Autoimmune diseases (ADs) encompass multisystem disorders, and cardiovascular involvement is a well-known feature of autoimmune and inflammatory rheumatic conditions. Unfortunately, subclinical and early cardiovascular involvement remains clinically silent and often undetected, despite its well-documented impact on patient management and prognostication with an even more significant effect on severe and future MACE events as the disease progresses. Cardiac magnetic resonance imaging (MRI), today, commands a unique position of supremacy versus its competition in cardiac assessment and is the gold standard for the non-invasive evaluation of cardiac function, structure, morphology, tissue characterization, and flow with the capability of evaluating biventricular function; myocardium for edema, ischemia, fibrosis, infarction; valves for thickening, large masses; pericardial inflammation, pericardial effusions, and tamponade; cardiac cavities for thrombosis; conduction related abnormalities and features of microvascular and large vessel involvement. As precise and early detection of cardiovascular involvement plays a critical role in improving the outcome of rheumatic and autoimmune conditions, our review aims to highlight the evolving role of CMR in systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS), rheumatoid arthritis (RA), systemic sclerosis (SSc), limited sclerosis (LSc), adult-onset Still's disease (AOSD), polymyositis (PM), dermatomyositis (DM), eosinophilic granulomatosis with polyangiitis (EGPA) (formerly Churg-Strauss syndrome), and DRESS syndrome (DS). It draws attention to the need for concerted, systematic global interdisciplinary research to improve future outcomes in autoimmune-related rheumatic conditions with multiorgan, multisystem, and cardiovascular involvement. Rheumatologists know cardiac involvement among diseases within the spectrum of autoimmunities, such as systemic lupus erythematosus (SLE) or antiphospholipid syndrome (APS). However, other less frequent conditions seen in their daily practice may impact the heart, which is rarely recognized during the subclinical period.Autoimmune disease (AD) comprises a broad spectrum that affects many levels and structures of the cardiovascular (CV) system. However, some of them, such as the different vasculitides and the spondyloarthropathies, are too extensive to be part of a generic revision since each could be a complete chapter. Therefore, to decide what diseases are included in this review, we conducted a literature search, as shown in the following algorithm that describes the broad spectrum of this group of pathologies beyond the scope of this review.Different non-invasive CV imaging modalities play an essential role in diagnosing the involvement of the heart in these diseases; however, their diagnostic accuracy varies depending on their pretest probability, the type and severity of involvement, and the local expertise. Therefore, such involvement is not always detected during their early phases . CardiovThis non-invasive imaging modality is considered the gold standard for many quantitative measurements of cardiovascular disease. Moreover, extensive scientific evidence supports a useful diagnostic tool for different pathologies such as ischemic cardiomyopathy (ischemia and viability), diverse non-ischemic cardiomyopathies, myocarditis, right ventricular disease, and congenital heart disease . Up to dUnfortunately, nowadays, many referring physicians have little or no training in this technique, provoking an unintended lack of knowledge of CMR general principles, terminology , and cliThe SCMR recognizes that several reasons exist for this problem which increases the complexity of selecting appropriate testing for a given clinical situation, such as the complex underlying physics and terminology that are not intuitively understood by the referring physician or non-CMR-expert, along with multiple and even vendor-specific terms uses for the same technique. To help the referring physicians and the non-CMR-expert users, a simplified CMR terminology was officially launched in 2014 by the Society to be used in clinically oriented publications to improve the acceptance and widespread use of CMR in clinical routine  are “black-blood CMR” used to study cardiac structure and morphology; by adding a specific fat saturation, the technique is possible to obtain an “edema CMR” image that is extremely useful to determine the presence and location of water (edema) within the myocardium and to delineate the pericardium in cases where it is thicker than normal. If using a specific type of black-blood CMR sequence is also possible to obtain the “iron CMR,” which allows for identifying and quantifying the iron in the heart. For functional analysis, such as all echocardiographic measurements and projections, CMR has the sequences generally called “cine CMR,” which are high-resolution electrophysiology (ECG) gated images with high endocardial border definition, allowing the analysis of cardiac function during the cardiac cycle. These cine sequences are the gold standard for analyzing left and right ventricular functions for which other imaging modalities are compared and validated , 30. To With the administration of intravenous contrast media, which is a paramagnetic agent (gadolinium), currently approved to be used even in patients with renal dysfunction without the risk of systemic nephrogenic fibrosis development , it is pSince up-to-date CMR is not included in the Clinical Guidelines for evaluating ADs with CV involvement, the following case description will serve as the preamble for the rest of the manuscript.A young woman, 34 years old, was recently diagnosed with RA and suddenly started with signs and symptoms of heart failure (HF), which was reviewed by her Rheumatologist, who considered that she would need to see a Cardiologist. During her consultation with an expert cardiologist, she was diagnosed using ECG, laboratory tests, and Echo as having mild left ventricular dysfunction with moderate pericardial effusion with no constrictive physiology; and she was started on proper maximum medical treatment for this condition. However, after two weeks of no improvement and being re-evaluated by her Rheumatologist, she was asked to take a second cardiology opinion with a cardiologist expert in ADs and advanced cardiovascular imaging. After being evaluated by the second cardiologist and using only the same information she had for her first cardiologist, she was recommended for an oriented autoimmune cardiac MRI protocol, where she was identified as having a normal left ventricular function, moderate pericardial effusion, unresponsive to the standard treatment and additional three key findings, the presence of amyloidosis probable secondary and related to the RA, an inflammatory component of the pericardial disease and the involvement of valvular and vascular structures. As a result, her Rheumatologist modified the medical treatment to a more aggressive immunomodulatory agent with an excellent immediate response .This case nicely illustrates and explains the motivation of the title and the purpose of this manuscript to review the pathophysiology of cardiac involvement and the cardiovascular magnetic resonance (CMR) findings of ADs.There are many different diseases in the field of Rheumatology, including those considered systemic or localized with autoantibodies, those secondary to hypersensitivity, and others with unknown etiology with or without autoantibodies that involve spondyloarthropathies and vasculitides  those ofBased on the literature research and the algorithm, we decided to include in this review the diseases that are of autoimmune origin with systemic presentation and known CV involvement and high prevalence, such as systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS), rheumatoid arthritis (RA), systemic sclerosis (SSc), polymyositis (PM), dermatomyositis (DM); one disease from the group of spondyloarthropathies, the adult-onset Still's a disease (AOSD), one disease from the group of vasculitides, the eosinophilic granulomatosis with polyangiitis (EGPA) (formerly Churg-Strauss syndrome), and finally, one rare condition secondary to hypersensitivity, the DRESS syndrome (DS) as an example of the complexity of the field, the high risk of cardiovascular involvement in specific clinical presentations that are not routinely recognized as autoimmune that could be even underdiagnosed and reported.Spondyloarthropathies and vasculitides  are too We theorize the potential role of CMR in the screening, diagnosis, prognosis, management guidance, and follow-up of response to treatment supported by current scientific evidence.Since 1924, when Libman and Sacks first published the association of aseptic vegetations and SLE , we haveRecently, the 2019 update of the EULAR recommendations  for the The most common CV manifestation is pericarditis presenting with pericardial effusion, which can occur in 11–54% of cases  during tValvular heart disease in SLE involves more than Libman-Sacks endocarditis . Valve tSpecific manifestations can cause HF in SLE, which has been reported with a prevalence of 1–10% in SLE , 50. MI Regarding the pathophysiology of CV manifestations in SLE, there is a role of immune complexes in CV manifestations of SLE. In pericarditis, for example, granular depositions of immunoglobulins and C3 complement have been found in pericardial tissue, and neutrophil predominance in pericardial fluid exudate, ANA , and othEven though autoimmunity is the hallmark of the disease, and immune complexes are presumed to be related to the CV manifestations of SLE, the exact pathophysiology behind them is still only somewhat understood .Endothelial dysfunction  is accepin situ coronary thrombosis when there is an association with aPL  classification criteria to define the disease . Serositn = 13) had abnormal CMR; the main findings were the presence of LGE . The of LGE –64. See Antiphospholipid antibody syndrome is characterized by thrombotic events, pregnancy-related comorbidities, or a series of non-thrombotic symptoms. Thrombotic events are arterial, venous, and/or in the microvasculature. This syndrome could affect the brain, lungs, extremities, and the heart. It is called a catastrophic antiphospholipid syndrome, which involves multiple organs . An obstThe antiphospholipid antibodies bind the beta-2-glycoprotein I, which is strongly linked to lipid surfaces and favors prothrombotic states by increasing cell adhesion of the E-selectin and tissue factor. It reduces the activity of the C-reactive protein, and the complement is activated. At platelets favors the expression of glycoprotein IIb/IIIa and the activation of neutrophils by generating NETosis and increasing the production of IL-8. Monocytes express higher levels of tissue factor. Recently, increased stimulation of the intracellular mTOR pathway involved in microvascular damage has been described .The pathophysiological abnormalities in APS include vascular thrombosis of large and/or small venous and arterial systems . The carIt is well described that APS affects the heart valves in approximately 30% of the patients . RecentlThe typical functional abnormality is non-hemodynamically significant mitral and aortic regurgitation, the most frequently affected mitral valve. This valvular involvement is reported as persistent or even progressive over time regardless of the anticoagulant or antiplatelet therapy. Clinically, most patients remain asymptomatic for a long time, but eventually, they will require surgical treatment .Intracardiac thrombosis is rarely reported ; it prodMany patients without the full criteria for APS or SLE have a stroke or this finding as to the initial manifestation, and since the initial diagnostic workup often does not include CMR; these patients end up at surgery without proper diagnosis and anticoagulation therapy until the histopathological result confirms the