent predictor of outcome in AM. Our study proved that the baseline GLS is not a predictor of the early recovery in FM.The present study also tried to evaluate whether strains by 2D STE during the early phase can predict in-hospital outcome or LV function recovery in FM. We thus correlated GLS in the early phase to CMR in the recovery stage of FM. The results found that the initial GLS did not correlate with the extent of LGE or oedema by T1/T2 mapping by CMR. In other words, the initial lower GLS did not predict more severe necrosis and/or oedema and thus poor cardiac function in the early recovery stage of FM by our study. This finding is different from the previous reports in AM. A retrospective study in paediatric myocarditis found that the presence of LVEF < 30% on admission was the major predictor for poor outcomes.5The present study has several limitations. First, the study was conducted in a single centre and the patients enrolled were in relatively small numbers. In addition, patients with high-degree heart block or irregular rhythm who are not rare in the population of FM and patients who died were excluded from the study, which can cause selective bias. Second, invasive EMB that is considered as the gold standard of myocarditis was not performed in the study. Third, the CMRs were performed only in the recovery stage of FM. The tissue characteristics of CMR in the early phase of FM and its correlation with GLS were not assessed in the present study. However, CMR is hardly performed in the acute phase of FM when patients’ statuses are not stable. Finally, fibrosis and oedema have different pathological and prognostic significance. Follow-up studies are needed to evaluate the long-term outcomes of FM patients, including death, heart transplantation, LV EF reduction and LV dilatation. We are aimed to define the significance of different CMR characteristics and/or myocardial strains for predicting the long-term outcomes of FM.6Myocardial deformation or strain analysis by 2D STE appears to be very informative in FM and may emerge as a new tool to monitor inflammatory myocardial injuries during the course of FM. FM in the early recovery stage has the presence of both chronic fibrosis and acute oedema as detected by CMR, which have good correlation with GLS by 2D-STE at the same stage. Moreover, GLS at admission shows no correlation with the extent of fibrosis and oedema at discharge by CMR and can’t predict the early recovery of myocardial inflammation and cardiac function in FM.Conceptualization: Houjuan Zuo, Hong Wang, Dao Wen Wang.Data curation: Houjuan Zuo, Haojie Li, Rui Li, Jiangang Jiang, Hong Wang.Formal analysis: Houjuan Zuo, Haojie Li, Rui Li.Funding acquisition: Houjuan Zuo, Hong Wang.Investigation: Houjuan Zuo, Haojie Li, Jiangang Jiang, Chenze Li.Methodology: Fei Ma, Jiangang Jiang.Project administration: Liming Xia, Dao Wen Wang.Resources: Hong Wang.Software: Houjuan Zuo, Rui Li, Fei Ma, Chenze Li, Liming Xia.Supervision: Jiangang Jiang, Chenze Li, Liming Xia, Hong Wang, Dao Wen Wang.Validation: Chenze Li, Hong Wang, Dao Wen Wang.Visualization: Fei Ma.Writing – original draft: Houjuan Zuo, Hong Wang.Writing – review & editing: Hong Wang, Dao Wen Wang.


