Background: Diagnosis of cardiac involvement in amyloid A (AA) amyloidosis is challenging since AA amyloidosis is a rare disease and cardiac involvement even less frequent. The diagnostic yield of currently available non-invasive imaging methods is not well-studied and rather limited, and invasive endomyocardial biopsy (EMB) is rarely performed due to the potential risk of this procedure. Cardiovascular magnetic resonance (CMR)-based myocardial tissue characterization by late-gadolinium-enhancement (LGE) imaging and novel-mapping approaches may increase the diagnostic yield in AA amyloidosis.Methods: Two patients with AA amyloidosis in whom cardiac involvement was suspected based on CMR findings and subsequently proven by biopsy work-up are presented. CMR studies were performed on a 1.5-T system and comprised a cine steady-state free precession pulse sequence for ventricular function and a late-gadolinium-enhancement (LGE) sequence for detection of myocardial pathology. Moreover, a modified Look-Locker inversion recovery (MOLLI) T1-mapping sequence was applied in basal, mid and apical short-axes prior to contrast agent administration and ~20 min thereafter to determine native T1 and ECV values.Results: Both patients showed slightly dilated left ventricles (LV) with mild to moderate LV hypertrophy and preserved systolic function. Only a very subtle pattern of LGE was observed in both patients with AA amyloidosis. However, markedly elevated native T1  and extracellular volume fraction (ECV) values  were measured in the myocardium suggesting the presence of cardiac involvement - with subsequent EMB-based proof of AA amyloidosis.Conclusion: We recommend a multi-parametric CMR approach in patients with AA amyloidosis comprising both LGE-based contrast-imaging and T1-mapping-based ECV measurement of the myocardium for non-invasive work-up of suspected cardiac involvement. The respective CMR findings may be used as gatekeeper for additional invasive procedures (such as EMB) and as a non-invasive monitoring tool regarding assessment and modification of ongoing treatments. Amyloidosis is a family of multifaceted, heterogenous diseases based on abnormally folded proteins characterized by pathological accumulation of insoluble, polymeric protein fibrils in the extracellular space of various tissues and organs—sometimes leading to organ dysfunction, organ failure, and death. So far, there are more than 30 different proteins, which have been identified as amyloidogenic—out of which at least 17 can cause systemic disease  are (i) immunoglobulin light chain (AL)  and (ii)To identify the underlying inflammatory process in newly diagnosed AA amyloidosis, several factors ranging from genetic variation to ancestral history of patients have to be taken into consideration. For example, SAA1 genotype is one of those predisposing factors supposed to affect amyloidogenesis  . LikewisAvailable knowledge indicates that SAA does not affect the human heart directly, and significant clinical cardiac manifestations are rare. However, it has been shown that SAA may be deposited in cardiac tissue . If presIn the present report, the use of multi-parametric CMR imaging was crucial to diagnose cardiac involvement in case of systemic AA amyloidosis. We present two similar cases of AA amyloidosis in whom cardiac involvement was suspected based on CMR findings and subsequently proven by biopsy work-up. Importantly, both cases showed only a very subtle pattern of LGE—not resembling the well-known characteristic pattern of LGE that can be found in those patients with ATTR and AL amyloidosis. However, additional ECV measurement based on T1-mapping was highly suggestive of an ongoing infiltrative process in the extracellular space of the myocardium.Early diagnosis of cardiac involvement in amyloidosis can be challenging due to unspecific or missing clinical manifestations. Although non-invasive imaging modalities such as echocardiography (with speckle-based strain measurement), bone scintigraphy  as well CMR has been established as a robust diagnostic tool for the work-up of different cardiac diseases including LV hypertrophy of unknown origin and was recently shown to offer a very high diagnostic yield regarding the diagnosis of cardiac ATTR and AL amyloidosis , 16. An Both subjects were Caucasian males who presented with end stage renal disease (ESRD) requiring dialysis. The first patient was a 44-year-old young male patient with terminal renal insufficiency and was on hemodialysis since 08/2018. A rectal biopsy performed in 11/2019 had revealed SAA depositions. Echocardiography showed a moderate to severe LV hypertrophy with preserved ejection fraction. Additional EMB samples were taken in this patient and confirmed the presence of cardiac AA amyloidosis. Subsequent genetic testing revealed heterozygosity for 2 pathogenic variants of the MEFV-gene and supported the diagnosis of FMF as a plausible cause of AA amyloidosis.The second subject, a 53-year-old male and tobacco-smoking patient, was initially referred from a regional hospital to our university hospital following clinical deterioration of the general condition during dialysis in addition to new-onset of diffuse abdominal pain. Incidental findings comprised a pericardial effusion with a maximal diameter of 2 cm. Noteworthy, he was treated with colchicine since his childhood due to suspected MFM. This treatment was stopped in 2012 due to onset of terminal renal insufficiency leading to haemodialysis. The suspected diagnosis of FMF was confirmed by molecular genetic analysis as an underlying inflammatory cause after SAA deposits were detected in EMB samples. In addition, liver biopsies were also performed and confirmed the aforementioned results. Details of the respective patient characteristics can be found in via a femoral artery access site using a 7F long-sheath without angulation following a retrograde approach) as described previously . EMBs were considered positive for viral infection if viral genomes were detected by nested PCR/reverse transcription PCR, as published previously . EMB speCMR studies were performed on a 1.5-T system . CMR data acquisition was performed according to the standardized protocol suggested by the Society for Cardiovascular Magnetic Resonance (SCMR) . Our CMRBoth patients showed similar results regarding cine-imaging: LVs were slightly dilated, mild to moderately hypertrophied with preserved systolic function. Right ventricles (RV) showed no abnormalities with regard to size and function. Regarding myocardial tissue characterization, a subtle and rather diffuse pattern of LGE was detected in the basal segments of the LV lateral wall. Moreover, a little pericardial effusion was observed . PatientBased on histopathology, there was no evidence of active lymphocytic myocarditis. Using Congo-red staining and immunohistochemistry, the presence of cardiac AA amyloidosis was confirmed with a very subtle and diffuse amyloid pattern in the extracellular space and a marked vascular involvement . In addiCardiac involvement in case of AA amyloidosis is not common and rather challenging to diagnose. An extensive literature search regarding the diagnostic value of non-invasive imaging modalities to diagnose cardiac AA amyloidosis did not result in any landmark studies nor in convincing case reports. Obviously, echocardiography is a widely available tool that has improved significantly the diagnosis of CA after the introduction of speckle-tracking-based strain analysis, however, is still lacking high sensitivity as well as specificity –23. In cin vivo quantification of myocardial edema suggestive of myocardial inflammation  sophisticated work-up of non-ischemic cardiomyopathies, and in this context to differentiate between CA and HCM based on the pattern of LGE. While the LGE pattern in case of CA is rather diffuse, starts mostly from the subendocardial layer of the basal segments and eventually spreads to all myocardial layers and segments , 24, claammation . Myocardammation .Several previous studies have shown that measurement of native T1 and ECV values are useful tools for the work-up of hypertrophic cardiac phenotypes of unknown origin . The degN = 134 non-diabetic patients with chronic kidney disease (CKD) stages 2 to 5 without myocardial ischemia at 1.5-Tesla and found native T1 values of 966 ± 21 ms in stage 2 patients vs. 994 ± 33 ms in stage five patients (p < 0.001) —again at 1.5-Tesla—and documented septal native T1-values of 1002 ± 30 ms and a myocardial ECV value of 28 ± 2%  myocardial fibrosis that in turn may lead to increased myocardial native T1 and ECV values. In this context, Hayer et al. recently studied In summary, unlike other well-known subtypes of amyloidosis (such as ATTR and AL), a characteristic pattern of diffuse LGE is not observed in case of AA amyloidosis based on CMR. However, measurement of myocardial ECV—in addition to myocardial T1-/T2-mapping—may be of paramount diagnostic value to detect cardiac involvement in case of AA amyloidosis—despite a missing characteristic LGE pattern. Therefore, we recommend a comprehensive multi-parametric CMR approach comprising the combined analysis of T1-/T2-mapping, measurement of ECV and careful assessment of LGE-images in patients with AA amyloidosis and suspected cardiac involvement.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.BC devised the project and the main conceptual idea, and wrote the manuscript. SD contributed to sample and data collection. MB and CM provided critical feedback and helped shape the research and analysis. KK performed the histological and immunohistochemical analyses. AY supervised the work, contributed to the interpretation of results, provided critical feedback and helped shape the research, analysis, and manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.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.