presence of thrombotic material suggesting the diagnosis –76. AddiPH is a rare but life-threatening condition in APS with or without SLE . The defRight ventricular (RV) subclinical dysfunction is more prevalent in APS with or without SLE, and it negatively correlates with the serum levels of anticardiolipin antibodies (ACA) . The sugLV dysfunction is a rare presentation , 85 and It is infrequent that APS patients develop dilated cardiomyopathy . HoweverIschemic heart disease is generally caused by microvascular endothelial dysfunction  with or Myocardial infarction (MI) is due to thrombosis or vasospasm  of the lCMR has identified a high prevalence of myocardial scar , diffuseAs mentioned before, APS can have many cardiovascular manifestations. Therefore, the “APS Task Force” has taken valvular heart disease related to APS as one of the “extra criteria” for its diagnosis . Even th3 of tissue.Sacré et al. evaluated 27 consecutive patients with established diagnosis of APS matched with 81 patients without known cardiovascular disease and who developed CMR. LGE was present in 29.6% of APS patients, with a typical ischemic pattern in 11.1%. Remarkably, myocardial scarring had no electrocardiographic nor Echo evidence. Authors concluded that CMR helps search for myocardial ischemia and myocardial fibrosis in APS patients even if they are asymptomatic  as CMR cIn patients with different comorbidities and the coexistence of more than one AD, CMR can help to differentiate by dissecting the components and timing of each one, orienting major procedures such as surgical valve replacements in high-risk patients with specific strategies to lower their risk as much as possible .Since VHD is the most frequent CV manifestation in APS but also myocardial fibrosis, silent ischemia, potential HF, and the presence of thrombus in different sizes might be present , CMR migEcho helps detect many of the CV involvement in APS. It has many advantages, such as broad availability and the possibility of performing the study on the patient's bed and in hemodynamically unstable ones. As a single modality, it is cheaper. However, it cannot detect the earliest involvement related to tissue characterization such as minor myocardial edema, inflammation, or diffuse fibrosis before it can modify global function or even more sensitive techniques such as strain. CMR can identify in a single study the involvement of different components of the CV system, including great vessels, lungs (where are grossly affected by its vasculature), and stress perfusion with high reproducibility allowing the patient to be its control in the future. It would be necessary to gather information from different imaging modalities such as echo, CT, nuclear, etc., impacting more tests, radiation exposure, and costs .See RA is a chronic autoimmune inflammatory arthritis that affects the joints and other systems, including the heart and CV system, even associated with the early development of atherosclerosis , 103 andTherefore, many efforts to identify patients at risk of CVD have been made through different approaches. It has been demonstrated that patients have hidden or incipient damage during the AD diagnosis . PatientAnimal model studies have investigated the correlation between the clinical phenotypes of RA and the inflammatory state to correlate the inflammatory activity with the biomarkers and findings in non-invasive imaging modalities , which hIt is common to find the association with other comorbidities that makes it challenging to identify the specific cause of damage to the CV system, increasing its risk . Common Cardiac involvement in RA includes VHD in 9% of cases . The mosThe incidence of congestive HF is approximately 2-fold higher than the general population .The pathophysiological mechanisms are related to myocardial inflammation , vasculaRA patients are at increased risk for developing PH and right HF. The underlying mechanisms are interstitial lung disease, vasculitis, and chronic thromboembolic disease .There are robust biomarkers for prognosis and therapeutics based on specific CMR findings . It is eIt has been proven that laboratory tests and specific inflammation imaging markers can predict the incidence of CV events , 148–153CMR can identify the indirect signs of PH in the same comprehensive study done to analyze the rest of the cardiac involvement of this disease , constitInterestingly, like in those patients with cardiac sarcoid, in some cases of RA, it is possible to visualize mediastinal extracardiac tissue .See SSc is a connective tissue disease classified based on skin involvement into two forms: diffuse cutaneous systemic sclerosis (DcSSc) and a focal, called limited cutaneous systemic sclerosis (LcSSc), previously known as CREST syndrome . LcSSc aCardiac involvement is reported high in histopathological reports as in CMR studies, reaching 75–80% of patients with this disease . The carThe pathophysiological mechanisms affect mainly the lungs with vascular damage, autoimmunity, loss of pulmonary microvasculature , and tisIt has been reported that the positivity of Anti-topoisomerase I autoantibodies is associated with cardiac involvement . The cliCMR evaluation of these patients allows for assessing the right-sided heart. It shows that, even in the absence of PH, there are hemodynamic abnormalities manifested as right atria and ventricle enlargement, which increases progressively along with the vascular resistance and the pulmonary artery systolic pressure (PASP) with the establishment of PH and finally with RV dysfunction in 5–10% of cases , 169. CMInterestingly, even with the detection of myocardial edema , focal aT1 mapping and ECV values are significantly higher in patients with SSc than in healthy controls . In addiThe UK Systemic Sclerosis Study Group proposed a comprehensive algorithm that classifies patients as asymptomatic, at-risk, and symptomatic for cardiac complications, including the standard assessment including patient history, blood pressure, lipid profile, and HbA1c, ECG, Echo, a core set of parameters to be measured at each Echo and laboratory parameters; the follow-up intervals are determined by the risk categorization. In this context, CMR is recommended in a more individualized analysis, depending on the clinical manifestation of each patient independent of their risk categorization in the algorithm . See TabAOSD is a non-hereditary, non-organ specific, polygenic autoinflammatory disease that affects young adults in a bimodal distribution with an average age of 15–25 and 36–46 years old and an incidence of 0.16–0.4/100,000 individuals . Its patBased on the Yamaguchi diagnostic criteria, the main clinical manifestations are the presence of febrile peaks, non-pruritic erythema, arthritis, polyserositis, odynophagia, lymphadenopathy, and hepatosplenomegaly. Associated with elevated serum biomarkers such as leukocytes, globular sedimentation rate, and ferritin .It affects the CV system within the spectrum of systemic alterations . This diCommon clinical CV manifestations are chest pain, dyspnea, tachycardia, atrial gallop, pericardial rub, and pulmonary congestion; physical examination data, all manifestations according to LV systolic dysfunction and the progression to HF even to cardiogenic shock. The development of cardiogenic shock is considered the second cause of mortality in these patients, accounting for 4.2% in the acute event and up to 21% in 1 year , 184. InIt is not surprising that the presence of myocarditis, which is often symptomatic in 96% of cases, with electrocardiogram abnormalities mentioned above and LV dysfunction with reduced LVEF <50% in 67% of cases ; can manThe presence of pericarditis is reported more often and usually correlates with white blood cell count, polymorphonuclear cell count, and higher serum ferritin levels .The pathogenic mechanism was hypothesized that cardiac involvement is secondary to excessive immune activation and, therefore, to the previously mentioned cytokine storm, which contributes to a partial response to the standard medical treatment , 184.As mentioned above, in the early stages of the disease, the myocardial and serosal involvement could course asymptomatic, leading to a misdiagnosed entity. Despite high-level serum inflammatory biomarkers or unspecific ECG changes, it is only suspected when there is clinical evidence of HF. Therefore, the evaluation of CMR with T1-weighted, T2-weighted, and post-gadolinium enhancement allows in a non-invasive manner with good sensitivity and specificity the early detection of cardiac involvement, tissue characterization, and left ventricle function, helping in the prompt initiation of steroids, biotherapies or neurohumoral blockage in cases of systolic dysfunction since it increases morbidity and could be potentially fatal.See An idiopathic inflammatory myopathy presents proximal, and symmetric muscle weakness due to inflammatory infiltrates in the skeletal muscle. In some cases, it has extraskeletal and muscular involvement in the skin, the lung, the joints, the heart, and distal arteries with Raynaud's phenomenon .It presents after the second decade of life and is more common between 45 and 60 years; females are mostly affected with a ratio of 2:1 .*03:01 and HLA-B*08:01 alleles of the ancestral haplotype 8.1 (8.1AH)  at chromosome 6, at the HLA-DRB1 (8.1AH) .The usual clinical presentation is symmetric proximal muscle weakness (in >90% of cases in PM and >50% in DM) with skin manifestations in DM. The onset of symptoms can be in days or more insidious, weeks or even months, with fever, malaise, weight loss, asthenia, and adynamic. Muscle atrophy is a late complication in advanced disease. In DM, the rash often precedes or accompanies muscle weakness. Cutaneous manifestations can be pathognomonic as (1) Gottron's papules, which involve extensor regions such as the knuckles, elbows, or knees, (2) heliotrope rash involving the periorbital region with or without edema, (3) erythematous rash on the chest, back in regions exposed to the sun, (4) facial erythema or a malar rash that does not spare the nasolabial fold, (5) periungual hyperkeratosis and telangiectasias, which represent rings of capillary dilation in the nail matrix, (6) dermal ulcers related to vasculopathy, (7) calcinosis of the subcutaneous tissue in the muscular fasciae, (8) lipodystrophy and hyperkeratosis with cracks in the palms , 191.Cardiac involvement in Polymyositis (PM) and dermatomyositis (DM) derives from exposure to an inflammatory process for a specific time, which causes structural and functional alterations of the heart. The affected cardiac structures are the valves, the conduction system, the myocardium, the endocardium, the pericardium, and the pulmonary and coronary arteries  Figure .Heart valves are affected due to the ongoing inflammatory process, causing leaflet thickening and dysfunction. Although rare, the aortic (46.7%) and the mitral (20%) valves are most frequently involved, often producing stenosis. Interestingly, mitral stenosis could be the primary manifestation in up to 6.7% of cases depicted by Echo studies .The histologic substrate is lymphocytic infiltration of the conduction system and the fibrosis of the sinoatrial node .Aside from the VHD previously described, it is common to identify conduction system disturbances at different levels, manifested with a diverse degree of severity and location of His bundle and its branches in 33–72% of cases  or arrhyIn PM, it is frequent to encounter the presence of LV hypertrophy easily assessed by Echo . InteresIn PM and DM, it is common to identify HF in a variable range from 32 to 77%, which could be diastolic or even severe systolic dysfunction . PatientMyocarditis has been described in up to 8% of cases . MyocardAs in other ADs, the association between PM/DM and aseptic endocarditis has been described. However, in this case, it is an infrequent entity with possibly catastrophic consequences