P < 0.05). There was no significant difference in the results of left and right ventricle two-dimensional conventional echocardiography before chemotherapy and 2 or 4 cycles after chemotherapy (P > 0.05). There were significant differences in the levels of RVGCS, RVGLS, RVGRS, LVGLS, and LVGRS before and after chemotherapy (P < 0.05). Specifically, RVGCS: after 6 cycles of chemotherapy < after 4 cycles of chemotherapy < before chemotherapy; RVGLS: after 6 cycles of chemotherapy < after 4 cycles of chemotherapy < after 2 cycles of chemotherapy < before chemotherapy; RVGRS: after 6 cycles of chemotherapy < after 4 cycles of chemotherapy < before chemotherapy; LVGLS: after 6 cycles of chemotherapy < after 4 cycles of chemotherapy < before chemotherapy; and LVGRS: after 6 cycles of chemotherapy < before chemotherapy. The results of Pearson correlation analysis showed that the dose of doxorubicin was negatively correlated with RVGCS, RVGLS, RVGRS, and LVGLS, but not with TAPSE, RVFAC, LVEF, and LVGRS. 3D-STI is helpful for early detection of the changes of left and right ventricular myocardial function after PAD chemotherapy in patients with multiple myeloma. And the early screening value of the RVGLS parameter is higher.In this manuscript, we have evaluated numerous changes of cardiac function in patients with multiple myeloma before and after PAD chemotherapy with 3D speck tracking imaging (3D-STI). For this purpose, 39 patients with multiple myeloma, from July 2019 to December 2020, who received the PAD regimen  were selected as subjects. A comparison of two-dimensional conventional echocardiographic parameters before and after chemotherapy and 3D-STI related parameters was carried out. After 6 cycles of chemotherapy, the levels of TAPSE, RVFAC, and LVEF were significantly lower than those before chemotherapy ( Multiple myeloma, also known as plasma cell myeloma or plasmacytoma, is a malignant tumor characterized by the abnormal proliferation of bone marrow plasma cells. It is a subtype of B-cell lymphoma. The PAD regimen (bortezomib + doxorubicin + dexamethasone) is commonly used in the treatment of refractory multiple myeloma. The results were satisfactory and this gradually became the standard chemotherapy regimen for newly diagnosed patients awaiting autologous stem cell transplantation. But doxorubicin in that protocol belongs to an anthracycline class. It has certain cardiotoxicity, leading to cardiac insufficiency and even heart failure, which limits its application. Therefore, how to detect cardiotoxicity early is the focus of various research –7. ColorP < 0.05). There was no significant difference in the results of left and right ventricle two-dimensional conventional echocardiography before chemotherapy and 2 or 4 cycles after chemotherapy (P > 0.05).In this paper, we have evaluated numerous changes of cardiac function in patients with multiple myeloma before and after PAD chemotherapy with 3D speck tracking imaging (3D-STI). For this purpose, 39 patients with multiple myeloma, from July 2019 to December 2020, who received the PAD regimen  were selected as subjects. A comparison of two-dimensional conventional echocardiographic parameters before and after chemotherapy and 3D-STI related parameters was carried out. After 6 cycles of chemotherapy, the levels of TAPSE, RVFAC, and LVEF were significantly lower than those before chemotherapy  ≥ 53%A total of 39 patients with multiple myeloma who received PAD chemotherapy in our hospital from July 2019 to December 2020 were selected as subjects. There were 18 males and 21 females (aged 17–21 years). The average is (52.63 ± 9.28) years. The inclusion criteria for the PE group were as follows:Complicated with coronary heart disease, congenital heart disease, rheumatic heart disease, valvular disease, severe arrhythmia, myocardial infarction, chronic obstructive pulmonary disease, pulmonary embolism, and other diseases affecting cardiac functionComplicated with severe chronic diseases such as hypertension and diabetesThe sound transmission window is poor, so it is difficult to obtain a satisfactory imageExclusion criteria were as follows:2/times, once a day. It was used on the 1st, 4th, 8th, and 11th days. Intravenous injection was performed within 3–5 seconds. Doxorubicin liposome was administered at 20 mg/m2 on day 1, intravenous drip, and dexamethasone was administered at 20 mg/times, once a day, for 1–2 days, 4 days, 5 days, 8 days, 9 days, 11 days, and 12 days. One course of treatment of the program is 12 days, and 6 courses are usually carried out if it can be tolerated. According to the dose of anthracycline doxorubicin liposomes (20 mg/m2), the increment of each cycle was calculated.All patients were treated with PAD chemotherapy. The specific scheme is as follows: bortezomib, 1.3 mg/mnd, 4th, and 6th cycles of chemotherapy. All parameters were measured continuously for 3 cardiac cycles, and their average values were taken. First of all, the left supine position was used. Conventional 2D echocardiography was performed via the chest with the M5S 2D probe. Simultaneous electrocardiogram was also performed. Tricuspid valve ring systolic displacement (TAPSE), right ventricular diameter (RVD), and right ventricular end systolic area (RVESA) and end diastolic area (RVEDA) were measured in the tricuspid valve ring on the standard apical four-chamber tangent plane. And the rate of change of right ventricular area (RVFAC), LVEF, left ventricular end systolic volume (LVESV) and end diastolic volume (LVEDV), and ventricular septal end diastolic thickness (IVSD) were measured on the long axial section of the left ventricle. Then, the three-dimensional full-volume image was collected, and the frame frequency of the image was adjusted. Full volume dynamic imaging of the left ventricle and right ventricle during 3 cardiac cycles was collected in multibeat mode. The images were then placed on the EchoPAC workstation for analysis. It can automatically judge ventricular systole and diastole according to an electrocardiogram. Trace echo of endocardium and epicardium was performed. Right ventricular global