We aimed to understand the role of the transcriptional co-factor Yes-associated protein (Yap) in the molecular pathway underpinning the pathogenic transformation of synovial fibroblasts (SF) in rheumatoid arthritis (RA) to become invasive and cause joint destruction.Pdgfrα-CreER and Gdf5-Cre mice, crossed with fluorescent reporters for cell tracing and Yap-flox mice for conditional Yap ablation. Fibroblast phenotypes were analysed by flow cytometry, and arthritis severity was assessed by histology. Yap activation was detected using Yap–Tead reporter cells and Yap–Snail interaction by proximity ligation assay. SF invasiveness was analysed using matrigel-coated transwells.Synovium from patients with RA and mice with antigen-induced arthritis (AIA) was analysed by immunostaining and qRT-PCR. SF were targeted using Pdgfrα-expressing SF during AIA, with predominant expansion of the Gdf5-lineage SF subpopulation descending from the embryonic joint interzone. Gdf5-lineage SF showed increased expression of Yap and adopted an erosive phenotype (podoplanin+Thy-1 cell surface antigen−), invading cartilage and bone. Conditional ablation of Yap in Gdf5-lineage cells or Pdgfrα-expressing fibroblasts ameliorated AIA. Interleukin (IL)-6, but not tumour necrosis factor alpha (TNF-α) or IL-1β, Jak-dependently activated Yap and induced Yap–Snail interaction. SF invasiveness induced by IL-6 stimulation or Snail overexpression was prevented by Yap knockdown, showing a critical role for Yap in SF transformation in RA.Yap, its binding partner Snail and downstream target connective tissue growth factor were upregulated in hyperplastic human RA and in mouse AIA synovium, with Yap detected in SF but not macrophages. Lineage tracing showed polyclonal expansion of Our findings uncover the IL-6–Yap–Snail signalling axis in pathogenic SF in inflammatory arthritis. Synovial fibroblasts (SF) are key drivers of rheumatoid arthritis (RA) pathogenesis; however, the SF lineages involved and the molecular mechanisms underpinning their pathogenic transformation are incompletely understood.Gdf5-lineage SF, defined by their ontogenic derivation from the joint interzone, are the key pathogenic SF in inflammatory arthritis. Mechanistically, interleukin (IL)-6 signals via Jak to activate Yes-associated protein (Yap), which forms a complex with Snail to drive the invasiveness of SF, and selective targeting of Yap in Gdf5-lineage SF ameliorates inflammatory arthritis.This study shows that This study supports the targeting of IL-6 and Jak in RA, not only for immunosuppression but also to directly control the Yap–Snail-mediated pathogenic behaviour of SF.Rheumatoid arthritis (RA) is a common immune-mediated chronic inflammatory disease causing joint damage and deformities. Current treatment consists of synthetic and biological disease-modifying antirheumatic drugs aimed at systemic immunosuppression. Nonetheless, some patients fail to respond to treatments, and joint damage progression can still occur despite clinical remission.A hallmark of RA pathology is synovitis, causing the synovium to thicken and form a pannus that invades cartilage and bone, driven by pathogenic transformation and proliferation of fibroblasts with infiltration of inflammatory/immune cells. A recent study reported two distinct subsets of synovial fibroblasts (SF), immune effector fibroblasts expressing podoplanin (Pdpn) and Thy-1 cell surface antigen (Thy1) found in the sub-lining synovial tissue and promoting inflammation, and destructive Pdpn+Thy1− fibroblasts in the lining layer mediating cartilage and bone damage.Gdf5-lineage cells, descend from the Gdf5-expressing joint interzone cells in the embryo.Gdf5-lineage cells include the SF in the lining as well as a subset of SF in the sublining.Cell lineage tracing studies have revealed that the adult synovium consists of ontogenetically diverse fibroblast subsets. One subset, the Gdf5-lineage cells underpins synovial lining hyperplasia following acute joint surface injury in mice.The synovial pannus is a tumour-like structure resulting in part from uncontrolled fibroblast expansion. Increased activity of the transcriptional cofactor Yes-associated protein (Yap) is known to cause tissue overgrowth in multiple tissues and organs through stimulating cell proliferation.The role of Yap in immune-mediated inflammatory arthritis and the signalling mechanisms that link Yap activity to the pathogenic transformation of SF await clarification. A reduced severity in the K/BxN serum-transfer arthritis model in mice was reported after treatment with the small molecule verteporfin,Here, we show that Yap is highly expressed by SF in both human RA and mouse AIA and that conditional genetic ablation of Yap in SF ameliorates AIA. Mechanistically, Yap is Jak-dependently activated by interleukin (IL)-6, a key inflammatory cytokine in RA, and forms a complex with the transcription factor Snail to drive the SF invasive phenotype. Our findings identify the IL-6–Yap–Snail signalling axis as a fibroblast-specific therapeutic target in RA synovitis.Materials and methods are available in the 10.1136/annrheumdis-2021-220875.supp1Supplementary dataYAP mRNA expression levels correlated non-significantly with the expression of SNAIL (p=0.083) and significantly with the expression of YAP downstream targets CTGF (p=0.024) and GP130  were mostly quiescent and located predominantly in the synovial lining, while other SF  were found throughout the synovium  phenotype during AIA, as compared with control knees  target cells. Immunostaining of synovium showed a significant decrease in Yap expression in the cKO mice , which moreover revealed a significantly higher expression of Yap in the Gdf5-lineage SF compared with other SF after 7 days of AIA  (Gdf5-lineage cells in synovium during AIA was observed in both Yap WT (p<0.001) and Yap cKO mice , immune infiltrates in synovium (p=0.026) and erosions at the joint margins (p=0.002), and a non-significant trend towards decreased cellular exudate, resulting in an overall arthritis score of 4.9  in the cKO mice, compared with 6.5  in p=0.002; . Despitep=0.023) , extensip<0.001, . Accordinduction . These dYap ablation on the expression of key catabolic and inflammatory mediators by qRT-PCR analysis of Tom+ Gdf5-lineage SF purified from AIA mice. Compared with Gdf5-lineage SF of Yap WT mice, the Gdf5-lineage SF from Yap cKO mice displayed reduced expression levels of critical enzymes mediating SF invasiveness, including Mmp9 (p=0.048), Mmp13 (p=0.044) and Mmp14 (p=0.012),Next, we investigated the effects of conditional Yap cKO mice compared with Yap WT controls after AIA  KO model in which Yap ciKO , althoug Yap cKO . Nonethe WT mice .Together, these findings indicate that Yap has crucial functions in pathogenic SF to promote inflammation and joint destruction, and demonstrate amelioration following its selective targeting in SF in inflammatory arthritis.Yap mRNA expression at least after 24 hours (To assess the ability of key inflammatory cytokines to activate Yap, we used a Yap–Tead reporter construct,24 hours , indicat24 hours , showing24 hours  and relySince the transcription factor Snail, previously reported to be involved in TNF-α-mediated SF activation in RA,Yap in SF ameliorates immune-mediated inflammatory arthritis in vivo and show that IL-6 increases Yap activity through Jak signalling and promotes interaction of Yap and Snail to drive the pathogenic behaviour of SF.SF are key cells in RA that sustain inflammation and induce tissue damage, but the molecular mechanisms underlying these functional characteristics remain to be fully elucidated. Here, we report that ablation of Yap in SF using two different mouse models, a specific role for Yap in driving the pathological behaviour of SF in inflammatory arthritis. The recent demonstration of additional roles for Yap in promoting synovial angiogenesis further supports the possible therapeutic benefits of targeting Yap in RA synovitis.In a previous study using the K/BxN serum-transfer mouse model of inflammatory arthritis and mice engrafted with cartilage and RA-SF, treatment with the non-specific Yap inhibitor verteporfin was shown to reduce arthritis severity and cartilage invasion by RA-SF, respectively.Gdf5-lineage SF drives synovial lining hyperplasia in a traumatic joint surface injury model in mice.Yap in Gdf5-lineage SF reduced not only synovial lining hyperplasia but also immune infiltration and erosive damage in inflammatory arthritis. Decreased synovial lining hyperplasia in AIA was also observed when Yap was knocked out in fibroblasts in adult mice, showing this is not a result of developmental defects resulting from Yap KO.We previously reported that increased Yap activity in Although the upstream regulators of Yap activity are likely to be context-dependent, we uncover a hitherto unappreciated molecular link between Jak-mediated IL-6 signalling, pivotal in RA pathogenesis, and the Yap-mediated invasive SF phenotype. While IL-6 treatment of SF enhanced invasive behaviour, Yap silencing completely prevented the IL-6-induced SF invasion. JAK inhibition with baricitinib was shown to abrogate cytokine-induced invasive behaviour of SF.YAP and GP130 expression in human RA synovium, in accordance with evidence that YAP upregulates GP130 expression in an autoregulatory loop,SF, which do not express the IL-6R, undergo pro-inflammatory sIL6R-mediated trans-signalling, facilitated by cell surface expression of GP130.Snail was previously reported to be highly expressed in RA synovium and SF, and its lentiviral vector-mediated silencing in the joint ameliorated collagen-induced arthritis in rats.Gdf5-lineage SF were largely confined to the synovial lining, as previously reported,Gdf5-lineage SF underwent extensive proliferation and expansion throughout the synovium, indicating a derangement of the anatomical segregation of fibroblast lineages during synovitis. Our findings show the Gdf5-lineage SF to become erosive and support a role for Yap in the destructive SF, possibly through modulation of MMP expression.Yap cKO mice with AIA suggests that the Gdf5-lineage also includes immune effector SF and that Yap may be needed in these cells to sustain inflammation. Indeed, Gdf5-lineage SF from Yap cKO AIA mice displayed reduced expression levels of IL-34, an inflammatory cytokine produced by RA-SF able to support osteoclastogenesisA recent study reported functionally distinct fibroblast subsets in RA synovium, with destructive fibroblasts restricted to the synovial lining layer and immune effector fibroblasts located in the synovial sub-lining.In summary, we report a novel IL-6-Jak-Yap–Snail signalling axis linking immune-mediated inflammation with pathogenic SF in RA. Our findings position Yap in RA-SF at the crossroads between the activated immune system and their destructive phenotype, and suggest Yap for SF-targeted therapy in RA.