if not diagnosed in time .Pericarditis is reported in 4–25% of adults with PM/DM, and most of them remain asymptomatic and hemodynamically insignificant . The excPH is a life-threatening entity that culminates in severe right ventricular dysfunction and HF. In PM patients with the antisynthetase syndrome, PH is present in 8% of cases, which are very ill .CMR shows LGE in the non-coronary territory consistent with non-ischemic cardiomyopathy, reported in 62.3% of cases consistent with myocarditis . CMR finThe presence of LGE in PM/DM has similar behavior to Duchenne muscular dystrophy , 207. ItChurg-Strauss syndrome, renamed eosinophilic granulomatosis with polyangiitis (EGPA), is a systemic vasculitis characterized by disseminated necrotizing vasculitis and extravascular granulomas . EGPA isHeart involvement has been described in 15–60% of cases, mainly in those antineutrophil cytoplasmic antibodies (ANCA) negative  and inclThe early diagnosis of cardiac involvement is crucial because the prognosis is poor once HF is established , even thMyocarditis in this syndrome is the most severe manifestation , 212. ItIts response to treatment is variable , 210 andIntracavitary thrombosis is attributed to the subendocardial eosinophilic infiltration in localized ventricular segments with impaired function  and its The involvement of the pericardium could be as inflammation with pericarditis or, more often, as the pericardial effusion of varying degrees of severity reported in 41% of the cases with cardiac involvement , 212. PeThe conduction disturbances are frequent with cardiac involvement; however, life-threatening arrhythmias are rare and often asymptomatic . CompletVHD is presented in as high as 73% of cases ; howeverLV dysfunction has been described in as high as 50% of the cases , 212. PaRV dysfunction accompanying LV dysfunction is prominent in EGPA, as demonstrated by Echo  and CMR.HF is uncommon –230 in aCoronary artery involvement in EGPA is often with arteritis  and rarein vitro)  , along wn vitro) .CMR allows functional analysis along with the pathophysiological assessment of the different components of the CV involvement described in detail in the above section by the detecting myocardial edema in the myocarditis, identifying and quantifying myocardial fibrosis, and the scars related to arteritis or coronary arteries occlusions .LGE in EGPA can be at mid-wall, epicardial, transmural, and often subendocardial locations , 248. ThDS is defined as Drug Reaction with Eosinophilia and Systemic Symptoms . DS is aCardiac involvement varies from 4 to 21%  and inclCMR has only being proposed as part of the diagnostic algorithm as in the EGPA  since thCardiovascular involvement is increasingly recognized and documented as an essential prognosticator for managing autoimmune and inflammatory rheumatic conditions; being recognized that cardiac involvement, a well-documented poor prognostic factor, is a leading cause of mortality. However, given that the condition remains clinically silent during the early stages of the disease process and often remains undetected by routine ECG, Echo, CT, and nuclear studies, increased awareness and a better understanding of the underlying multi-system pathophysiology mechanisms are imperative, with the incorporation of a robust diagnostic non-invasive modality to ensure screening, early detection, diagnosis, prognostication, guide management and follow-up of early cardiovascular involvement in patients with ADs.In a recent publication from Sacilotto et al. , they foPH is a common feature of almost all AD, at least in advanced stages; however, the early signs of the pulmonic vasculature involvement are often missed until the late stages, resulting in higher morbidity and mortality rates. In PH, the RV is a critical determinant of the clinical course and response to treatment of these kinds of patients. Early detection of RV dysfunction may offer a better response to therapeutic measurements. CMR allows analysis of function, morphology, and the interactive hemodynamics between PA and RV. Most cine-CMR-derived parameters (volumes and function) and flow-CMR measurements have been suggested as powerful markers for response to treatment and prognosis . Recent A recent meta-analysis of PH confirmed CMR as a powerful prognostic marker in PH, confirming that RV function and RV and LV volumes predict mortality and that RV volumes and function predict clinical worsening and poor response to medical treatment. Therefore, significant scientific evidence strongly supports the proposal of considering CMR as part of the diagnostic algorithm in AD .CMR promises the accuracy, precision, and reproducibility required in this group of patients because of its non-invasive, non-radiation linked assessment of myocardial tissue characterization by conventional and novel multiparametric methods, the gold standard in biventricular function and volumes assessment, and ability to assess microvascular dysfunction. CMR is also excellent in evaluating valves, thrombosis, and conduction-linked myocardial disorders, besides pericardial, vascular, and aortic involvements linked to ADs.Recent advances in CMR, including broad availability, less operator dependence, faster sequences, and cost-effectiveness , supportCardiac involvement in all mentioned ADs is there, waiting to be correctly and optimally discovered with current state-of-the-art imaging modalities. Using the proper imaging technique at the precise moment will translate into earlier and better diagnosis, adequate treatment, appropriate follow-up, and less long-term morbidity and mortality.Currently, it is in-press and European Association of Cardiovascular Imaging (EACVI) Position Paper, entitled Role of Cardiovascular Magnetic Resonance in Autoimmune Rheumatic Diseases, where Mavrogeni et al.  review tWell-designed multicenter trials to broadly confirm the findings, pathophysiological meaning, and prognostic information are needed to include CMR as part of the clinical routine in the future guidelines for the AD.LS-G, MB, AA-D, JM-S, CS, BS, EM, and MS-L outlined, drafted, and contributed to the writing of the manuscript. All authors approved the final version of the manuscript.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. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Congenital heart disease (CHD) is a major public health concern, as it is the most common birth defect and the leading cause of death in the first year of life if adequate surgical interventions were not provided. Unfortunately, in Lebanon, a country that has been assailed by devastating social and economic crises, many specialized Lebanese pediatric heart surgeons fled abroad to secure more stable careers. This has led to the death of many newborns with CHDs. Public health authorities must find urgent solutions for this national tragedy that is projected to last for years. Housing some of the most brilliant medical minds, Beirut has attracted international patients for the past several decades. However, nothing could have prepared Lebanon for its recent downfall. According to the World Bank, Lebanon’s economic crisis falls under the top three crises globally, since the nineteenth century, with an inflation rate of over 131.9% over the first 6 months of 2021 [Four pediatric cardiac surgery centers exist in Lebanon, including the American University of Beirut Medical Center, Hotel Dieu Hospital, Hammoud Hospital and Beirut Heart Center . HoweverMeanwhile, Congenital Heart Disease (CHD) is a major public health concern as it is the most common birth defect and the leading cause of death in the first year of life. One in every 100 babies is born with congenital heart defects . ConsequOn top of the existing shortage in pediatric cardiac surgeons, patients are limited by further obstacles. First, the economic decline in Lebanon produced shortages in a variety of medications, which is detrimental for both surgical and non-surgical candidates . In addith Beirut Port Explosion [The threats faced by our medical systems are only expected to amplify. A cross-sectional, multicentered study was conducted to assess physicians’, clinical fellows’, residents’, interns’, and medical students’ attitudes towards emigration . The stuxplosion .On the other hand, however, Lebanon has witnessed significant developments in pediatric cardiology over the past decade . After sImproving access to prenatal care to identify potential risk factors for CHD and ensure early diagnosis and treatment.Addressing risk factors such as maternal smoking, alcohol consumption, and certain infections during pregnancy.Immunization against certain infections such as rubella.Improving the maternal nutritional status during pregnancy.Promoting healthy lifestyles, such as regular exercise and a healthy diet.Increasing awareness of the risk factors and symptoms of CHD.Though philanthropic organizations exist both locally and internationally to provide aid to patients from impoverished areas, there still remains an overwhelming majority that are left to their own devices. Unfortunately, with so much going wrong in the country, this issue falls low on the government’s list of priorities. Nevertheless, Lebanon is in need for well-planned financial strategies combining philanthropic organizations, private university hospitals, and the public sector under a collective movement to allow pediatric cardiac programs to function without financial loss. In addition to implementing a strategic plan to improve the management of newborns with CHD, it is also important to apply preventive measures in order to decrease their incidence. This will be possible by:


This study aimed to determine whether lower values of feature-tracking cardiovascular magnetic resonance (CMR)-derived left atrial reservoir strain (LARS) and impaired left ventricular (LV) global longitudinal strain (GLS) were associated with the presence of symptoms and long-term prognosis in patients with SSc.A total of 100 patients {54 [interquartile range (IQR) 46–64] years, 42% male} with SSc who underwent CMR imaging at two tertiary referral centres were included. All patients underwent analysis of LARS and LV GLS using feature-tracking on CMR and were followed-up for the occurrence of all-cause mortality.P = 0.049] was independently associated with New York Heart Association (NYHA) class II–IV heart failure symptoms. Over a median follow-up of 37 (21–62) months, a total of 24 (24%) patients died. Univariable Cox regression analysis demonstrated that LARS [hazard ratio (HR) 0.94 per 1%, 95% CI 0.91, 0.97, P < 0.0001) and LV GLS  were associated with all-cause mortality, while LV ejection fraction was not. Likelihood ratio tests demonstrated that LARS provided incremental value over prognostically important clinical and imaging parameters, including late gadolinium enhancement.The median LV GLS was –21.8% and the median LARS was 36%. On multivariable logistic regression, LARS [odds ratio (OR) 0.964 per %, 95% CI 0.929, 0.998, In patients with SSc, LARS was independently associated with the presence of NYHA class II–IV heart failure symptoms. Although both LARS and LV GLS were associated with all-cause mortality, only LARS provided incremental value over all evaluated variables known to be prognostically important in patients with SSc.  