circumferential strain (RVGCS), right ventricular global longitudinal strain (RVGLS), and right ventricular global radial strain (RVGRS) were obtained. And LVGCS, LVGLS, LVGRS, and other 3D-STI related parameters were also obtained.A VividE9 echocardiogram produced by GE was used. The M5S 2Dprobe, the 4V 3D probe, and the EchoPAC workstation were included. The frequency and frame frequency wee 1.7–3.3 MHz and 25–40 frames per second, respectively. All patients were treated with PAD chemotherapy. Two-dimensional conventional echocardiography and 3D-STI image acquisition were performed after the 2x ± s). Then, the comparison between groups was performed by the LSD-T test. Pearson's correlation coefficient was used to analyze the correlation between the doxorubicin dose and each parameter (P < 0.05). The difference was statistically significant.The data were processed by SPSS23.0 software. The measurement data of this study have a normal distribution, which is expressed by the sample mean ± standard deviation (P < 0.05). There was no significant difference in the results of left and right ventricle two-dimensional conventional echocardiography before chemotherapy and 2 or 4 cycles after chemotherapy (P > 0.05) . Specifically, RVGCS: after 6 cycles of chemotherapy < after 4 cycles of chemotherapy < before chemotherapy; RVGLS: after 6 cycles of chemotherapy < after 4 cycles of chemotherapy < after 2 cycles of chemotherapy < before chemotherapy; RVGRS: after 6 cycles of chemotherapy < after 4 cycles of chemotherapy < before chemotherapy; LVGLS: after 6 cycles of chemotherapy < after 4 cycles of chemotherapy < before chemotherapy; and LVGRS: after 6 cycles of chemotherapy < before chemotherapy  but not with TAPSE, RVFAC, LVEF, and LVGRS (P > 0.05)  .Streptomyces posset. It is a double-edged sword with a strong antitumor effect. It has an ideal effect on various hematological malignancies (such as multiple myeloma and acute leukemia) and solid tumors  [Anthracycline is a class of commonly used chemotherapeutic drugs derived from  cancer) –22. It i3D-STI is a new ultrasonic imaging technology developed on the basis of speckle tracking imaging technology and three-dimensional imaging technology. It can not only realize three-dimensional full volume imaging but also make up for the deficiency of two-dimensional space observation and evaluation. It can also track the motion trajectory of myocardial “spots.” It can also track the motion trajectory of myocardial “spots” and reflect the motion state comprehensively and accurately, so as to quantitatively analyze the cardiac function, especially to show the early changes of exercise after myocardial ischemia . The motPatients with multiple myeloma who received at least 6 cycles of the PAD regimen were included in this study. The related parameters of two-dimensional conventional echocardiography and 3D-STI before and after chemotherapy were systematically observed. The results showed that TAPSE, RVFAC, and LVEF decreased significantly after 6 cycles of chemotherapy. However, there was no significant change in left and right ventricular parameters in 2 or 4 cycles after chemotherapy. It is suggested that anthracyclines have toxic effects on the function of both the left and right ventricles. However, it is difficult to detect the changes of cardiac function in the early stage after chemotherapy by two-dimensional conventional echocardiography. There is no significant change until the end of all six cycles of chemotherapy. Relatively speaking, the related parameters of 3D-STI changed significantly in the early stage after chemotherapy. RVGLS after 2 cycles of chemotherapy was significantly lower than that before chemotherapy. The RVGCS, RVGLS, RVGRS, and LVGLS after 4 cycles of chemotherapy were significantly lower than that before chemotherapy. The results of Pearson's correlation analysis also confirmed that doxorubicin dose had no significant correlation with the parameters of two-dimensional conventional echocardiography.Furthermore, there was a significant negative correlation among the RVGCS, RVGLS, RVGRS, and LVGLS. Among them, RVGLS has the strongest correlation. After 2 cycles of chemotherapy, it decreased significantly. Only LVGLS had a significant correlation with doxorubicin dose among left ventricular parameters. This may be due to the fact that the ejection of the left and right ventricles is mainly accomplished by the contraction of longitudinal myocardial fibers. The longitudinal strain capacity of the ventricle decreases at an early stage. It reflects the change of ventricular systolic function earlier. It is earlier than radial and circumferential deformation. Xu Yi et al. showed that 3D-STI could significantly reduce RVGLS, RVGRS, RVGCS, and other parameters in uremic peritoneal dialysis patients when the right ventricular ejection fraction was normal. RVGLS can be used as an important indicator of early improvement of right ventricular function . There aIn this manuscript, we have evaluated numerous changes of cardiac function in patients with multiple myeloma before and after PAD chemotherapy with 3D speck tracking imaging (3D-STI). For this purpose, 39 patients with multiple myeloma, from July 2019 to December 2020, who received the PAD regimen  were selected as subjects. A comparison of two-dimensional conventional echocardiographic parameters before and after chemotherapy and 3D-STI related parameters was carried out. 3D-STI is helpful for early detection of the changes of left and right ventricular myocardial function after PAD chemotherapy in patients with multiple myeloma. And the early screening value of RVGLS is higher. The results of Pearson's correlation analysis also confirmed that doxorubicin dose had no significant correlation with the parameters of two-dimensional conventional echocardiography. Furthermore, there was a significant negative correlation among RVGCS, RVGLS, RVGRS, and LVGLS. Among them, RVGLS has the strongest correlation. After 2 cycles of chemotherapy, it decreased significantly. Only LVGLS had a significant correlation with doxorubicin dose among left ventricular parameters.