Since the prevalence of heart failure (HF) increases with age, HF is now one of the most common reasons for the hospitalization of elderly people. Although the treatment strategies and overall outcomes of HF patients have improved over time, hospitalization and mortality rates remain elevated, especially in developed countries where populations are aging. Therefore, this paper is intended to be a valuable multidisciplinary source of information for both doctors  and pharmacists in order to decrease the morbidity and mortality of heart failure patients. We address several aspects regarding pharmacological treatment , as well as the particularities of patients (age-induced changes and sex differences) and treatment . The article also highlights several drugs and food supplements that may worsen the prognosis of HF patients and discusses some potential drug–drug interactions, their consequences and recommendations for health care providers, as well as the risks of adverse drug reactions and treatment discontinuation, as an interdisciplinary approach to treatment is essential for HF patients. Heart failure is defined by the European Society of Cardiology Guidelines as a clinical syndrome derived from structural and/or functional cardiac abnormalities . This syDrug therapy is a well-established strategy in treating heart failure (HF) and there are guidelines that cover most of the long-standing and recent research, although specific situations cannot be extensively analyzed .HF affects a wide range of patients and thus occurs in several forms that are widely based on the assessment of left ventricular (LV) ejection fraction (EF): heart failure with preserved ejection fraction (HFpEF), with mildly reduced ejection fraction (HFmrEF), and with reduced ejection fraction (HFrEF) . HFpEF iThe diagnosis of HFpEF is relatively demanding, as patients usually have a normal LV, with a certain degree of wall hypertrophy and/or increased left atrial (LA) volume. Diagnosis requires proof of increased LV filling pressure or impaired LV filling, which explains the terminology of diastolic HF/dysfunction. However, diastolic dysfunction is also found in most HFrEF and HFmrEF patients (previously referred to as systolic HF) .It seems that the prevalence of HF significantly varies with age, starting from approximately 1–2% among adults and increasing strikingly to more than 10% in people older than 70 years, and is more common in men than in women . Since HExcept for the pathology itself, HF is also associated with co-morbidities such as prior stroke or myocardial infarction, atrial fibrillation, diabetes mellitus, chronic lung disease, osteoarthritis, thyroid disease, dementia, depression, and chronic renal/hepatic failure, and all of these pathologies require additional treatment strategies .Moreover, several aspects, such as changes in the mechanisms  involved in the physiopathogenesis of HF , the preMoreover, because the worldwide population is aging and the number of people ≥80 years old will triple by 2050, it is extremely important to decrease the prevalence and incidence of cardiovascular pathologies in order to decrease multi-morbidity and health care costs .Herein, we discuss the main important aspects regarding pharmacological approaches, treatment strategies, and the particularities of patients and treatment that should absolutely be taken into account in order to improve treatment outcomes for HF patients.f channel blocker, highly selective for sinoatrial node pacemaker current) and symptom relief medication . Except for loop diuretics and digoxin, all of these options for treatment have been shown to improve symptoms, reduce hospitalization rates and/or prolong survival, in large randomized controlled trials [The pharmacological treatment of HF is oriented towards the following: long-term management of the pathology and improvement in survival , ARBs (angiotensin receptor blockers), beta-blockers, MRA , ARNI (angiotensin receptor-neprilysin inhibitors), SGLT2 (sodium-glucose cotransporter-2) inhibitors and ivabradine, an Id trials ,17.Drug selection for HF depends on the type of HF and on the personal characteristics of the patients, the most important goals being as already mentioned: to reduce mortality, to improve clinical status and functional capacity and to prevent hospitalization ,17.Later, we summarize the mechanisms of actions and the benefits of the main classes of drugs/pharmaceutical substances used in the treatment of HF.1-receptors located in the heart and kidneys; β2-receptors located in the vessels, lungs, gastrointestinal tract, liver, uterus, and skeletal muscle; β3-receptors located in the adipocytes). By binding toβ1-receptors, they block the deleterious actions of catecholamines: noradrenaline and adrenaline [1 receptors in the juxtaglomerular apparatus), thus decreasing the severity of angiotensin II-induced vasoconstriction and aldosterone-induced volume expansion [1-selective, e.g., atenolol, metoprolol, bisoprolol and nebivolol). Certain beta-blockers are associated with vasodilating properties . The vasodilating properties are beneficial because they decrease the peripheral vascular resistance, thus improving stroke volume, left ventricular function and therefore, cardiac output [Beta-blockers bind to β adrenergic receptors  and blood pressure. In this way, they decrease the left ventricular afterload, thus increasing cardiac output and decreasing filling pressures (both left and right), which will improve pulmonary and systemic venous congestion .ARBs work on the same angiotensin pathway, the difference being the fact that they bind to AT1 receptors located on the vascular smooth muscle, as well as in other tissues  and thus, they block the damaging actions of angiotensin II. They induce less vasoconstriction and antidiuretic hormone and aldosterone secretion and lower blood pressure. Therefore, as well as ACEIs, they prevent damage to the vasculature, heart and kidneys .As in some cases, the ACEIs or ARBs do not suppress the excessive formation of aldosterone sufficiently, patients with moderate to severe heart failure can also benefit from aldosterone antagonists. MRAs work by competitively blocking the binding of aldosterone to the mineralocorticoid receptor, thus decreasing the reabsorption of sodium and water, as well as decreasing the excretion of potassium, leading to cardioprotective effects .Loop diuretics act by inhibiting the luminal sodium-potassium chloride cotransporter located in the thick ascending limb of the loop of Henle, where approximately 20–30% of the filtration of sodium occurs. Therefore, compared with other diuretics, loop diuretics reduce the reabsorption of a much greater proportion of sodium, leading to the excretion of it, alongside water. This will decrease the plasma volume, cardiac workload, and oxygen demand, thereby relieving the signs and symptoms of volume excess. They are currently used to relieve symptoms associated with pulmonary congestion and peripheral edema in HF patients .If the patient is intolerant to ACEIs/ARBs/ARNIs, other vasodilators can be used, such as isosorbide dinitrate or hydralazine. Isosorbide dinitrate acts by releasing nitric oxide into the vascular smooth muscle cell, which activates guanylyl cyclase . Therefore, the increased intracellular cGMP will activate a series of reactions, which will decrease the intracellular calcium and thus, the contractility of vascular smooth muscle, leading to smooth muscle relaxation and vasodilatation. Hydralazine also acts on the vascular smooth muscle, with multiple effects such as the stimulation of nitric oxide release from the vascular endothelium , opening of potassium channels and inhibition of calcium release from the sarcoplasmic reticulum, thus inducing smooth muscle relaxation and subsequent vasodilatation .+/K+/ATPaze pump in the cardiac muscle, a pump responsible for moving sodium ions out of the cells and bringing potassium ions into the cells. When sodium concentrations in the cardiac cell increases, another electrolyte mover known as the sodium-calcium exchanger pushes the excess of the sodium ions out, while bringing additional calcium ions in. Therefore, the intracellular calcium increases, which will later increase the force of contraction and thus the cardiac output. Cardiac output increases followed by a decrease in ventricular filling pressures. Moreover, it inhibits the atrio-ventricular node, by stimulating the parasympathetic nervous system. Therefore, it diminishes the electrical conduction in the AV node and thus the heart rate. However, it has not been shown to reduce mortality [Digoxin increases cardiac muscle cells’ contractility by inhibiting Naortality .f current channel, responsible for the cardiac peacemaker, which regulates the heart rate. In this way, it prolongs the diastolic time and decreases the heart rate without affecting myocardial contraction/relaxation or ventricular repolarization [Ivabradine acts by blocking the Irization .As several pharmacological classes of drugs have emerged in recent years with proven long-term benefits, in the following, we describe some of the most important aspects, as they are currently underused.The combination of sacubitril and valsartan is the first from the class of angiotensin receptor–neprilysin inhibitors (ARNI). Agents in this new therapeutic class  act at the level of RAAS and the neutral endopeptidase system. Sacubitril acts by inhibiting neprilysin and slowing down the degradation of natriuretic peptides, bradykinin, adrenomedullin, and other peptides . It is iSacubitril/valsartan also improves symptom severity and heart functionality in patients with HFpEF, reducing the serum levels of the biomarker NT-pro BNP (and increasing BNP), an indicator of heart failure severity, and improves quality of life after 24 weeks .One of the largest HF trials ever performed  compared enalapril with sacubitril/valsartan. In this trial, 8442 patients with HFrEF with FEVS ≤ 40% were enrolled and randomly received enalapril or sacubitril/valsartan twice daily. The trial was stopped early after 27 months because sacubitril/valsartan met the pre-specified stopping endpoint for an overwhelming benefit. All of the outcomes showed a 20% lower event rate in favor of sacubitril/valsartan; even the death rate from any cause was 16% lower in the group receiving sacubitril/valsartan . ARNIs hIn the PROVE-HF and EVALUATE-HF trials, sacubitril/valsartan showed efficacy in improving the structural and functional changes that occur during heart failure. It improves cardiac remodeling and decreases the biomarker NT-pro BNP, so the drug reverses the damage to the heart in HFrEF patients .Sacubitril/valsartan is recommended to replace ACE inhibitors when HFrEF patients are still symptomatic after optimal therapy. When initiating therapy with sacubitril/valsartan, there are some safety issues, including symptomatic hypotension, angioedema, and risk of hyperkalemia, so monitoring blood pressure levels, kidney function, and kalemia is extremely important ,33. AlthIt is known that patients with type 2 diabetes mellitus (T2DM) are prone to developing cardiovascular events and heart failure, which can lead to high rates of hospitalization and premature mortality .A new class of antidiabetics, sodium glucose co-transporter-2 (SGLT2) inhibitors, has also been found to have beneficial effects in patients with cardiac diseases ,37. The Aside from the direct mechanism of action on glucose control, other indirect mechanisms are taken into account regarding possible cardiovascular benefits .In The main trials reporting the benefits of SGLT2 inhibitors in HF patients with reduced EF, more precisely of dapagliflozin and empagliflozin, are as follows: DAPA-HF , DEFINE-2) and having a median period of 18 months. The obtained results were as follows: a reduction in all-cause mortality and HF symptom aggravation, and the improvement in physical condition and overall quality of life. Their excellent benefits were seen very soon after starting the treatment with dapagliflozin. Regarding the incidence of adverse effects, they were attributed to volume depletion, renal dysfunction or hypoglycemia, but they did not differ between the studied groups [The DAPA-HF trial evaluated the long-term effects of dapagliflozin on the incidence of cardiovascular death or HF hospitalization, regardless of the presence of diabetes. It was a phase 3 randomized placebo-controlled study, enrolling 4744 patients suffering from chronic HFrEF . In total, 263 patients were included . Dapagliflozin induced an improvement in the patients’ health conditions or in their natriuretic peptides’ plasmatic concentrations [The DEFINE-HF trial assessed the effect of dapagliflozin on the symptoms and biomarker plasmatic concentration of HFrEF patients . It was a double-blind clinical trial involving 3730 patients who received either empagliflozin (10 mg/once daily) or a placebo, in addition to the recommended HF therapy, for a median period of 18 months. Cardiovascular death and hospitalization rates (due to the worsening of HF) were reduced by empagliflozin, regardless of the presence of diabetes mellitus. The annual decline in the renal filtration rate was reduced, as well as the severity of renal complications. Non-complicated fungal infections of the genital tract were reported more often in patients taking empagliflozin [The EMPEROR-reduced clinical trial evaluated the outcome of empagliflozin in patients with chronic HFrEF . In total, 5988 patients were included, who were randomized 1:1 and received either empagliflozin (10 mg/once daily) or a placebo, in addition to their classical HF therapy. Over a period of 26.2 months, the primary outcome was obtained . Beneficial effects were also seen in eGFR, without considering the renal outcomes by themselves. It is important to note the fact that the most used medicines for HFrEF have not shown benefits in patients with HFpEF; therefore, empagliflozin is superior in improving HF outcomes even in patients with HFpEF, which are symptomatic and stable [The EMPEROR-preserved study assessed the effects of empagliflozin in patients with chronic HFpEF , the guidelines recommend the prescription of diuretics, as first line therapy . The othThe treatment strategy also focuses on treating co-morbidities such as: hypertension, atrial fibrillation, cardiac ischemic disease, pulmonary hypertension, diabetes mellitus, chronic kidney disease, COPD (chronic obstructive pulmonary disease), anemia and obesity. The optimal management of co-morbidities has been shown to improve symptoms and to improve the patient’s quality of life .In the case of congestion, diuretics will be very effective and will improve the symptomatology. There is proof that nebivolol, candesartan, digoxin and spironolactone might reduce hospitalization for patients with HFpEF in sinus rhythm . MoreoveFor patients in atrial fibrillation, the prescription of an anticoagulant is very important for reducing thrombo-embolic events . For theAmiodarone and non-dihydropyridine calcium-channel blockers (CCB) are able to reduce heart rate, but due to their adverse effects profile, they should be replaced, if possible. In the case of a fast ventricular rate and symptoms, it might be appropriate to consider AV node ablation, and if there are indications for ICD (implantable cardioverter-defibrillator), AV node ablation with the implantation of CRT-D (cardiac resynchronization therapy–defibrillator) might be preferred. The rhythm control strategy has not been shown to be superior to the rate control strategy. Urgent cardioversion is indicated if atrial fibrillation is life threatening .Regarding HFrEF treatment, the evidence base for drug treatment in HF is for HFrEF. Either an ACEI/ARB/ARNI or a beta-blocker should be started , with doses up-titrated to the maximum tolerated/targeted dose every 2 weeks. ACEI, beta-blockers and MRA proved to improve survival and are recommended for the treatment of every patient with HFrEF. The new ARNI  has been shown to be superior to ACEI in reducing the risk of death and hospitalization. Thus, ARNI is recommended to replace ACEI in cases of HFrEF patients if they are symptomatic despite optimal therapy .In the case of decompensated patients, beta-blockers should not be initiated or if already initiated but patients develop worsening of HF symptoms  caution should be applied regarding their prescription. Moreover, in the case of frailty or other complications , a longer period of time may be required for dose up-titration .ARNI can be prescribed as an alternative to ACEI/ARB intolerance  or in the absence of hypotension, electrolyte or renal imbalance. It is recommended to avoid the association of an ARNI with an ACEI and if previously administered ACEI, to ensure a 36 h washout period before the initiation of an ARNI, due to the high risk of angioedema . This deIf the patients have LVEF ≤ 35%, the guidelines recommend the use of MRAs to reduce mortality and hospitalization. MRAs  are added in patients with symptomatic chronic HFrEF, as a triple therapy (ACEI/ARB/ARNI + beta-blockers + MRA), in the absence of contra-indications. It is essential to achieve the targeted dose of other drugs before initiating the treatment with an aldosterone antagonist and to monitor the potassium levels and renal function under the treatment .SGLT2 inhibitors can also be added, as part of the quadruple therapy (ACEI/ARB/ARNI + beta-blocker + MRA + SGLT2 inhibitor), in the absence of contra-indications. There is no need to achieve targeted doses of other drugs before adding SGLT2 inhibitors, although the loop diuretic dose might require adjustments based on the close monitoring of symptoms and weight .Isosorbide dinitrate/Hydralazine could be prescribed especially for African American patients once the targeted dose of ACEI/ARB/ARNI + beta-blockers + MRA has been achieved .f channel inhibitor ivabradine is recommended in patients with symptomatic HFrEF or LVEF ≤ 35%, in sinus rhythm and heart rate ≥ 70 bpm, and in patients that have been hospitalized for HF in the last year, despite receiving beta-blockers at the maximum tolerated dose, ACEI and an MRA. The titration of the dose should be performed every 2 weeks in order to decrease the heart rate. In the case of patients ≥ 75 years old or in those with a history of conduction defects, the recommended initial dose is 2.5 mg twice daily, administered with meals [The Ith meals .A reduction in the response after beta adrenergic stimulation was observed (due to impaired coupling of G-protein receptors to adenyl cyclase and a decrease in adenyl cyclase concentration), which damages the capacity of the aging heart to increase cAMP as a response to the stimulation of beta receptors ,51. ThusThe filling of left ventricular diastole is impaired by the aging process, as it is a process that depends on energy and active myocardial relaxation. Altered calcium release by the cardiomyocytes, with resulting prolonged contractile period of the heart, was also observed in elderly people ,53.The high deposits of collagen, amyloid, and lipofuscin in the interstitial space and myocyte hypertrophy seen in older people increase cardiac stiffness and decrease cardiac compliance, altering cardiac filling, especially in critical situations ,54,55,56The increased vascular  stiffness , together with impaired endothelium-dependent vasorelaxation  observed in aging lead to a higher afterload and a predisposition to systolic hypertension in the elderly ,58.Inadequate mitochondrial synthesis of adenosine triphosphate in response to stress will lead to altered energy release, thus altered cellular reactions, such as gene expression, chromatin remodeling, intra/extra-cellular signaling, ion homeostasis, muscle contraction, protein and hormone synthesis and secretion, and neurotransmitter release and reuptake .Age-associated modifications in the glomerular filtration rate and electrolyte imbalances ,61 oftenThe aging of the respiratory system can lead to decreased compliance in pulmonary function. Moreover, the presence of chronic lung disease or sleep-related breathing disorders can increase the risk of pulmonary hypertension, exacerbate the sensation of dyspnea, and decrease biventricular filling ,63,64.The aging of the autonomic nervous system is characterized by sympathetic hyperreactivity and increased plasma concentrations of catecholamines, but a reduced sympathetic response is observed due to the diminished response of catecholamine receptors. Thus, tachycardia is felt less in elderly than middle-aged adults .Regarding sex differences in heart failure, it seems that a large percentage of women tend to develop HRpEF, with the etiology of HF being either hypertension, diastolic dysfunction, or valvular pathology, whereas men tend to develop HFrEF or HFmrEF (HF with mid-range ejection fraction), with the etiology usually being an ischemic condition . MoreoveThe cardioprotection found in women seems to be due to the secretion of 17β-estradiol, an estrogen with a very clear established role in counteracting ischemic, hypertrophic, apoptotic, and cytotoxic impulses related to the heart ,68,69.Animal studies have shown that the cardiomyocytes of female models had a higher rate of survival after they were exposed to oxidative stress, which led to cell death, with the explanation relying on the fact that highly expressed estrogen receptor alpha (ER-α) can mediate the inhibition of pro-apoptotic pathways and the activation of the Akt signaling pathway ,70.Other differences regarding plasma B-type natriuretic peptide (BNP) levels, left ventricular mass index, left ventricular ejection fraction, and peak oxygen consumption between the sexes were also noted, suggesting that men are more susceptible to HF development than women ,71,72.Concerning treatment, it seems that although angiotensin-converting enzyme (ACE) inhibitors decrease the morbidity and mortality rates in both men and women, their effect seems to be more pronounced in men . On the No sex-related differences were observed in terms of treatment outcomes in patients under treatment with beta blockers or mineralocorticoid receptor antagonist .Differences between