Rheumatology key messagesFeature-tracking CMR-derived left atrial reservoir strain was independently associated with NYHA class II–IV heart failure symptoms.Left atrial reservoir strain provided incremental prognostic value in patients with SSc.SSc is a rare autoimmune CTD characterized by multisystem microangiopathy, inflammation and fibrosis, and is associated with significant morbidity and mortality . CardiacPresently, standard evaluation of left cardiac chamber function using echocardiography and cardiovascular magnetic resonance (CMR) imaging involves only the evaluation of left ventricular (LV) ejection fraction. However, LV ejection fraction is less sensitive than LV global longitudinal strain (GLS) and may fail to detect the onset of subclinical cardiac involvement , 8. FurtCMR is currently indicated in patients with SSc to evaluate for evidence of inflammation and/or fibrosis, findings that may indicate primary myocardial involvement . HoweverThe study population consisted of consecutive patients included in the prospective Leiden CCISS cohort   and the Rheumatology online). LGE images were acquired 10 to 15 minutes after bolus injection of gadolinium diethylenetriamine pentaacetic acid  or gadoterate meglumine  (0.15 mmol/kg) with an inversion recovery–prepared 2- or 3-dimensional segmented gradient echo pulse sequence in standard long-axis and short-axis views. Images were stored digitally for offline analysis. Right ventricular (RV) and LV end-systolic volume, end-diastolic volume, mass, and ejection fraction were measured using commercially available software . Left atrial volumes were measured on the cine CMR 2- and 4- chamber views, averaged, and were subsequently indexed to body surface area. The presence or absence of LGE (or hyperenhancement) was visually assessed, defined as the presence (or absence) of myocardial high signal intensity in both the short-axis and corresponding long-axis views [All participants underwent CMR on 1.5-T CMR scanners, the Gyroscan ACS-NT/Intera MR system  or Siemens Avanto , or a 3.0-T CMR scanner, Ingenia MR system . All images were ECG-gated and acquired during mild end-expiration breath-holding. The scanning protocol included balanced steady-state free precession (SSFP) cine CMR images in long-axis  and short-axis views covering the left ventricle, and late gadolinium enhancement (LGE) imaging (is views .Pulmonary artery systolic pressure (PASP) was estimated from contemporaneous transthoracic echocardiography by applying the modified Bernoulli equation to the tricuspid regurgitation jet peak velocity and adding mean right atrial pressure. Estimated right atrial pressure was calculated from the inferior vena cava diameter and its collapsibility. The presence of diastolic dysfunction was defined using guideline recommendations , using cFeature-tracking CMR-derived analysis of LV GLS was performed utilizing dedicated software  by study site investigators who were blinded to follow-up data . LV endoThe first end point of the study was the presence or absence of NYHA class II to IV heart failure symptoms at the time of baseline CMR. The second end point of the study was all-cause mortality at follow-up. Mortality data were collected through the Social Security Death Index or by medical record review and were complete for all patients. Follow-up began from the date of CMR, and data for all patients were included up to the last date of follow-up.2 test for categorical variables and the Mann–Whitney U-test for continuous variables. To investigate the association of clinical and imaging parameters with the presence or absence of heart failure symptoms at baseline (defined as NYHA class ≥II), univariable logistic regression was performed. Variables with a univariable value of P < 0.05 were incorporated into the multivariable model. For the evaluation of the end point of all-cause mortality, penalized spline curve analysis was utilized to investigate the hazard ratio (HR) change for all-cause mortality across a range of LARS and LV GLS values. A threshold of LARS and LV GLS to dichotomize the population for Kaplan–Meier analysis was estimated using the fitted spline curves. Cumulative survival rates were calculated using the Kaplan–Meier method, and the log-rank test was used to compare groups. Associations between clinical and CMR variables and all-cause mortality were investigated by univariable Cox proportional hazards regression models. The proportional hazards assumption was verified through the assessment of scaled Schoenfeld residuals. The HR and 95% CI were calculated and reported for each variable. To test for the incremental prognostic value of LARS and LV GLS, likelihood ratio (LR) χ2 tests were used to assess whether feature-tracking CMR-derived strain of the left cardiac chambers added prognostic value to variables shown to be important for risk stratification in patients with SSc according to prior epidemiological data [P-values of <0.05 were considered statistically significant. Statistical analysis was performed using SPSS version 25.0  and R version 4.0.1 .Categorical variables are expressed as numbers and percentages, while continuous variables are presented as median and interquartile range (IQR). Differences between groups divided by the presence or absence of NYHA class II to IV heart failure symptoms were compared using the Pearson χcal data , 9. Ten A total of 100 patients with SSc were included. The median age of the population was 54 (IQR 46 to 64) years, 42% were male and 52% had a diagnosis of dcSSc. Overlapping CTD was present in 6% of the overall population, 4% had PM overlap and 2% had SLE overlap. The median disease duration since first non-RP symptom was 38 (IQR 16 to 96) months. Patients were referred for CMR for the evaluation of cardiac involvement in 86%, screening prior to haemopoietic autologous stem-cell therapy or lung transplantation in 10%, while 4% of patients had no specific indication. The study population was dichotomized according to the presence or absence of heart failure symptoms at baseline: a total of 39 patients (39%) were in NYHA class I, while 61 (61%) were in NYHA classes II to IV. Patients in NYHA class II to IV had lower predicted DLCO than those in NYHA class I, the only significant difference between the two groups of patients. 2, while the LV ejection fraction was preserved (LVEF ≥50%) in the majority of the population (79%) [Rheumatology online). Clinical and imaging parameters associated with LARS are presented in Rheumatology online. The ICCs for intra- and inter-observer variability for LV GLS were 0.988 and 0.967, and for LARS, 0.963 and 0.917, demonstrating excellent agreement (Rheumatology online).The CMR characteristics of the population are presented in on (79%) . The feaRheumatology online) were associated with the presence of NYHA class II to IV heart failure symptoms at baseline. Notably, LV GLS, LV ejection fraction, LGE and left atrial volume index did not demonstrate an association on univariable analysis. On multivariable analysis, LARS  and predicted DLCO  retained an independent association with the presence of NYHA class II to IV heart failure symptoms at baseline.To investigate the association between NYHA class II to IV heart failure symptoms and feature-tracking CMR parameters, univariable logistic regression analyses were performed . On univvs 96% and 87%, at 1 and 5 years of follow-up, respectively, P < 0.0001, vs 92% and 86%, at 1 and 5 years of follow-up, respectively, P = 0.033, P < 0.0001), and all-cause mortality and LV GLS . In addition, an association was observed between all-cause mortality and LGE, PASP, atrial fibrillation, diastolic dysfunction, male sex, NYHA functional class, and LA volume index, although not with LV ejection fraction (Rheumatology online).Over a median follow-up of 37 (IQR 21 to 62) months, a total of 24 (24%) patients died. Spline curve analyses were performed to investigate the association between values of LARS , LV GLS 2 7.82, P = 0.005), atrial fibrillation , LV diastolic dysfunction , DLCO , predicted FVC , PASP , RV ejection fraction , NYHA class II to IV heart failure symptoms  and left atrial volume index . Likewise, LR tests were utilized to evaluate the incremental prognostic value of LV GLS. LR testing demonstrated that LV GLS provided incremental prognostic value over atrial fibrillation , RV ejection fraction , NYHA class II to IV heart failure symptoms , DLCO , predicted FVC  and LA volume index , although it was not incremental over the presence of LGE , PASP  or LV diastolic dysfunction . Moreover, LARS demonstrated significant incremental prognostic value over a model including LV GLS , while LV GLS did not provide additional prognostic information to a model including LARS . Likewise, evaluation of LV diastolic dysfunction did not provide additional prognostic value to a model including LARS .To evaluate the incremental prognostic value of LARS for the end point of all-cause mortality, LR tests were performed. LARS demonstrated incremental value over the presence of LGE  LARS derived by CMR was independently associated with the presence of heart failure symptoms at baseline, and (ii) LARS and LV GLS were associated with all-cause mortality, although only LARS provided incremental value over all included variables known to be prognostically important in patients with SSc.Prior literature has demonstrated an independent relationship between NYHA functional class and all-cause mortality in patients with SSc , 24, 25.The present study is the largest to evaluate feature-tracking CMR-derived strain of the left ventricle in patients with SSc, and the only study to evaluate feature-tracking CMR-derived strain of the left atrium , 15. In While echocardiography remains the first investigation of choice for the evaluation of cardiac structure and/or function in patients with SSc, CMR represents the gold standard for chamber quantification and the detection of subclinical disease . In routThis study is limited by a retrospective, observational design, and patient enrollment from two specialist academic referral centres may create a selection bias. Moreover, CMR data were not acquired for the explicit purpose of evaluating left cardiac chamber function; rather, CMR was performed as a component of routine clinical practice. In addition, this study was not designed to evaluate whether left cardiac chamber strain assessed by CMR offered incremental prognostic value over left cardiac chamber strain evaluated by speckle-tracking echocardiography. Further studies adequately powered to detect any differences in prognostic utility are required to evaluate this question. Furthermore, data regarding the cause of death were not available. For the end point of all-cause mortality, multivariable analysis adjusting for an extensive number of covariates in a single model was not feasible due to the limited number of events and the risk of model overfitting. In addition, due to missing data and CMR imaging protocols/machines varying between institutions, analyses of T1 imaging data were not performed. The prevalence of pulmonary arterial hypertension was also likely underestimated, as right heart catheterization was not performed for all patients.In patients with SSc, LARS was independently associated with the presence of NYHA class II to IV heart failure symptoms at baseline. In addition, although both LARS and LV GLS were associated with all-cause mortality, only LARS provided incremental value over variables known to be prognostically important in patients with SSc.Funding: This work was supported by funding from the European Society of Cardiology (ESC Research Grant App000080404) to S.C.B.Disclosure statement: The Department of Cardiology of the Leiden University Medical Center received research grants from Abbott Vascular, Bioventrix, Medtronic, Biotronik, Boston Scientific, GE Healthcare and Edwards Lifesciences. J.J.B. received speaking fees from Abbott Vascular. N.A.M. received speaking fees from GE Healthcare and Abbott Vascular and is in the Medical Advisory Board of Philips Ultrasound. V.D. received speaker fees from Abbott Vascular, Medtronic, MSD, Novartis, Edwards Lifesciences and GE Healthcare. R.N. received speaker fees from Sanofi Genzyme and Bayer, and has received research grants from Philips and Biotronik. M.C.V. received research grants from Boehringer Ingelheim, Ferrer, Galapagos, and Janssen, and consulting fees from Boehringer Ingelheim, Corbus, and Janssen. The remaining authors have nothing to disclose.keac256_Supplementary_DataClick here for additional data file.