The severity of myocardial infarction lies in its complications. Certainly, there was a significant decrease in their impact thanks to the improvement of medical care and advent of early reperfusion methods, but there is still a considerable rate of complications that pose diagnostic and therapeutic problems. Among them, there are left ventricular aneurysm and pseudoaneurysm. These two complications are relatively rare, their diagnosis and treatment are often difficult. We have attempted to review the existing literature and discuss the characteristic findings of each entity. •Aneurysm and pseudoaneurysm of the left ventricle are relatively rare, their diagnosis and treatment are often difficult.•We have attempted to review the existing literature and discuss the characteristic findings of each entity.•Despite the evolution of medical imaging, differentiation between these two pathologies remains difficult. ACSAcute coronary syndromeACE inhibitorAngiotensin-converting–enzyme inhibitorARBsAngiotensin II receptor antagonistsCTcomputed tomographyLADLeft anterior descending arteryLVLeft ventricularLVALeft ventricular aneurysmMRIMagnetic resonance imagingMIMyocardial infarctionNSAIDsNonsteroidal anti-inflammatory drugSTEMIST-segment elevation myocardial infarctionTTETransthoracic echocardiogram1With the development of interventional cardiology, the occurrence of post-infarction ventricular aneurysms and pseudo-aneurysms has become rare. These complications must, however, be well known to the clinician, in particular because of their different evolutions see .Table 1C2This review article is based on a literature search over a period of 3 months, using Google Scholar, PubMed, ScienceDirect, and Springer Link as search engines. We combined the terms aneurysm, pseudo-aneurysm, left ventricle, myocardial infarction, as either keywords or MeSH terms. The search was limited to English and French articles. The retrieved articles were reviewed for potentially relevant studies and reviews.3The left ventricular aneurysm (LVA) corresponds to a scar area in the form of a thin-pocket shape communicating with the rest of the LV by a wide necked losing its contractile function due to transmural necrosis. It is about a change in the shape of the necrotic wall and not of the extension of myocardial infarction (MI). Its incidence has clearly decreased after the advent of coronary reperfusion; it went from 38% to 15% even 8% of MI .Left ventricular aneurysm most commonly results from acute myocardial infarction (MI). Other causes of LVA include Chagas’ disease, cardiac sarcoidosis, and presence of Lewitic gummas in the myocardium. Midventricular hypertrophy and obstruction have been associated with apical infarction and LVA . Aneurys3.1True left ventricular aneurysm (LVA) probably occurs when the intraventricular pressure causes stretching of the infarcted, non-contractile, myocardial zone, which leads to the expansion of this relatively fragile zone, and thus the necrotic tissue swells out with each cardiac contraction . Over ti3.2LVA is often asymptomatic, and may be revealed either due to a complication or during a systematic transthoracic echocardiogram (TTE). Mitral regurgitation murmur, signs of left or right heart failure of and double auscultation area at the apex can be noted on the physical exam. The most suggestive electrical sign of LVA is the persistence of the elevated ST segment for more than 3 weeks after an acute myocardial infarction, which is stable in all records with necrosis Q waves in the same territory and T waves, whose amplitude are relatively weak in comparison with EGG complex, during acute myocardial infarction. The amplitude and the extent of the elevation do not correlate with the size of the aneurysm .Chest X-ray may show a cardiomegaly, aneurysmal deformation of left–side arch of the heart, sometimes calcified aneurysm indicating its age.Trans-thoracic echocardiography has a high diagnostic performance in left ventricular aneurysm, with sensitivity and specificity exceeding 90% .Fig..Fig.6].FIn certain circumstances, where the diagnosis is difficult, cardiac MRI may show the presence or not of the myocardium in the aneurysmal wall, the thing that will make the difference between the LV aneurysm and the LV pseudo-aneurysm.4.3Although some authors report series of non-operated patients with satisfactory survival rates ,26. Surg5Left ventricular aneurysm and pseudoaneurysm are a mechanical complications of MI that pose a problem of management. The surgical indication is difficult to carry and the operative result is not always brilliant. Prevention of remodeling is currently significantly improved by early revascularization techniques for myocardial infarction, as well as early prescription of ARBs, ACE inhibitors and anti-aldosterones.Not commissioned, externally peer reviewed.All the authors have no conflict of interest neither financial nor ethical.We have no funding for this work.A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.A copy of the written consent is available for review by the Editor-in-Chief of this journal on request”.Dr. IJ analysed and performed the literature research; Dr. EJ performed the examination and performed the scientific validation of the manuscript. Dr. El ouazzani Jamal was the major contributors to the writing of the manuscript. All authors read and approved the manuscript.1.Name of the registry:2.Unique Identifying number or registration ID:3.Hyperlink to your specific registration (must be publicly accessible and will be checked):Dr. El ouazzani Jamal.