the sexes were also noted in the case of digoxin treatment; women with a digoxin plasma concentration of 1.2–2.0 ng/mL had a higher mortality rate than men, although plasma levels of 0.5–0.9 ng/mL in men were associated with reduced mortality, but not any effect in women .Reduced blood flow to the gastrointestinal tract causes decreased absorption of drugs . In the Intestinal wall dysfunction secondary to hypoperfusion can, over time, induce chronic enteral inflammation and malnutrition. On the other hand, increased intestinal permeability in patients with HF can stimulate the transfer of drugs from the gastrointestinal tract to the portal blood .Decreased blood perfusion in the central and peripheral organs results in an irregular tissue distribution of drugs . DifferePlasma protein binding may also be affected, especially after a myocardial infarction (production of α1-glycoproteins in the liver increases tissue necrosis and inflammatory reactions in the myocardium) or in patients with cachexia .Reduced hepatic and renal blood flow induces an altered metabolism and elimination of administered drugs and their metabolites. In addition to an irregular distribution of drugs in the liver (a consequence of poor hepatic blood infusion), hepatic congestion and/or hypoxia (as a major consequence) and hepatocellular lesions may occur, manifested by hepatocytolysis (and thus increased liver transaminases) and disorders affecting enzymatic activity ,84.Since the concentration of active substances at the site of action cannot yet be directly determined, plasma concentration is often measured as a surrogate marker of the drug effect, depending on the concentration of active substances at the site of action .Practically, changes in pharmacokinetics have been only observed in patients with renal and/or hepatic complications ,84,85.Increased action of the following drugs was observed after oral administration in patients with decompensated HF: captopril, enalapril, perindopril, carvedilol, felodipine, candesartan, furosemide, milrinone, and enoximone ,84,85.Since most studies to date  have not included patients with decompensated HF or major renal or hepatic problems (which involve more severe changes in PK and PD), the pharmacokinetic and pharmacodynamic parameters are currently under-studied in patients with HF. Thus, we recommend paying more attention to monitoring the efficacy and safety of drugs used in HF. Furthermore, the progressive titration of drugs should be implemented and the benefit/risk ratio should be periodically evaluated ,84,85.The pharmacodynamics of drugs, as well as their tolerability, may also be affected by several neuronal and endocrinological compensatory mechanisms in HF, including the activation of the renin-angiotensin (RAA) and sympathetic system. Moreover, nodal activity and baroreceptor sensitivity are affected, and peripheral vascular resistance is increased; these are aspects that could cause an altered response to administered drugs ,84,85.The activation of the sympathetic nervous system can alter the perfusion of the viscera, especially the splenic organs , to maintain the perfusion of vital organs (brain and heart), resulting in hypoperfusion in the liver and kidneys. Furthermore, increased central pressure in patients with right HF causes hepatic congestion and dilation of the central vein in the hepatic acini, inducing hepatocellular ischemia and necrosis, and reducing the activity of microsomal enzymes ,84,85,86Therefore, it is advisable to consider all changes that might occur in heart failure patients  13,84,8,86.It is well known that the acute/chronic dysfunction of one organ could induce the acute/chronic dysfunction of the other organ , therefoIn summary, the drop in cardiac output induces the activation of the sympathetic nervous system which will increase the stroke volume and the heart rate, as a compensatory mechanism. Sympathetic nervous system activation will also stimulate the release of renin from the kidneys, with the consequence of RAAS activation. Moreover, the drop in cardiac output will also induce a decreased perfusion of the kidneys, leading to kidney injuries . A reduced perfusion in the kidneys will stimulate renin release, RAAS activation and thus sodium and water retention , which will later increase the mean arterial pressure and the preload and decrease the cardiac output. RAAS activation will also cause vasoconstriction, which will contribute to reduced renal perfusion ,89,90.Moreover, chronic kidney disease (CKD) can lead to cardiovascular dysfunction, as a low glomerular filtration rate activates RAAS, which will lead, in time, to cardiac remodeling and left ventricular hypertrophy. CKD also implies a reduction in erythropoietin production over time, leading to anemia, which will increase the risk of ischemic events in the heart. Moreover, CKD induces a decrease in vitamin D production and parathormone stimulation, leading to an increase in calcium and phosphate levels and thus, increased risk of coronary and vessel calcification, augmenting the high risk of ischemic events . ElectroTherefore, the management of cardiorenal syndrome is challenging and must be directed towards the specific pathophysiologic mechanism involved. The volume overload can be either addressed by prescribing diuretics  or using ultrafiltration methods. The addition of a thiazide diuretic to a loop diuretic may be preferred in the case of diuretic resistance, as an initial approach to restore euvolemia ,89. Rega2), the ARBs/ACEIs are considered safe. The starting dose of ARNI  should be reduced to 24/26 mg, twice a day, in patients with severe renal impairment. The dose of ARNI might also need to be reduced in the case of hypotension or hyperkalemia. MRAs are contraindicated in patients with severe renal impairment, creatinine > 2.5 mg/dL in men, creatinine > 2 mg/dL in women or potassium > 5.0 mEq/L. As for SGLT2 inhibitors, there is currently no evidence regarding dose adjustments in patients with eGFR < 30 mL/min/1.73 m2 for dapagliflozin and eGFR < 20 mL/min/1.73 m2 for empagliflozin [In patients with severe renal impairment  . TherefoRegarding the management of HF before pregnancy, ACEIs, ARBs, ARNI, MRA and SGLT2 inhibitors, as well as ivabradine should all be avoided and stopped prior to conception due to an increased risk of fetal harm. It is recommended that the pregnancy be planned and closely monitored by a multidisciplinary team of specialists in order to avoid HF decompensation and fetal harm (induced by either the pathology or the treatment) .Hydralazine, methyldopa, or oral nitrates can also be recommended during pregnancy .In patients with atrial fibrillation, low-molecular-weight heparins are the first choice of anticoagulant treatment (NOAC should be avoided due to insufficient data regarding their safety) .Concerning the breastfeeding period in HF women, it is important to know that the mother’s treatment prevail over breastfeeding compatibility, and that the benefits of breastfeeding are important for both the mother and child ,96. EnalThe treatment of HF patients is very complex and includes not only lifestyle changes but also multiple pharmacological therapies, as well as the presence of co-morbidities and individual pharmacological strategies; this leads to polypharmacy in HF patients, generating increased iatrogenic risks ,98.In Several studies have shown a strong association between the number of drugs taken by HF patients  and the occurrence of potential drug–drug interactions, leading to the conclusion that the incidence of drug–drug interactions in HF patients is extremely high ,171,172.The coordinated efforts of a multidisciplinary team of healthcare providers also involving a clinical pharmacist could reduce the medication-related problems and improve the efficacy, tolerability, and safety of the pharmacological strategies implemented by physicians ,173,174.Adverse drug reactions (ADRs) have been estimated to account for approximatively 10–20% of hospital admissions in geriatric units . MoreoveIt seems that there are also sex-related differences between men and women regarding ADRs. Although women are underrepresented in all phases of clinical trials and little is known about this aspect, several meta-analyses concluded that women are more susceptible (1.5–1.7×) to developing ADRs than men and are also at higher risk of hospitalization due to the severity of ADRs ,190.2+ and K+ channels implicated in ventricular repolarization [As women usually present HFpEF with additional risk factors (co-morbidities and advanced age) compared with other types of HF, there seems to be a high incidence of polypharmacy, as they tend to take more drugs than men (including over-the-counter drugs and food supplements); thus, they have an increased risk of iatrogenic events (due to ADRs and drug interactions) and low adherence to treatment. Other explanations may underline this problem of high iatrogenic risk. Sex differences in the pharmacokinetics and pharmacodynamics of administered drugs  predispose women to a higher probability of overdosing than men ,193,194.rization ,195. Difrization ,190.All of the aforementioned sex-related differences in female patients predispose women to a higher probability of drug-induced complications such as bleeding problems , electrolyte abnormalities , cough and increased creatinine (under treatment with ACE inhibitors), myopathy (under statin treatment), hepatotoxicity, skin diseases, etc. ,196,197.Thus, it is important to adjust the drug dosage as a function of total body weight/size or glomerular filtration rate and titrate it to the required clinical effect, especially in those with a narrow therapeutic index, in order to avoid the incidence of ADRs ,190.Several articles also discuss the negative outcomes of HF patients after discontinuing chronic HF treatment ,199,200.It was observed that RAAS  inhibitors provide the most beneficial outcomes in terms of mortality reduction in patients with HFrEF, although renal function is affected at baseline . The cesRegarding beta blocker discontinuation, although they are associated with a risk of negative inotropic effects and hypotension, ESC has recommended not to disrupt beta blocker treatment unless severe hypotension is present, due to the risk of rebound effects  and the correlation with increased mortality and readmissions rates after cessation of treatment ,199,203.In order to reduce exacerbations, hospital readmission rates, morbidity, and mortality and to improve the overall quality of life, an interdisciplinary approach to treatment strategies is mandatory for HF patients. The treatment strategy must be individualized for each HF patient, periodically monitored and reviewed by the healthcare team. Moreover, patient education, including topics such as dietary counseling, healthy lifestyle habits, regular exercise in a tolerable amount, alcohol and smoking cessation; moreover, understanding the alarming signs and symptoms of HF decompensation  is another extremely important action that needs to be urgently implemented by societies with aging populations.