Despite the existence of effective medicines, heart failure continues to be the largest cause of illness and death worldwide. As a prospective family of drugs with potential cardiovascular advantages in non-diabetic patients, sodium-glucose co-transporter 2 inhibitors (SGLT2-I) have recently come to the forefront. In this comprehensive study, we assessed the favorable cardiovascular outcomes of SGLT2-I in three sizable, randomized trials with both diabetic and non-diabetic populations. The results from these studies revealed a substantial reduction in heart failure hospitalizations and cardiovascular and all-cause deaths. To further support our assertion that SGLT2-I has the potential to be a novel addition to the standard treatment plan for heart failure, we also tried to assemble several post hoc and prespecified studies of the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) study. The details of two clinical investigations that supported their use in acute decompensated heart failure were also examined, along with the most plausible mechanism of action generating their cardioprotective effects. Additionally, positive cardiovascular advantages were addressed in chronic heart failure with both preserved and reduced ejection fractions. The role of SGLT2-I in ST-elevation myocardial infarction (STEMI) and hypertrophic cardiomyopathy (HOCM) patients is currently being studied, and this research has the potential to be revolutionary. The purpose of this systematic review is to compile all information that supports the use of this life-saving drug in patients who do not have diabetes so that cardiac care can be improved globally. The need for innovations in heart failure (HF) therapy is critical due to the enormous morbidity and death linked to the condition. Worldwide, the number of instances of cardiovascular disease nearly quadrupled from 271 million to 523 million between 1990 and 2019. Cardiovascular mortality increased as well, from 12.1 million in 1990 to 18.6 million in 2019 [First identified as a novel anti-diabetic medication, sodium-glucose cotransporter-2 inhibitors (SGLT2-I) were introduced into the market after multiple clinical trials proved their magical role in appropriate diabetic control. Canagliflozin (CANA) was approved by the Food and Drug Administration (FDA) in March 2013 as the first SGLT2 inhibitor, followed by dapagliflozin (DAPA) and, empagliflozin (EMPA) in 2014 . The mecIn recent years, studies have been done to see if SGLT2-I treatment has any favorable cardiovascular effects, even in individuals with HF who are not diabetic. Beginning with two large, randomized trials, the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) and the Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction (HFrEF) , which included both diabetic and non-diabetic population, showed a significant reduction in the incidence of heart failure events -12. AddiThis systematic review's goal is to compile all the information that supports SGLT2-I's favorable therapeutic effects on non-diabetic heart failure patients so that it can be utilized as a standard for future studies and enhance the quality of care for cardiac patients globally.MethodsThe inclusion and exclusion criteria, the search method used, the bias calculation in each research, and the selection of studies are discussed in this section.Inclusion and Exclusion CriteriaTable Search StrategyTwo research databases including PubMed and Cochrane library were extensively used to find literature on the subject. All databases were last accessed on June 28, 2022. As shown in Table To eliminate duplicate references, the ones retrieved from databases were alphabetically sorted using Microsoft Excel 2022 . The studies were further scrutinized using the titles and abstracts to filter out any that did not fit the inclusion criteria. Based on the titles and abstracts, the records were examined, removing studies that were not relevant. Retrieval of the full-text articles came next, after reviewing.Quality Appraisal of Individual StudiesAll publications that satisfied the inclusion requirements underwent risk of bias assessment using instruments designed specifically for the original study type. As shown in Table Selection of Individual StudiesTwo authors (Paghunda Ehsan and Rawia N. Aburumman), who participated in the study selection process, performed an initial screening of all papers that satisfied the inclusion criteria by reading their titles and abstracts. Studies in English and those which included non-diabetic heart failure patients taking SGLT2-I for heart failure treatment were accepted. In the second stage of screening, the papers that were determined to be pertinent to the research issue were further examined. RCTs and NRCTs that met the requirements for inclusion and demonstrated minimal bias risk on the quality assessment tools were then subjected to full-text review.This systematic review was conducted based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines and the search strategy is outlined in Figure ResultsA total of 2833 studies were obtained after searching using two databases, namely PubMed and Cochrane Library, using the search strategy described. 6663 duplicates were removed using Microsoft Excel 2022 version. Of the 2833 studies, 127 articles were screened after duplication removal and removal of records marked ineligible owing to exclusion criteria. Nine studies were excluded as their topics were irrelevant. The abstracts of the remaining 118 articles were thoroughly read by the author to select the studies which fit the research question better. Out of 118 articles, only 16 articles managed to match the inclusion criteria of the study and were included in this systematic review, out of which characteristics of 14 articles are outlined in Table DiscussionThis comprehensive review firmly supports the claim that, regardless of diabetes status, treatment with SGLT2-I lowers the risk of CV death or a composite of deteriorating heart failure . In this section, we will address the most likely mechanism of action and the most recent data on the positive cardiovascular benefits of SGLT2-I in nondiabetic patients. The variations in cardiovascular outcomes across trials, their flaws, and suggested next steps will also be discussed. In the end, it will be clear what must be done more in this area to enhance the cardiovascular outcome for individuals with heart failure.SGLT2-I Cardioprotective Mechanism of ActionWhile the precise mechanism of SGLT2-I is unknown, multiple studies have validated a myriad of hypotheses. The advantages of SGLT2-I in the treatment of HF are mostly due to the stimulation of natriuresis and osmotic diuresis which these drugs induce, which improves cardiac output and reduces afterload and preload ,19,27-29From March 6, 2018, to September 10, 2019, Omar et al. enrolled 70 patients with stable euvolemic HFrEF (54 non-diabetic patients) to receive either 10 mg of EMPA or a matching placebo once daily based on a standard heart failure treatment regimen for 12 weeks to evaluate the hemodynamic effect of SGLT2-I using right heart catheterization (RHC) at rest and during exercise. The ratio of pulmonary capillary wedge pressure (PCWP) to cardiac index (CI) at maximum exertion after 12 weeks was the main result. In contrast to the placebo, the PCWP/CI ratio did not change during exercise or at rest, but PCWP was reduced across the board in all hemodynamic parameters, lowering LV filling pressures [In 2021, Kolwelter et al. randomized 2:1 participants with HF New York Heart Association (NYHA) II-III and an ejection fraction of 49 percent or less to receive EMPA 10 mg once daily or a placebo for three months to determine the impact of EMPA on vascular function. Vascular metrics such as central systolic blood pressure (cSBP), central pulse pressure (cPP), forward pressure height (FPH), and reflected pressure pulse height (RPH) under basal conditions decreased in the EMPA therapy group (n = 45) after one and three months. The decreased afterload of the left ventricle caused by greater arterial and aortic compliance perhaps led to a better prognosis seen in HF patients taking SGLT2 inhibition [Evidence Presently Available, Issues, as well as Future Suggestions for SGLT2-I's Cardiovascular BenefitsThe impact of SGLT2-I in chronic heart failure patients in a handful of trials will be reviewed in the upcoming paragraphs.DAPA-HF TrialThe Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial, which involved 4,744 patients, 2,605 of whom did not have diabetes, was the first notable groundbreaking RCT of SGLT2-I to include both diabetic and non-diabetic patients . The triA 2020 exploratory analysis of the DAPA-HF trial by Petrie et al. showed a substantial reduction on in the primary composite outcomes of worsening HF or cardiovascular death in patients without diabetes  . MartineThe risk of cardiovascular mortality or worsening heart failure rapidly decreased, with particularly high absolute and relative risk reductions in those with more recent heart failure hospitalizations, according to Berg et al. in a secondary analysis of the DAPA-HF study in 2021 .Owing to sex-related variations in pharmacokinetics and pharmacodynamics, women may react to certain HF therapies differently than the male population ,32,33. IEMPEROR-Preserved TrialImproved health status and quality of life as judged by the Kansas City Cardiomyopathy Questionnaire, across all areas and at all measured periods , were shown by Butler et al. to extend to HFpEF in the "EMPEROR-Preserved study" in 2021 .EMPEROR-Reduced TrialIn 2019, the results of DAPA-HF were mirrored by the "Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and Reduced Ejection Fraction (EMPEROR-Reduced)", with EMPA's effects being similar in diabetics and non-diabetics  .DEFINE-HF TrialIn the clinical trial entitled "Dapagliflozin Effects on Biomarkers, Symptoms, and Functional Status in Patients with HF with Reduced Ejection Fraction (DEFINE-HF)", Nassif et al. included 236 adult ambulatory patients with or without type 2 diabetes mellitus. Compared to the placebo, a significantly higher percentage of patients receiving dapagliflozin for 12 weeks showed clinically significant changes in their functional status, quality of life, or natriuretic peptides . The impEMPULSE TrialIn 2022, Voors et al. in the "EMPA in patients hospitalized for acute heart failure (EMPULSE) trial" randomly assigned 524 non-diabetic patients with a primary diagnosis of acute or decompensated chronic heart failure, regardless of LV ejection, to receive either 10mg EMPA or placebo when they were clinically stable , and they were treated for up to 90 days. The main goal was met by EMPA curing more patients than placebo . A five-point or greater difference in variation from baseline in the Kansas City Cardiomyopathy Questionnaire Total Symptom Score at 90 days, or death from any cause, the number of heart failure events, and the time since the first heart failure event, as a hierarchical composite, were deemed clinical benefits .EMPA RESPONSE-AHF TrialTrials were conducted to determine SGLT2-I's positive effects on individuals with acute heart failure as well, considering growing evidence of its benefits for people with chronic heart failure. In a multicenter pilot study, Damman et al. randomly assigned 80 patients with acute HF with and without diabetes (EMPA RESPONSE-AHF) to receive either EMPA 10 mg/day or a placebo for 30 days. Results revealed that EMPA was safe, increased urine output, and decreased a composite endpoint of worsening HF, rehospitalization for HF, or mortality at 60 days, but it did not affect change in visual analog scale (VAS) dyspnoea, diuretic response, N-terminal {NT}-prohormone brain natriuretic peptide (NT-proBNP), or length of hospital stay .Recent GuidelinesIn the past years, numerous guidelines have been added that recommended the use of SGLT2-I in non-diabetic heart failure patients. For instance, In September 2020, UpToDate added SGLT2 inhibitors as an option for patients with continued symptoms of HF despite the use of appropriate primary agents, whether they have type 2 diabetes or not . SGLT2-IOngoing TrialsCurrently, new clinical trials are being conducted worldwide to check the efficacy of SGLT2-I in numerous cardiovascular issues like ST-segment elevation myocardial infarction (STEMI), atrial fibrillation, and hypertrophic obstructive cardiomyopathy (HOCM). An interventional clinical trial, namely "Impact of Dapagliflozin on Cardiac Function Following Anterior Myocardial Infarction in Non-Diabetic Patients (DACAMI)" has recently been conducted by Omar Younis at National Heart Institute, Egypt, and completed on June 30, 2022, checking its role in anterior wall ST-elevation myocardial infarction (MI) .Similarly, there is a new clinical trial "Empagliflozin in Hypertrophic Cardiomyopathy (EMPA-REPAIR)", started on June 1, 2022, in Warsaw, Poland, for EMPA administration at the recommended dose of 10 mg per day for 12 months to patients with hypertrophic cardiomyopathy as the suggested intervention. Diabetic patients will not be included in the trial. A total of 250 patients will be randomized in a double-blind method to either EMPA or a placebo. The study's main outcome measure will be the variation in maximum oxygen uptake (VO2 max), as determined by a cardiopulmonary exercise test. Before and after receiving EMPA or a placebo, VO2max, an objective measure of physical performance, will be measured. Secondary outcomes include modifications to the maximal LV wall thickness, LV mass, measures of diastolic dysfunction, degree of myocardial fibrosis, and improvement in the heart's energy status . This stAll the precedent data point to the enormous potential that SGLT2-I has outside of its current use in diabetic control and point to positive results in several cardiovascular health measures in both diabetics and non-diabetics. As a result, this miraculous medication should be further investigated for its undiscovered advantages.LimitationsWe limited our search to just two databases that contained English-language studies published during the last five years; as a result, good publications from earlier years and in other languages would have gone undiscovered. Grey literature and other databases were not incorporated. As far as we are aware, there are no larger clinical trials with a purely non-diabetic population only. Furthermore, non-diabetic populations had a smaller sample size in recent studies. Most of the studies we discussed were post hoc analyses or prespecified subgroup analyses on previously completed bigger RCTs with a significant proportion of diabetes participants. Finally, we didn't discuss much of the side effects of SGLT2-I.In addition to its ability to lower blood glucose levels, SGLT2-I has been shown in various studies to improve patients' cardiovascular health. Therefore, this systematic review aimed to learn more about its application in non-diabetic cardiac patients, whether they had acute or chronic HFs. Even though no significant clinical trial has been carried out solely on the non-diabetic population, recent studies have demonstrated cardiovascular benefits in the cohorts of both diabetic and non-diabetic populations and have demonstrated a significant reduction in HF hospitalization and mortality from cardiovascular causes. The above-stated efficacy in both populations is identical, which is surprising. The outcomes of present and upcoming RCTs in patients with MI, atrial fibrillation, and hypertrophic cardiomyopathy will likely expand the clinical indications for SGLT2-I in a variety of patient categories, enabling us to explore their potential beyond anti-glycemic effects. Future research will, however, require more trials with bigger non-diabetic sample size.