Background: Diastolic function in patients with heart failure is usually impaired, resulting in increased left ventricular (LV) filling pressures, whose gold standard assessment is right heart catheterization (RHC). Hemodynamic force (HDF) analysis is a novel echocardiographic tool, providing an original approach to cardiac function assessment through the speckle-tracking technology. The aim of our study was to evaluate the use of HDFs, both alone and included in a new predictive model, as a potential novel diagnostic tool of the diastolic function.Methods: HDF analysis was retrospectively performed in 67 patients enrolled in the “Right1 study.” All patients underwent RHC and echocardiography up to 2 h apart. Increased LV filling pressure (ILFP) was defined as pulmonary capillary wedge pressure (PCWP) ≥ 15 mmHg.Results: Out of 67 patients, 33 (49.2%) showed ILFP at RHC. Diastolic longitudinal force (DLF), the mean amplitude of longitudinal forces during diastole, was associated with the presence of ILFP . The PCWP prediction score we built including DLF, ejection fraction, left atrial enlargement, and e' septal showed an AUC of 0.83 [0.76–0.89], with an optimal internal validation. When applied to our population, the score showed a sensitivity of 72.7% and a specificity of 85.3%, which became 66.7 and 94.4%, respectively, when applied to patients classified with “indeterminate diastolic function” according to the current recommendations.Conclusion: HDF analysis could be an additional useful tool in diastolic function assessment. A scoring system including HDFs might improve echocardiographic accuracy in estimating LV filling pressures. Further carefully designed studies could be useful to clarify the additional value of this new technology. Risk variation of presenting increased left ventricular filling pressure (upper graph) and PCWP variation (lower graph), according to the proposed scoring system. EF, ejection fraction; DLF, diastolic longitudinal force; LAe, left atrial enlargement; ILFP, increased left ventricular filling pressure; NLFP, normal left ventricular filling pressure; PCWP, postcapillary wedge pressure. Heart failure involves up to 10% of the population over 75 years old; 33% of males and 28% of females aged more than 55 will present at least one episode of heart failure in their life, making heart failure one of the main causes of hospitalization in subjects over 65 years old  in PCWP estimation , becominRecently, many studies have introduced ventricular blood flow analysis as an innovative method to assess cardiac function –13. BlooTo date, echocardiographic flow analysis has always been studied in relation to the systolic pattern of the cardiac cycle, particularly in patients with dilated cardiomyopathy. Hemodynamic forces (HDFs) were able to properly predict the response to cardiac resynchronization therapy , 11, whiThe aim of this retrospective pilot study was to evaluate, in a population of patients who underwent RHC, the HDF analysis as a potential novel diagnostic tool of diastolic dysfunction, both as a single entity and included within a new predictive model, considering other conventional echocardiographic parameters.The Right1 Study was a prospective study, whose enrollment took place between July 2011 and November 2013, involving patients referred to the Division of Cardiology of the University of Turin with a specialistic indication for RHC , mainly In the present study, we retrospectively analyzed clinical and instrumental data of the patients enrolled in the Right1 Study, excluding those with atrial fibrillation or pacing devices. Adequate echocardiographic windows were required to be analyzed by a dedicated software: visualization of endocardial borders throughout the whole cardiac cycle and proper image contrast between endocardial borders and blood.The Right1 Study was approved by our local ethic committee , and all patients provided written informed consent before enrollment, even authorizing the retrospective use of the records for scientific purposes.RHC was performed through femoral or jugular access. Pulmonary capillary wedge pressure (PCWP) was acquired with the zero-reference level always set at the midthoracic