P < 0.001). In multivariate logistic regression analysis, RV dysfunction was associated with in-hospital death , lethal arrhythmia , and tendency for increased blood lactate levels  independent of left ventricular (LV) dysfunction. RV dysfunction was associated with lower cardiac output, pulmonary artery pressure index, and RV stroke work index. In patients with septic shock, visually-assessed RV dysfunction was associated with in-hospital mortality, lethal arrhythmia, and circulatory insufficiency independent of LV dysfunction. Visual assessment of RV dysfunction using echocardiography might help to identify the short-term prognosis of patients with septic shock by reflecting hemodynamic status.We retrospectively analyzed data from the Medical Information Mart for Intensive Care-III critical care database to determine whether visually-assessed right ventricular (RV) dysfunction was associated with clinical outcomes in septic shock patients. Associations between visually-assessed RV dysfunction by echocardiography and in-hospital mortality, lethal arrhythmia, and hemodynamic indicators to determine the prognostic value of RV dysfunction in patients with septic shock were analyzed. Propensity score analysis showed RV dysfunction was associated with increased risk of in-hospital death in patients with septic shock (adjusted odds ratio [OR] 2.15; 95% confidence interval [CI] 1.99–2.32;  Cardiac dysfunction in sepsis, known as septic cardiomyopathy (SCM), is common and associated with increased mortality of patients with sepsis or septic shock6. SCM has been defined as left ventricular (LV) dysfunction, such as a decrease in the LV ejection fraction10. In recent years, the effect of right ventricular (RV) dysfunction on the prognosis of patients with sepsis or septic shock has received attention14.Sepsis is defined as life-threatening organ dysfunction due to a dysregulated host immune response to an infection, and it is associated with a high mortality rate of 30%, even in developed or developing countries14. Management of cardiac dysfunction is considered to be important, especially in unstable patients with septic shock, but the clinical effect of RV dysfunction in this population remains unclear.The effect of RV dysfunction on prognosis in sepsis or septic shock depends on population characteristics16. Furthermore, how RV dysfunction interacts with LV dysfunction in terms of contractility and ventricular size in patients with septic shock remains unknown.Although many parameters of RV function have been studied as prognostic indices, no consensus has been reached regarding what echocardiographic parameters should be used to define RV dysfunction. Visual estimation of RV function, which shows low interobserver variability and is a useful screening tool as a point-of-care evaluation for RV dysfunction, has not yet been evaluated in this contextTherefore, this study aimed to investigate the clinical significance and prognostic impact of visually assessed RV function in patients with septic shock.17. We used the Medical Information Mart for Intensive Care III (MIMIC-III) version 1.4 critical care database. This is a large, freely available database comprising de-identified health-related data associated with more than 40,000 patients who stayed in the intensive care unit (ICU) of the Beth Israel Deaconess Medical Center from 2001 to 2012. The MIMIC-III database was developed and is maintained by the Laboratory for Computational Physiology at the Massachusetts Institute of Technology19.This was a retrospective observational study, and the article was prepared in accordance with the RECORD reporting guidelines1, septic shock was defined as hypotension with the presence of any suspected infections, the need for vasopressors, and the lactate level exceeding 2 mmol/L. Doses of other catecholamines were converted to norepinephrine-equivalent doses20. The decision to perform TTE was based on the clinical judgment of the medical team. Only the data of each patient’s first ICU admission were used in this study. Patients were excluded if they had the following miscellaneous etiologies of cardiac dysfunction: acute myocardial infarction, prior myocardial infarction, heart failure, infective endocarditis, aortic dissection, myocarditis, or admission to the cardiac surgery recovery unit.The eligibility criteria were septic shock on ICU admission and performance of transthoracic echocardiography (TTE) within the first 24 hours of ICU admission. In accordance with the Sepsis-3 criteria14.In addition to the patients’ demographic data, we collected the following TTE parameters that were extracted from the echocardiography report summary data recorded by a sonographer or a cardiologist within the first 24 hours of ICU admission: visual assessment of the grade of biventricular systolic dysfunction and the degree of biventricular dilation. The quality of the TTE report, blood pressure, and heart rate at the time of TTE were also recorded. LV dysfunction was defined as an LV ejection fraction of ≤ 50% or documentation of any description of LV systolic dysfunction. The presence and grade of visual RV dysfunction were documented and categorized into two levels  in line with the description in the summary reports. Other echocardiographic parameters, such as the fractional area change and tricuspid annulus systolic plane excursion, were not used as criteria of RV dysfunction because they were collected in only a few patientsDetailed hemodynamic parameters and data on fluid administration within 24 hours of ICU admission were also extracted to describe the association between visual RV dysfunction and the trend or maximum values of the hemodynamic status; the same variables acquired from different modules were combined for simplicity.The primary outcome was in-hospital mortality. For a surrogate endpoint, the incidence of lethal arrhythmia during hospitalization was recorded. Lethal arrhythmia was defined as ventricular tachycardia or ventricular fibrillation. In addition, as a surrogate marker of systemic circulation, the trend of increasing blood lactate levels within the first 24 hours of entering the ICU was examined. An increased lactate level was defined as an increasing trend in occurrence, with a maximum after a minimum value.Continuous variables are expressed as median and interquartile range. Categorical variables are expressed as number (%). The relationships between LV function and RV function and between LV and RV size in patients with septic shock were visualized using chord diagrams. The hemodynamic parameters or fluid trends in association with RV function were described using locally weighted scatter plot smoothing. Non-parametric variables were compared using the Mann–Whitney U-test.21. To consider the severity of visually assessed RV dysfunction, additional analyses focusing on the effect of moderate to severe RV dysfunction were performed. Using a directed acyclic graph, the following confounders were used to calculate the propensity score: age, body weight, ethnicity, infection focus, SOFA score, catecholamine dosage, Elixhauser comorbidity index, mechanical ventilation, infusion fluid volume, and presence of LV dysfunction  score ≥ 3 points).For sensitivity analysis, multivariate logistic regression analysis was performed to evaluate the prognostic impact of RV dysfunction and LV dysfunction. The catecholamine dosage and SOFA score were used for the covariates24. A P value of < 0.05 was considered statistically significant. All statistical analyses were performed using freely available statistical software (R version 4.0.2).Before carrying out multivariate analysis and propensity scoring analysis, multiple imputation with chained equations were performed to handle missing data, and non-normal data were log-transformed in this step. The results of 10 imputed datasets were combined with the MICE package19. In addition, the ethical approval statement by the local Institutional Review Board  and the requirement for informed consent were waived for the use of this de-identified public database.Use of the MIMIC-III database for this study was approved by the institutional review boards of the Beth Israel Deaconess Medical Center  and the Massachusetts Institute of Technology  This study included 1563 patients with septic shock. Of these patients, 544 underwent TTE  had TTE images of adequate technical quality. The details of the echocardiographic data are shown in Supplementary Table Associations between visual RV function and hemodynamics are shown in Fig. The results of the propensity scoring analysis using the inverse probability of weighting method are shown in Table P < 0.001), and the estimated effect size was greater than that for LV dysfunction. The increasing trend of the blood lactate level  was not associated with LV dysfunction (adjusted OR 0.80), but was associated with RV dysfunction (adjusted OR 1.31). LV dysfunction and RV dysfunction were associated with lethal arrhythmia, but the adjusted OR of RV dysfunction was higher than that of LV dysfunction . Interaction analysis showed that respiratory failure did not modify the relationship between RV dysfunction and in-hospital mortality (P for interaction = 0.538).The results of multivariate regression analysis are shown in Table 14. Moreover, this study may add value to hemodynamic management of septic shock using point-of-care ultrasound.The two main findings of the present study were that, in patients with septic shock, (1) RV dysfunction predicted in-hospital mortality, lethal arrhythmia, and circulatory insufficiency independently of LV systolic function and (2) visual assessment of RV dysfunction effectively identified the risk of mortality. Our findings may provide rationale for visually assessing RV dysfunction and they support prior studies that showed an association between RV dysfunction and mortality in patients with sepsis or septic shock25. We speculate that RV dysfunction causes secondary cardiogenic shock accompanied by septic shock, which exacerbates systemic perfusion, and ventricular arrhythmias are more likely to occur as complications of cardiogenic shock. A previous study identified the presence of RV dysfunction in patients with cardiac disease as an independent predictor of sudden cardiac death and lethal arrhythmias, irrespective of LV ejection fraction26, while another study found that RV ejection fraction was incremental to LV ejection fraction for the prediction of lethal arrhythmic events in patients with LV systolic dysfunction27. The results of the current study support these previous findings.In this study, RV dysfunction was associated with increased circulatory insufficiency and lethal arrhythmia, with a larger effect than LV systolic dysfunction. Our finding of a relationship between RV dysfunction and mortality is consistent with several previous reports, as well as with a previous study, which showed that LV systolic dysfunction was not associated with the prognosis14. In contrast, a dilated RV tended to be associated with a