A severe secondary mitral regurgitation (SMR) can be found in a significant portion of patients affected by advanced heart failure (AHF). Conventional therapies  present restricted clinical efficacy in this stage of the left ventricle disease which is burdened by high mortality and morbidity rates. Although the treatment of choice is represented by heart transplantation (HTx), there is an unmet need related to the limited supply of donor hearts  and the low eligibility of highly symptomatic patients. In case of concomitant severe SMR, transcatheter mitral valve therapies (repair and replacement) may play a crucial role in this setting. While a direct prognostic improvement after correction of SMR has yet to be proved, AHF patients can benefit from the following: hemodynamic stabilization, symptomatic relief, normalization of pulmonary arterial pressures, and reduction in hospitalizations for acute heart failure. Obtaining these results may lead to the clinical consequences of reaching the HTx in good enough clinical status (bridge to heart transplantation), becoming eligible for the HTx (bridge to HTx candidacy), and being delisted for clinical improvement (bridge to recovery). Therefore, achieving traditional secondary endpoints in patients with AHF and SMR can translate into significant clinical implications. The burden of heart valve diseases represents a major public health problem. In the developed countries, mitral regurgitation is the most common valve disorder with a prevalence increasing with age . ParticuThe latter constitutes both a diagnostic and a therapeutic challenge. Up to 24% of patients with SMR are affected by heart failure due to left ventricular (LV) dysfunction leading to an underestimation of the mitral valve disease itself . Since LChronic heart failure is a common condition among adults, with an increasing prevalence because of the aging of the population and improved cardiovascular treatments . Although it is a heterogeneous syndrome, all etiologies share a final common pathway with progressive worsening of symptoms and cardiac function. The final stage when conventional therapies  are no more effective is represented by the AHF, clinically diagnosed on the basis of patient’s symptoms, cardiac dysfunction, functional capacity indices, and prognostic markers. The low incidence and the evolving definitions of AHF make it difficult to estimate its prevalence. Data from ADHERE (Acute Decompensated Heart Failure) national registry of ~ 23,000 hospitalized patients report a prevalence of AHF close to 5% . Since tThe treatment of choice for most patients with AHF is represented by heart transplantation (HTx). To date, the complications related to infectious diseases, immunosuppression, and donor/recipient selection have been significantly reduced. As a result, survival, quality of life, and exercise tolerance increased. The main limitations of this treatment consist in the limited availability of donor hearts and the poor eligibility of patients who are often in such a compromised stage that no benefit can be expected. While the number of transplants appears to have reached a plateau, the HTx waiting lists are persistently expanding. Prolonged (over 12 months) times on waiting lists are associated with mortality rates ranging between 13% at 1 year and 19% up to 3 years .Long-term mechanical circulatory support (MCS) obtained through left ventricular assist device (LVAD) implantation represents a successfully therapeutic solution for this population. The Risk Assessment and Comparative Effectiveness of Left Ventricular Assist Device and Medical Management in Ambulatory Heart Failure Patients (ROADMAP) study provided the risk–benefit ratio for a shared decision on elective LVAD therapy for AHF. Higher survival with improved functional status, improved quality of life, and reduced depression favored LVAD over optimal medical therapy; on the other hand, LVAD implantation caused more hospitalizations for heart failure and major adverse events  that reduced after the first year of follow-up .Class IIb, Level of Evidence: C)  can can20] c2 and mean mitral valve gradient > 4 mmHg need to be excluded to prevent a procedural failure related to intractably high transmitral gradients . Tr. Tr20]. TMVRpl experience in native mitral valves is still limited to trials with slightly more than 500 procedures. The Tendyne  has been the first transcatheter mitral valve implantation system to be approved in Europe in 2020 and, to date, no device has gained the Food and Drug Administration approval for the USA. The analysis of the first 308 TMVRpls shows that the procedure is feasible and, compared to the COAPT trial, provides better results in terms of post-procedural mitral regurgitation reduction , symptomatic improvement , and hospitalizations for heart failure  , 32. HowTMVRpl for severe SMR in patients at high surgical risk and previous mitral surgery (bioprosthesis or annuloplasty) or severe mitral annular calcification  can be performed with the transcatheter aortic SAPIEN XT and S3 , the MyVal , or the transcatheter pulmonary Melody  valve –37. DataA limitation to TMVRpl is represented by the transapical access: patients with a remodeled LV or with ischemic scars may not tolerate well this approach. As they are developed, systems that deliver the valve with a transseptal route through transfemoral introducers are expected to result in fewer complications and better outcomes.Valve durability after TMVRpl is another great concern that needs to be better elucidated. The age of patients undergoing TMVRpl  plays an important role in the rate of structural valve degeneration . EnhanceA relevant risk of valve thrombosis undermines TMVRpl: 6% to 8% after the implantation of Tendyne , Fortis , and HighLife  device –43. The At present, there are limited exploratory studies on the transcatheter treatment of SMR in patients with AHF. While a direct prognostic improvement after correction of SMR has yet to be proved, AHF patients can greatly benefit from the following: hemodynamic stabilization, symptomatic relief, normalization of pulmonary arterial pressures, and reduction in hospitalizations for acute heart failure. Obtaining these results may lead to the clinical consequences of reaching the HTx in good enough clinical status (BTT), becoming eligible for the HTx (BTC), and being delisted for clinical improvement (BTR). Therefore, achieving “not-so-hard endpoints” in patients with AHF and SMR can translate into great clinical implications.More studies are needed to investigate who more likely will benefit the most from SMR treatment at this advanced stage of LV disease. Since left and right ventricular reverse remodeling have been found as turning points of favorable outcomes, it should be assessed whether this phenomenon can also occur in this population , 46.The lack of sufficient evidence and the lesson learned from the surgical experience make TMVr preferable over TMVRpl . HoweverTranscatheter therapies for SMR may play an important role in AHF patients. Exploratory studies proved the procedural safety and clinical efficacy  of this treatment. Further investigations are needed to better characterize AHF patients with concomitant SMR, identify optimal candidates for transcatheter therapies, and understand the consequences of the different bridge strategies. While TMVr has more evidence in this setting, TMVRpl is expected to become a valid alternative in the near future. Having a complete mitral toolbox will be the key to handle all the anatomies and provide a patient-tailored approach.