level. All measurements were made at end expiration. Hemodynamic values were interpreted according to an international consensus . PhysiciTransthoracic echocardiography was performed before RHC, within 2 h of the examination, by an experienced operator, with a commercially available machine  equipped with a S5 probe for two-dimensional and Doppler acquisition. All echocardiographic measurements were performed following the current international recommendations, while the patient was in left lateral decubitus .2 in women or > 115 g/m2 in men  and lateral TDI-E-wave  were considered pathological when <7 cm/s and <10 cm/s, respectively, transmitral PW-E-wave/mean TDI-E-wave (E/A) when >14, and maximum tricuspid regurgitation velocity (TRv) when >2.8 m/s.Left ventricular hypertrophy (LVH) was defined as a left ventricular mass (LVM) normalized for BSA (LVMi) > 95 g/m2 in men . Accordi2 in men , PCWP waBSA was calculated using the Dubois and Dubois formula :VLV HDFs were obtained by off-line analysis of echocardiographic DICOM files with a dedicated software . Speckle-tracking analysis of LV was performed in the three routinely acquired apical scans: four-chamber, two-chamber, and three-chamber views. HDFs can be detected through endocardial velocities, LV geometry, and aortic and mitral orifices areas, obtained after measuring the internal diameter of the valve anulus in parasternal long axis-view , 22. In SLV surrounding of the same volume .or the integral on the surface SLV are given directly from speckle tracking. The average velocity of blood on the open part of the boundary SLV  is estimated by mass conservation . The longitudinal component of the HDF is then taken as the component of the vector that is parallel to the direction of the LV axis. In order to make patients with different LV sizes comparable, the instantaneous value of HDFs has been normalized by the corresponding value of LV volume. It was then divided by blood density and gravity acceleration, obtaining a dimensionless value that corresponded to the force expressed as a percentage of gravity acceleration . The normal distribution of variables was verified by graphical evaluation (histogram and Q-Q graph) and Shapiro–Wilk test. Data were presented as “mean ± standard deviation” or “median [interquartile range]” and as “observations (percentage frequency)” as appropriate. Differences between groups were analyzed by ed model  to the ued model . The added model .p < 0.05 for two-tailed tests was considered significant in all statistical analysis.A Out of 190 enrolled patients, 148 met inclusion criteria. Among these, 81 patients were excluded . Thus, the study population was composed of 67 patients, whose demographic and echocardiographic features are resumed in p < 0.001) and lower LAe rate (p = 0.010) than the ILFP one, while no differences were observed concerning LVMI and LVH . EF and GLS were higher in NLFP, compared to ILFP . Among left ventricular diastolic disfunction (LVDD) parameters, E/A, E/e' average, and e' septal differed between NLFP and ILFP , while e' lateral and tricuspidal regurgitation velocity (TRv) did not . No gender-based differences were detected in the considered parameters.Thirty-four patients showed normal left ventricular filling pressure  and 33 patients showed increased left ventricular filling pressure . No demographic features differed between the NLFP and ILFP group. NLFP group had lower LAVi (p = 0.865), 20 patients as “increased filling pressure” , and 24 as “indeterminate filling pressure” .According to current recommendation , 23 patip = 0.034), and at univariate regression analysis, it showed to be a possible predictor of PCWP class  and GLS . Weaker correlations were also present with age , E/e' average , and e' septal , while DLF did not become significantly associated to LVMi, LAVi, and TRv .As previously illustrated, 33 subjects (among 67 studied) presented ILFP. Univariate logistic regression analysis for prediction of ILFP is displayed in We performed variable selection by penalized regression  in orderp < 0.001). When DLF was not included within the scoring system, its sensitivity became 78.8% and specificity became 76.5%, for an overall AUC of 81% (p < 0.001). The developed score including DLF showed a positive predictive value of 82.8% and a negative predictive value of 76.3% in the study population, considering an ILFP prevalence of 49.3%  as NLFP, while scoring values ≥ 3 correctly classified four out of six patients (66.7%) as ILFP .p = 1.000) but a fairer sensitivity , although not statistically significant. Even NRI improved , although statistical significance was not reached.On the other hand, among patients who were not classified as “indeterminate,” our scoring system showed similar specificity to current recommendation  patients classified as “indeterminate filling pressure” by the current echocardiographic