Background and Objectives: Left atrial hypertension is one of the pathophysiologies of heart failure with preserved ejection fraction. We hypothesized that left atrial pressure response (LAPR) to incremental pacing is higher in patients with atrial fibrillation (AF) and can predict left ventricular diastolic dysfunction. Materials and Methods: Patients requiring left atrial access as a part of a therapeutic procedure for AF  or supraventricular tachycardia  were analyzed . LAPR was measured during incremental pacing. Results: Baseline left atrial pressure and LAPR at all pacing rates were not different between the AF and control groups. They were higher in patients with a high E/e’ (≥ 8) than in those with a low E/e’ (<8). LAPR at a pacing interval of 400 ms and E/e’ were positively correlated . Body mass index and a high E/e’ were independent predictors of pacing-induced left atrial hypertension. Conclusions: LAPR to incremental pacing was constant regardless of AF. The non-invasive echocardiographic marker E/e’ reflected pacing-induced left atrial hypertension. Heart failure (HF) is one of the leading causes of hospitalization and cardiovascular mortality regardless of the left ventricular (LV) ejection fraction (EF). Several studies have demonstrated similar mortality rates between individuals having HF with preserved EF (HFpEF) and those having HF with reduced EF ,2. The mThus, LA remodeling reflects the cumulative effects of elevated LVFP. Elevated LA pressure (LAP) is related to LA remodeling in the general population regardless of atrial fibrillation (AF). It provides diagnostic and prognostic information about LV diastolic dysfunction and the chronicity of the disease. A recent study showed that elevated LAP is associated with extended electro-anatomical remodeling of the LA and poor clinical outcomes after AF ablation . In addiTherefore, we hypothesized that the LAP response (LAPR) to incremental pacing reflects LV diastolic dysfunction. The objective of this study was to reveal the clinical implications and non-invasive predictors of LAPR.n = 0), (2) LV systolic dysfunction (LVEF < 50%) or structural heart disease including ischemic lesion (n = 15), (3) moderate to severe mitral and aortic valve disease (n = 0), (4) recurrent triggers, that induced sustained arrhythmias interrupting the maintain sinus rhythm (SR) (n = 1), and (5) AF induction during right atrial pacing (n = 14 in AF group and n = 1 in control group) were excluded via a screening test. A total of 204 patients in the AF group and 34 patients in the control group were finally analyzed . In addition, the cohort was divided into two groups based on the criteria of E/e’ = 8 , which is an echocardiographic LV diastolic dysfunction marker. We compared 144 patients with low E/e’ and 124 patients with high E/e’. All patients provided written informed consent for inclusion in the cohort. The research protocol complied with the principles of the Declaration of Helsinki and was approved by the Institutional Review Board of the Korea University Anam Hospital.We screened a population who needed LA access as a part of a therapeutic procedure for AF or supraventricular tachycardia . From JuAll candidates underwent transthoracic echocardiography within a month prior to the procedure. Cardiac chamber size, LV wall thickness, blood flow velocity, and tissue Doppler images of the mitral annular septal region were assessed. The measurement of E and e’ criteria followed the current guidelines . The E wAll patients fasted eight hours prior to invasive LAP measurement and catheter ablation. Saline fluid (0.9%) was injected during that time at a rate of 40 mL/hour without taking medication. Sedation was used during the procedure and pressure measurements. We did not use general anesthesia. Intracardiac echocardiography and measurement of hemodynamics were performed using a Prucka CardioLab electrophysiology recording system . A septal puncture was performed to assess the LA. Systemic anticoagulation was initiated with intravenous heparin, maintaining an active coagulation time of 300 to 350 s immediately before septal puncture. A Swartz left 1 long sheath  was used for septal puncture. To measure LAP, a 6-F pigtail catheter  was inserted into the LA through the long sheath. Baseline LAP was measured during SR at the height of the v wave. If AF was sustained at the initial time of the procedure, SR was restored with internal cardioversion  with 5–20 J of energy and LAP was measured 5 min after restoring SR. To increase the heart rate, incremental right atrial pacing was performed. The LAPRs at heart rates of 60, 75, 100, 120, and 150 beats per minute (bpm) were observed. If the patient’s breathing was unstable, LAP was measured during inspiration.p < 0.10 in the univariate analyses for a variable to enter the model. AF-free survival was measured by the Kaplan–Meier survival curve analysis, and the difference between both groups was assessed by a log-rank test. A p-value < 0.05 was considered statistically significant.Statistical analyses were performed using the SPSS 20.0 software package . Continuous variables are expressed as mean ± standard deviation. They were compared by Student’s t-test, Mann–Whitney U-test, and ANOVAs, followed by post hoc analyses using Bonferroni’s method. Categorical variables are reported as counts with percentages and were compared using a Chi-square test or Fisher’s exact test. The difference in pacing-dependent LAP changes was determined by ANOVA. Multivariate analysis was conducted with a logistic regression model reporting odds ratios (ORs) to predict high LAPR (LAP ≥ 26 mmHg). Predictor variables included age, female sex, hypertension, diabetes mellitus, atrial fibrillation, body mass index, LA volume index, LV mass index, LVEF, and high E/e’. Multiple regression analysis was performed using the criterion of p < 0.001) and included more men . This group had a higher BMI  and more hypertension . In echocardiographic data, the AF group had a larger LV diastolic diameter , higher LV mass , larger LA volume index , and higher E/e’ . The LVEF was preserved, and there were no significant differences between the two groups. Additionally, we analyzed the difference between patients with high E/e’ and low E/e’ (p < 0.001), included fewer men , and had a greater number of hypertensive  and diabetic  patients than the low E/e’ group. The high E/e’ group had a more common history of myocardial infarction . In echocardiographic data, the high E/e’ group had a higher LV mass index , a larger LA volume index , and higher pulmonary artery systolic pressure . Baseline LAP was not significantly different between the high E/e’ group and the low E/e’ group.The baseline characteristics of the AF and control groups are presented in low E/e’ . The higp < 0.10 in the univariate analysis) were included in the multivariate analysis. BMI  and high E/e’  were independent predictors of high LAPR.The heart rate changed according to the right atrial pacing (RAP) interval . LAP didp = 0.299) (p = 0.299) (p = 0.541)The presence of RAP-induced high LAPR could not predict AF recurrence after catheter ablation (log-rank = 0.299) A. AF fre= 0.299) B. It alsLAP increased with incremental atrial pacing. The LAPR was not correlated with the presence of AF but was closely related to E/e’, an echocardiographic marker of LV diastolic dysfunction. LAP is influenced by several factors such as LV systolic and diastolic function, LA chamber stiffness, and intravascular volume status. If LV diastolic function worsens, LV end-diastolic pressure (LVEDP) increases to maintain adequate LV stroke volume . The LA LAP does not increase at the normal range of heart rate but increases rapidly beyond its threshold. This means that insufficient time to fill the appropriate volume leads to an increase in LVEDP. In our study, LAPR was closely related to E/e’ regardless of the rhythm status. These results imply that the main factor of LAPR is LV diastolic dysfunction rather than atrial remodeling. LV diastolic function determines the boundary value of the LAPR. Particularly, it is helpful in identifying the cause in patients who complain of non-ischemic exercise-related dyspnea. Increased LAP during exercise or tachycardia causes dyspnea, and E/e’ can be a marker of exertional dyspnea of cardiac origin. At rest, patients with diastolic dysfunction may have a cardiac output or filling pressure similar to that of healthy individuals who have a normal diastolic function. Exercise echocardiography  is usualE/e’ measured by echocardiography is a non-invasive method that reflects LV diastolic dysfunction. LAPR is a marker of LV diastolic reservoir, but it has to be obtained using an invasive method. E/e’ measured by echocardiography is a non-invasive method and was found to be closely correlated with the LAPR . SeveralBaseline LAP, LAPR, and E/e’ were not able to predict the outcome after catheter ablation. The most relevant predictor of prognosis after catheter ablation is LA remodeling, including enlargement and fibrosis. The main determinant of both LAP and LAPR is LV diastolic dysfunction rather than LA remodeling. This study included only people with relatively mild HF. In other studies, increased E/e’ was a predictor of poor outcomes after ablation, such as low LA voltage . As a reThe following limitations should be considered when interpreting this result. This was a single-center observational study that included only patients selected for catheter ablation of AF or supraventricular tachycardia. Therefore, it is difficult to generalize this finding to the entire population. Since most of the patients in the AF group had compensated for HF and proper general condition, there may not be any difference from the control group. This tends to ignore the effect of atrial remodeling on LAP. Next, the difference in rhythm status should be considered when LAP was measured. In patients with persistent AF, LAP was measured after returning to SR after cardioversion; however, it may not have recovered from stunning even after 5 min. However, this result was consistently observed in other patients who were measured without cardioversion. Lastly, LAP measured during tachycardia induced by pacing may differ from that during increased heart rate due to exercise and emotional changes in daily life. This is because the increase in heart rate by activity is accompanied by an increase in LV contractility, aortic stiffness, and preload in response to an increase in sympathetic tone. For this reason, it is difficult to mention that the results of this study perfectly reflect the heart response during ordinary exercise.In conclusion, LAP showed a constant increase with the heart rate change according to pacing. The echocardiographic non-invasive marker, E/e’, reflected the LAPR measured during incremental pacing. It can be an indication to evaluate the cause of exertional dyspnea regardless of AF.