recommendation.In the study population, morphometric characteristics were similar between NLFP and ILFP, reducing the related confounding risk in subsequent analyses. None of these variables were a plausible determinant of PCWP class.Our study is a further confirmation of the well-known echocardiographic parameters associated with the diastolic function  included in the diagnostic flowchart suggested by the current guidelines . HoweverPrevious studies tried to develop simple methods, such as scores –28 and sSpeckle-tracking analysis, particularly atrial strain, has already been applied to study the diastolic function. Left atrial strain has proven to be the most sensitive parameter in detecting diastolic dysfunction at an earlier stage, before it is evident through standard echocardiographic parameters . These dIn a study aimed at assessing functional echocardiographic changes in patients with CRT , HDFs weAmong all measurable HDFs, we focused on DLF, which is closely related to the diastolic phase of the cardiac cycle, and for the first time, we proposed DLF as an index of the average force that is swapped along the longitudinal axis (apex to base) during diastole.p = 0.737). This finding seems to be in contrast with previous studies, describing E/e' average as a strong variable to distinguish precapillary from postcapillary pulmonary hypertension . Although statistical significance is not reached, we believe that these data are promising. Surely, in a larger population, the possibility to perform subgroup analyses and the stratification for systolic function would be required for a rigorous comparative approach.The developed score showed an optimal internal validation. Using two scoring points as diagnostic threshold to identify patients with a positive test, the predictive model reached high specificity (85.3%) and positive predictive value (82.8%) in detecting ILFP. The accuracy of the scoring system including HDF became higher by a few percentage points than the scoring system without DLF , but also to its punctual value, as a severity index.No clinical features  were included in the present study for score development. These elements are mandatory in the heart failure diagnosis  and cannThe present study is a retrospective study performed on patients who underwent RHC and echocardiography. The presented data are potentially very innovative, but the methodology of the study is exposed to some limitations.First, the HDF analysis requires ultrasound images of discrete quality and a good ECG gating in order to perform a reliable speckle-tracking analysis. Since Right1 Study was not designed for this kind of investigation, the image quality was not always optimal for HDF assessment; a prospective analysis following good standards of speckle-tracking image acquisition  can certSecond, the actual knowledge and availability of HDFs prevent them from being applied in clinical practice, but our preliminary results bode well for future appropriately designed studies.Third, a proper assessment of the HDF added value would require a larger study population, with subgroup analysis according to normal or reduced systolic function, even giving importance to the intra- and inter-operators' variability.Moreover, since the scoring system has been obtained from a highly selected cohort of patients, its accuracy should be confirmed using an independent and prospectively acquired population. However, the good internal validation of the model seems to be promising. Finally, ILFP was defined on the basis of PCWP, as recommended , but LV HDFs might be a novel echocardiographic parameter for the evaluation of diastolic function. DLF showed a great association with increased LV filling pressure. A new scoring system including DLF and other well-known echocardiographic variables showed a good accuracy in predicting PCWP class, both in the whole population and in patients classified as “indeterminate filling pressure” by the current recommendation. HDF analysis is a promising and still poorly explored domain of echocardiography. Further studies are needed in order to sharpen our knowledge on HDFs, allowing the evaluation of cardiac function from a new perspective.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Comitato Etico Interaziendale A.O.U. Città della Salute e della Scienza di Torino – A.O. Ordine Mauriziano. The patients/participants provided their written informed consent to participate in this study.LA, FVa, FVe, and AM contributed to conception and design of the study. EA, AI, and CMa organized the database and performed echocardiography. PO and CMo performed right heart catheterization. LA, FVa, TF, and CG performed the statistical analysis. LA wrote the first draft of the manuscript. FVe, AA, GM, TF, and MC wrote sections of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. 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