Several adults with repaired tetralogy of Fallot (rToF) undergo pulmonary valve replacement (PVR) to reduce the right ventricular volume and retain right ventricular function. However, there is currently no consensus on the ideal time for PVR surgery in asymptomatic patients with rTOF with pulmonary regurgitation (PR). Clinical outcomes after PVR are also indeterminate. Recently, myocardial strain and strain rate derived from cardiac magnetic resonance (CMR) feature tracking were found to be more sensitive to right ventricular dysfunction than conventional parameters and therefore may add prognostic value in patients with rToF. We aimed to analyze whether pre-PVR left ventricular (LV) strain and strain rate detected by CMR feature tracking are associated with midterm outcomes after PVR in patients with rToF.Seventy-eight asymptomatic patients with rToF who required PVR due to moderate or severe PR were prospectively enrolled between January 2014 and June 2020. CMR cine sequences were obtained, and feature tracking parameters were measured preoperatively. Adverse events were documented during the follow-up. Receiver operating characteristic analysis was performed to determine the cutoff value. Kaplan–Meier curves were drawn with log-rank statistics; moreover, univariate and multivariate Cox proportional hazards regression analyses and Harrel C-indices were analyzed.p < 0.05). The cutoff values of LS and LSRe were −12.30 (%) and 1.07 (s–1), respectively.During 3.6 ± 1.8 years of follow-up, 25 adverse events were recorded. Kaplan–Meier survival curves and univariate Cox analysis verified that patients with significantly reduced radial strain (RS), circumferential strain (CS), longitudinal strain (LS), RS rate at systole and diastole (RSRs and RSRe), and circumferential and LS rates at diastole (CSRe and LSRe) had worse event-free survival. After multivariate correction, only LS and LSRe remained significantly associated with adverse outcomes (hazard ratio = 1.243 [1.083–1.428] and 0.067 [0.017–0.258], respectively, all The LV strain and strain rate prior to PVR are important prognostic factors for adverse events after PVR in rToF. Tetralogy of Fallot (ToF) is one of the most common types of congenital heart disease, affecting 356 per million live births . When su2 and the end-diastolic volume index exceeds 160 ml/m2; however, this cutoff for reintervention may not correlate with clinical benefit. A more sensitive parameter that can predict adverse outcomes at an earlier stage may help identify the optimal time for PVR surgery (The guidelines issued by the AHA/ACC and ESC recommend the right and left ventricular end-diastolic volume index (RVEDVI and LVEDVI), tricuspid regurgitation (TR), arrhythmia, and other cardiac function and clinical parameters to determine the timing of PVR surgery , 5. The In comparison with the traditional measurements, including ejection function (EF) and ventricular volume, the myocardial strain detected by cardiac magnetic resonance (CMR) feature tracking, which reflects myocardial deformation, has added value to predict the outcome of various cardiovascular diseases , 8. AlthOwing to ventricular coupling, LV strain is also implicated in RV volume overload . Thus, LTo date, there have been studies comparing the changes in strain and strain rate before and after PVR –13 or thThis prospective study was conducted at our hospital. The study protocol was approved by the ethics committee of our hospital. All participants provided written informed consent prior to enrolment.Asymptomatic patients were defined as those who maintained a functional status in New York Heart Association class I or II without arrhythmia or heart failure symptoms/signs that cause syncope .via telephone inquiring with patients or their contacts every 3 months after enrolment. Adverse events that occurred after PVR surgery were recorded. Adverse events included sudden cardiac death   , cardiacn alive) , heart fn alive) , and arrn alive) , 21, reon alive) .2, (2) RV end-systolic volume index (RVESVI) > 80 ml/m2, (3) RVEF < 47%, (4) LVEF < 55%, (5) QRS duration > 160 ms, (6) sustained tachyarrhythmia related to right heart volume load, and (7) the presence of other hemodynamically significant lesions.Patients with rToF who were candidates for PVR were initially screened for this study from January 2014 to June 2020. According to the indications for PVR in asymptomatic patients with moderate or severe PR after rToF recommended by Boston Children’s Hospital in 2013 , asymptoThe following exclusion criteria were established: (1) obvious symptoms, (2) the presence of residual severe right ventricle outflow tract obstruction , (3) RV pressure surpassing or equal to LV pressure, (4) ICD insertion or history of PVR, (5) contraindications for CMR or surgery, and (6) incomplete or poor-quality CMR .2; matrix, 184 × 256; slice thickness, 6 mm; TR/TE/flip-angle: 3 ms/1.6 ms/45°; temporal resolution, 43 ms; and parallel acquisition technique factor, 2). The two-dimensional phase-contrast images perpendicular to the main pulmonary artery (PA) were used for quantification of the PR fraction .CMR examinations were performed on a 3.0 T system within 6 months prior to PVR surgery using a 3.0 T scanner  with front and back surface coils and retrospective ECG triggering for capture of the entire cardiac cycle by the same senior operator. Cine images were obtained using a balanced steady-state free precession (SSFP) sequence, including 2-chamber, 4-chamber, and short-axis acquisitions with 25 image frames per cardiac cycle. The short-axis scans covered the entire LV  by the same surgeon. A longitudinal incision was made in the pulmonary artery trunk or the position where the patch was previously placed. The replacement valve was inserted in the orthotropic position.The LV and RV cardiac function analysis and strain analysis were measured using CVI 42 software  with the help of artificial intelligence  . The endThe global cardiac strain and strain rate representing the average of the entire heart were calculated from CMR cine images using the mature feature tracking software CVI 42 version 5.12. The method has been described in detail in a previous study . In brie**) after at least 1 week of blinding to previous results. Inter-observer reliability was independently assessed by two radiologists with more than 3 years of work experience and more than 650 cases of cardiac MRI analysis (** and AA), where one radiologist measured once and then a second radiologist measured again (blinded to the first radiologist’s measurements).Intra- and inter-observer reliabilities were assessed in 20 randomly selected patients using Bland–Altman plots. Intra-observer reliability was derived from repeated measurements by one radiologist  and MedCalc . Continuous data were descriptively reviewed and statistically analyzed using the Kolmogorov–Smirnov test to check for normality of the continuous variables. Continuous variables were described as means ± standard deviations or as median values with interquartile range, with respect to the normality of distribution. Comparisons between demographic and strain variables determined in the adverse event and non-adverse event groups were performed using either Student’s tributed . The BonP < 0.05) to identify the independent risk factors of prospective adverse events. Harrel C-indices were used to compare the relative predictive abilities of strain and strain rate. Statistical significance was set at P < 0.05.To visualize the difference in event-free survival between different patient categories, Kaplan–Meier curves were drawn, followed by the log-rank test. The optimal preoperative strain and strain rate cutoffs were identified using receiver operating characteristic (ROC) curve analysis using the Youden index. The ROC curve was then drawn with the corresponding calculated area under the curve (AUC). The parameters satisfying the pH assumption were included in the univariate Cox regression analysis. Univariate Cox regression analysis was used to evaluate the predictive value of the strain and strain rate. Multivariate analysis Cox regression (forward LR) was performed for those parameters that were confirmed to be statistically significant in univariate analysis (n = 56). The mean QRS duration (150.78 ± 30.89 ms) was extended. On average, patients had slightly reduced LVEF (50.47 ± 10.94%) and RVEF (38.37 ± 12.53%). Meanwhile, the RVEDVI and RVESVI were significantly enlarged . The mean PR fraction was 49.98 ± 18.58%.From January 2014 to June 2020, 78 asymptomatic patients with rToF with moderate or severe PR  were included for analysis with an average follow-up duration of 3.6 ± 1.8 years. The reasons for failure to be included are detailed in the study flowchart . The patp < 0.001; –1, p < 0.001) and RSRe . Furthermore, patients with adverse events noted had lower absolute preoperative CSRe  and LSRe  than those without adverse events. Significant differences were also observed in heart rate, age at surgical repair, age at PVR, LVEF, LVESVI, RVESVI, RV mass, and RV mass index between the two groups  patients had noted adverse events , and 53 (68%) patients did not have any adverse events. Significant differences were noted between the two groups in LV RS, CS, and LS , −1.65 s–1 , 0.84 s–1 , and 1.07 s–1 , respectively. The AUCs of RS, CS, LS, RSRs, RSRe, CSRe, and LSRe were 0.863, 0.959, 0.916, 0.792, 0.889, 0.788, and 0.871, respectively , preoperative CS of < −12.35% (p < 0.001), and preoperative LS of < −12.3% (p < 0.001), respectively. As for the strain rate, the 5-year event-free cumulative survival rates were 74, 82.4, and 65.2% for patients with a preoperative RSRs of > 1.69 s–1 (p < 0.001), preoperative RSRe of < −1.65 s–1 (p < 0.001), and preoperative CSRe of ≥ 0.84 s–1 (p = 0.004), respectively. The median survival time was 62% for patients with a preoperative LSRe of > 1.07 s–1 (p < 0.001).The Kaplan–Meier survival curves  verifiedIn univariate Cox analysis, both strain  and strain rate  were significantly associated with adverse outcomes in patients with rToF after PVR . The HRsRegarding cardiac function parameters, in the univariate Cox analysis, RVESVI, LVEDVI, and LVESVI were associated with worse outcomes after PVR, whereas RVEDVI, RVEF, and LVEF were not. In addition to NYHA class III or IV prior to PVR, severe tricuspid regurgitation, ≥ 3 previous cardiac surgeries, sustained atrial arrhythmias prior to PVR, and the time interval between PVR and endpoint were related to adverse events after PVR . However–1 and 0.01 ± 0.29–0.10 ± 0.30 s–1, respectively; Bland–Altman plots are presented in In a subgroup of 20 patients, reliability of strain was generally high with an intra-observer difference of approximately 0.01 ± 0.28%–0.12 ± 0.26%, and an inter-observer difference of approximately 0.01 ± 0.24%–0.15 ± 0.31%. Similarly, intra- and inter-observer differences were also small for strain rates  factors, including conventional volume parameters of both ventricles, ≥ 3 previous cardiac surgeries, severe TR, sustained atrial arrhythmias prior to PVR, and NYHA III/IV, were all associated with outcomes of PVR in patients with rToF; (2) preoperative LV RS, CS, LS, RSRs, CSRe, RSRe, and LSRe were significantly associated with adverse outcomes after PVR surgery in patients with rToF, suggesting that they serve as a novel index for risk stratification assessment in patients with rToF after PVR; and (3) multiple variable analysis demonstrated that patients with the highest incidence of adverse events were those with a severe reduction in LV LS and/or LSRe prior to PVR surgery.Progressive PR is one of the most common complications occurring after rToF, despite the current treatment strategies used to treat ToF, demonstrating long-term survival  . In respSeveral factors influence the prognosis of PVR, most of which are clinical indicators or surgery-related factors. Jang et al.  conducteP = 0.03). The reason may be that the RVEF values of our study, in both the event and no event groups, were relatively low (<40%), and our study had a shorter average follow-up time (3.6 vs. 9.5 years). Similar to the INDICTOR study, we found that LVESVI and atrial arrhythmias prior to PVR are related to prognosis; however, we did not find the predicted value of the RV mass-to-volume ratio and RV systolic blood pressure, as mentioned in their study. In addition, we found that LVEDVI and RVESVI were correlated with prognosis, which is consistent with the findings of other studies. However, after incorporating the strain parameter into the multivariate analysis, the predictive value of these parameters ceased to exist.Furthermore, in our study, the pre-PVR LV and RVEF were not associated with adverse events, whereas previous studies, including the INDICTOR study , found t2 peak (%), which assesses the degree of exercise tolerance, may be a useful predictor of adverse events after PVR , right ventricular end-systolic volume , and age at PVR can predict adverse events . HoweverThis study had some limitations that must be highlighted. For instance, our study was conducted in one medical center with a relatively small sample size; thus, in addition to GLS, the feasibility of other parameters, such as GCS, should be further explored. Large-sample multicenter studies with possible confounders are required to validate and improve the power of assessing events. Another limitation of the study is the cardiac endpoint utilized, which includes a wide range of heterogeneous events from hard to softer ones. Moreover, it was determined that the number of outcomes was modest, although this is the largest study of patients with rToF after PVR . The numIn conclusion, PVR in patients with rToF has relatively low mortality and fewer adverse events. Preoperative LV RS, CS, LS, RSRs, RSRe, CSRe, and LSRe were significantly associated with adverse outcomes after PVR. In particular, LS and LSRe assessed with CMR are independent predictors of survival in patients with rToF after PVR and offer incremental information for risk stratification beyond clinical parameters, biomarkers, and standard CMR parameters.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 Fuwai Hospital Ethics Department. Written informed consent to participate in this study was provided by the participants or their legal guardian/next of kin.SZ, SL, and ML: guarantors of integrity of entire study. BZ, SY, ZF, and ML: literature research. BZ, SY, FH, and YJ: clinical studies. BZ and ML: statistical analysis. BZ, SZ, SL, and ML: manuscript editing. All authors have study concepts/study design or data acquisition or data analysis/interpretation, manuscript drafting or manuscript revision for important intellectual content, approval of final version of submitted manuscript, and agreed to ensure any questions related to the work are appropriately resolved.