normal or relatively small LV size. The relationship between a severely dilated right ventricle and a small or normal LV  suggests that diastolic dysfunction of the left ventricle is exacerbated because of RV dilation, even though LV contractility is preserved28. Conversely, acute LV dilation occurs as a compensatory response to depression of LV systolic function to maintain cardiac output before full functional and structural recovery30. These factors may explain why the estimated effect of RV dysfunction on mortality is greater in patients with isolated RV dysfunction. Consequently, not only LV systolic dysfunction, but also a decrease in RV function and relative expansion of the right ventricle compared with the left ventricle could be important findings of SCM in visual evaluation of echocardiography.This study also showed that LV dysfunction and RV dysfunction were positively correlated in terms of severity. Additionally, biventricular dysfunction was found in 64% of patients with RV dysfunction, which is similar to findings in a previous study33. In this study, the presence of RV dysfunction was associated with a lower cardiac output status. Furthermore, the pulmonary artery pulsatility index and RV stroke work index were significantly increased in patients with preserved RV function, while they appeared to be absent in patients with RV dysfunction. These results imply that a depressed right ventricle is unable to meet the surge in demand for LV preload, resulting in low cardiac output.RV dysfunction is caused by systemic inflammation or specific interventions to increase RV afterload and preload . This reduces the pulmonary circulation and results in reduced cardiac output from the left ventricleAlthough excessive fluid loading can clearly induce RV dysfunction, the optimal or excessive fluid infusion is difficult to define because appropriate fluid administration depends on the fluid volume status based on each patient's pretreatment background. Since this study was a retrospective observational study, the timing of TTE and infusion strategy were not standardized. On the other hand, there was no significant difference in the trend of infusion administration between patients with and without RV dysfunction. This suggests that the main trigger of RV dysfunction is not due to differences in infusion strategies.14. We demonstrated that visual assessment of RV dysfunction sufficiently identified an association with increased risk of mortality in patients with septic shock. There is growing evidence of the requirement for mechanical circulatory support in patients with refractory septic shock who have unstable hemodynamics36. Although visual assessment of RV function by echocardiography is simple, it has low interobserver variability and correlates well with hemodynamic parameters, even compared with assessment by magnetic resonance imaging16. In the present study, we found that visually assessed RV dysfunction was correlated with trends of hemodynamic parameters as monitored by a pulmonary artery catheter. Notably, despite the fact that the quality of TTE was suboptimal in 38% of patients, the OR of visually assessed RV dysfunction for in-hospital mortality was 2.15. This value is similar to the results of prior studies14. This result suggests that visual assessment is sufficient for evaluating clinically important RV dysfunction in patients with septic shock. This is the case even when detailed evaluation of right heart function by TTE parameters, such as the fractional area change or tricuspid annulus systolic plane excursion, is difficult to perform. In contrast, however, the marginal odds of moderate to severe RV dysfunction for mortality were similar to those of all grades of RV dysfunction. This finding suggests that visual assessment of RV dysfunction may maintain adequate prognostic capacity without considering its severity.Visual assessment of RV function by echocardiography is simpler than assessment of other indices, and it is rapid, noninvasive, and suitable for assessing hemodynamics in patients with septic shockThis study has several limitations. First, this was a retrospective study of a relatively heterogeneous group of patients whose data were extracted from electronic medical records in a large clinical database. Therefore, indication bias may have occurred in patients in whom TTE was performed. In addition, we included patients with a high median SOFA score. Our findings were not extrapolated to the less severe population. Second, although patients with obvious heart disease were excluded, the possibility that they had chronic right heart dysfunction cannot be completely ruled out because there were no records of previous echocardiographic findings. Finally, some variables that were not captured in the database may account for residual confounding. An example of this possible confounding is that pulmonary thromboembolism was not ruled out by contrast-enhanced computed tomography in all cases. Additionally, the possibility that RV dysfunction might have been caused by factors other than sepsis could not be excluded. Further prospective research is required to confirm our results.In patients with septic shock, RV dysfunction is associated with increased risks of in-hospital mortality, lethal arrhythmias, and circulatory insufficiency independently of LV dysfunction. Visual assessment of RV dysfunction using echocardiography may thus help to identify the short-term prognosis of patients with septic shock by reflecting hemodynamic status.Supplementary Information.


The classification, phenotyping, and management of heart failure (HF) has been based on the left ventricular (LV) ejection fraction (LVEF) . In the HF is a very complex syndrome, and it is unrealistic to predicate its classification on a single biomarker . MoreoveMoreover, the controversies regarding the delineation of normal range show there is substantial discordance between the various imaging modalities in LVEF measurement among expert laboratories . ImportaEqually disturbing with the variability in measurements is the vague physiological significance of LVEF. The LVEF, which equals the LV stroke volume (LVSV) divided by the LV end-diastolic volume (LVEDV) and is usually expressed as a percentage, is inappropriately assumed to be an index of myocardial contractility . HoweverFinally, LVEF has long been used for the guidance of medical treatment in HF. In this regard, the lack of effective medications for HFpEF has represented for years a large and growing unmet need in cardiology . HoweverTo have a meaningful impact, classification systems should reflect current approaches in HF evaluation and management. Although the LVEF has served for a long time as the holy grail of HF, the time to be ejected as the primary classification system for this global pandemic has arrived ,16.


Patients with eosinophilic granulomatosis with polyangiitis (EGPA) most commonly die from cardiac causes, however, cardiac involvement remains poorly characterised and the relationship between cardiac and pulmonary disease is not known. This study aimed to characterise myocardial and pulmonary manifestations of EGPA, and their relationship. Prospective comprehensive cardiopulmonary investigation, including a novel combined cardiopulmonary magnetic resonance imaging (MRI) technology, was performed in 13 patients with stable EGPA. Comparison was made with 11 prospectively recruited matched healthy volunteers. Stable EGPA was associated with focal replacement and diffuse interstitial myocardial fibrosis , which drove a borderline increase in left ventricular mass . Corrected QT interval was significantly prolonged and was associated with the severity of myocardial fibrosis . Stable EGPA was not associated with increased myocardial capillary permeability or myocardial oedema. Pulmonary tissue perfusion and capillary permeability were normal and there was no evidence of pulmonary tissue oedema or fibrosis. Forced expiratory volume in one second showed a strong inverse relationship with myocardial fibrosis . In this exploratory study, stable EGPA was associated with focal replacement and diffuse interstitial myocardial fibrosis, but no evidence of myocardial or pulmonary inflammation or pulmonary fibrosis. Myocardial fibrosis was strongly associated with airway obstruction and abnormal cardiac repolarisation. Further investigation is required to determine the mechanisms underlying the association between heart and lung disease in EGPA and whether an immediate immunosuppressive strategy could prevent myocardial fibrosis formation. Eosinophilic granulomatosis with polyangiitis (EGPA), formerly known as Churg-Strauss syndrome, is a hybrid condition comprising a systemic antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and a hypereosinophilic disorder with frequent lung involvement that is associated with asthma , 2.Whilst a wide range of cardiac manifestations are described, including pericarditis, pericardial effusion, tamponade, myocarditis, cardiomyopathy, myocardial infarction and heart failure , clinicaMagnetic resonance imaging (MRI) provides unparalleled evaluation of cardiac structure, function and tissue characterisation and its application in EGPA has provided insight into cardiac disease expression , 8–11. HIn this study, we sought to apply a novel combined cardiopulmonary MRI technology, which provides comprehensive and simultaneous interrogation of cardiac and pulmonary structure, function and tissue character, in patients with stable EGPA in order to: (1) Characterise myocardial and pulmonary manifestations of EGPA; and (2) Investigate the relationship between cardiac and pulmonary disease in EGPA.This prospective research study aimed to apply a combined cardiopulmonary MRI protocol in patients with stable EGPA and matched healthy volunteers in order to investigate myocardial and pulmonary manifestations of EGPA, and their relationship.Stable patients with a clinical diagnosis of EGPA according to the 2012 Chapel Hill consensus [2.Exclusion criteria included: history of any cardiovascular disorder other than cardiac disease that was thought, by the attending clinical team, to be secondary to EGPA, contraindication to MRI, hypersensitivity to gadolinium-based contrast agent (GBCA), estimated glomerular filtration rate < 40 ml/min/1.73mParticipants underwent blood sampling for blood count, renal function, c-reactive protein, high sensitivity troponin I, and B-human chorionic gonadotropin in females of childbearing potential, ECG and MRI scanning on the same day (see below). Clinical pulmonary function tests performed closest to the study visit were recorded.Steady-state free precession (SSFP) cine imaging of the heart (standard long- and short-axis views) to provide measurement of cardiac function.T1 mapping (by MOdified Look-Locker Inversion Recovery (MOLLI)) at basal and mid left ventricular (LV) short axis level before and 15 min following the final bolus of GBCA (see below) to provide evaluation of myocardial oedema and fibrosis. T2 mapping (by T2-prepared SFFP) at the same locations to provide further assessment of myocardial oedema. Late gadolinium enhancement (LGE) imaging beginning at 6 min following the final GBCA bolus (see below) to assess for focal replacement myocardial fibrosis.T1 mapping (by MOLLI) in the central sagittal plane of both lungs to provide evaluation of lung tissue injury.trans)), pulmonary extracellular volume fraction (Ve) and blood flow (F). GBCA (gadoterate meglumine (Dotarem), Guerbet, France; 3 ml/s) administration was divided into three doses in order to avoid saturation of the peak of the arterial input function (AIF), which occurs as a result of the non-linear relationship between contrast agent concentration and signal intensity, and T2 shortening effects, at higher contrast agent concentrations [Dynamic contrast enhanced (DCE) imaging using free-breathing 2D saturation-recovery fast low angle shot (FLASH) dynamic acquisitions in four planes  to assess myocardial and pulmonary capillary permeability . Scan duration 60 min. It included the following sequences  according to current guidelines .T1 and T2 maps were generated in Siemens Argus  and transferred into Horos (Horos2K v2.2.0 The Horos Project) where epicardial, endocardial and blood pool regions of interest (ROI) were drawn. Partial volume effects of blood were minimised in myocardial ROIs by using the middle third of myocardium. Lung borders were contoured in Horos, excluding the cardiac outline, to define whole-lung ROI. Individual lobes were identified as previously described . Myocardtrans and Ve [DCE imaging was analysed using custom written Matlab code . Cardiac motion correction was achieved using an intensity-based rigid registration algorithm. Lung registration was performed using Advanced Normalisation Tools (ANTs) symmetric normalization non-linear registration algorithm, employing cross-correlation as the similarity measure . Epicards and Ve . Pulmonas and Ve , 19.This was an exploratory study, and there were limited data upon which to base a power calculation. As a guide, 10 patients were required in each group to detect an absolute minimum difference, between EGPA and healthy control groups, in myocardial ECV of 3% , 15. Dat9/L; p = 0.001), however, eosinophil count was no different . High sensitivity troponin I was within the normal range in all participants. Pulmonary function tests were available in seven patients with EGPA.Thirteen patients with stable EGPA and 11 healthy volunteers were recruited . Four patients with EGPA exhibited ST segment  or T wave abnormalities (T wave inversion in two). No patients exhibited clinically significant arrhythmias.Ventricular size, ventricular ejection fraction and atrial size were no different in EGPA compared to control Table . Body suEGPA was associated with elevated myocardial ECV (26.9% (25.9–28.5%) vs 24.7% (23.6–26.4%); p = 0.034), increased extracellular matrix mass  and elevated native T1 . Ten patients with EGPA exhibited non-ischaemic LGE ). Myocardial T2 and capillary permeability were no different in EGPA compared to control. Figure There was no relationship between corrected QT interval and medications. Corrected QT interval was significantly associated with myocardial ECV interval  on LGE imaging: in one patient it was previously unrecognised and the other was the patient with a history of coronary artery dissection.Pulmonary tissue T1, capillary permeability, extracellular volume fraction and blood flow were no different in EGPA compared to healthy volunteers Table .Table 3P1) was strongly negatively correlated to native myocardial T1  and ECV . Perhaps as a result, we did not find an association between cardiac manifestations and circulating eosinophil levels. Seventy-seven percent of patients were ANCA-negative at diagnosis.trans measures capillary permeability [The multiparametric nature of MRI, i.e. its ability to measure multiple aspects of tissue structure, function, injury and adaptation within one scan, without radiation, means that it is uniquely placed to elucidate underlying disease mechanisms and understand their relationships. Myocardial ECV, measured using cardiac MRI, quantifies myocardial extracellular matrix volume and in the absence of significant inflammation, is a robust measure of myocardial fibrosis, having been extensively validated against histological collagen volume fraction , 22, 23.eability ; both artrans), findings which are in keeping with the known histology, described earlier. Our findings also show that the evident myocardial fibrosis comprises both diffuse interstitial and replacement components, and that it is myocardial fibrosis that drives the borderline left ventricular hypertrophy i.e. rather than cellular hypertrophy.Using these techniques, we show that stable EGPA is associated with myocardial fibrosis (elevated ECV and T1) and an absence of myocardial inflammation  was found to have an otherwise unrecognised MI. MI that is not detectable from patient history or ECG is well described in non-EGPA populations. Cardiac MRI with LGE has a sensitivity such that it is able to detect 0.7 g of infarcted myocardium . SeveralDemonstrating the unique utility of cardiac MRI, the cardiac MRI findings were not evident from circulating biomarkers (e.g. high sensitivity troponin) or on ECG. Furthermore, despite there being evidence of significant myocardial injury and adaptation, ventricular size and ejection fraction were normal, which is in keeping with most previous studies in EGPA, demonstrating the low sensitivity of ventricular size and ejection fraction for detecting cardiac injury , 28, 30.Our cardiopulmonary MRI protocol, which simultaneously interrogates cardiac and pulmonary inflammation, fibrosis and blood flow characteristics, provides a methodology to directly investigate cardiac and pulmonary pathophysiology, and their relationship. In the first study to apply pulmonary MRI in EGPA, we show that that in the setting of stable EGPA with effective immunosuppression, pulmonary tissue characterisation is normal with no evidence of inflammation or pulmonary fibrosis. Active pulmonary inflammation is associated with increased pulmonary T1, capillary permeability and pulmonary tissue blood flow , 36, 37.1 and incident heart failure, and between FEV1 and adverse outcome in patients with HF, particularly heart failure with preserved ejection fraction, are widely recognised [We found a strong association between myocardial fibrosis and the severity of airflow limitation. This is a novel finding and the underlying mechanism is unclear. Associations between FEVcognised –49. The cognised –52. In Ccognised . It is pThe number of patients included was small, although we were able to demonstrate significant results despite the small numbers. EGPA is a rare condition with estimated prevalence of 2 to 22 per/million and the size of our study is in keeping with other recent studies , 11. It In this exploratory study that utilised a combined multiparametric cardiopulmonary MRI protocol, we demonstrate that stable EGPA is associated with focal replacement and diffuse interstitial myocardial fibrosis, but no evidence of myocardial or pulmonary inflammation or pulmonary fibrosis. Myocardial fibrosis is strongly related to airway obstruction and abnormal cardiac repolarisation. Further investigation is required to determine the mechanisms underlying the association between heart and lung disease in EGPA, the impact myocardial fibrosis has on prognosis, and whether an immediate immunosuppressive strategy could prevent myocardial fibrosis formation.


Purpose: Left ventricular global function index (LVGFI) assessed using cardiac magnetic resonance (CMR) seems promising in the prediction of clinical outcomes. However, the role of the LVGFI is uncertain in patients with heart failure (HF) with dilated cardiomyopathy (DCM). To describe the association of LVGFI and outcomes in patients with DCM, it was hypothesized that LVGFI is associated with decreased major adverse cardiac events (MACEs) in patients with DCM.Materials and Methods: This prospective cohort study was conducted from January 2015 to April 2020 in consecutive patients with DCM who underwent CMR. The association between outcomes and LVGFI was assessed using a multivariable model adjusted with confounders. LVGFI was the primary exposure variable. The long-term outcome was a composite endpoint, including death or heart transplantation.Results: A total of 334 patients (mean age: 55 years) were included in this study. The average of CMR-LVGFI was 16.53%. Over a median follow-up of 565 days, 43 patients reached the composite endpoint. Kaplan–Meier analysis revealed that patients with LVGFI lower than the cutoff values (15.73%) had a higher estimated cumulative incidence of the endpoint compared to those with LVGFI higher than the cutoff values (P = 0.0021). The hazard of MACEs decreased by 38% for each 1 SD increase in LVGFI (hazard ratio 0.62[95%CI 0.43–0.91]) and after adjustment by 46% (HR 0.54 [95%CI 0.32–0.89]). The association was consistent across subgroup analyses.Conclusion: In this study, an increase in CMR-LVGFI was associated with decreasing the long-term risk of MACEs with DCM after adjustment for traditional confounders. The most common causes of heart failure (HF) include ischemia dilated cardiomyopathy (IDCM) and non-ischemia dilated cardiomyopathy (NIDCM) . Both DCNumerous studies have demonstrated that the measurement of LV ejection fraction (LVEF) as a marker of global systolic myocardial function is a robust predictor of morbidity and mortality in patients with DCM , 6. HoweCMR imaging is the gold standard for evaluating cardiac function and morphology and plays a central role in the diagnosis of HF, the assessment of prognosis, and monitoring of therapy , 9. ReceThis study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines .Patients with stage C or D HF were identified from January 1, 2015 to April 30, 2020 and enrolled non-selectively and consecutively in this prospective observational cohort study at the Department of Heart Failure Program at Anzhen Hospital . The current study enrolled 493 patients with DCM according to the World Health Organization/International Society guidelines and the Federation of Cardiology . AccordiThis study protocol was approved by the Human Subjects Review Committee at Anzhen Hospital . The patient's identity remained anonymous, and the requirement for informed consent was waived due to the observational design of this study, as reported elsewhere .CMR acquisition was performed on a 3.0 T scanner  with retrospective electrocardiogram gating and 32-channel phased-array coil. The steady-state free precession breath-hold cine images with 25 reconstructed phases were acquired. The detailed scanning parameters of cine images have been described previously .One experienced and independent radiologist blinded to clinical data gathered the CMR readings for all standard cardiac parameters and LVGFI. The LVGFI was the primary exposure variable in this study and acquired by drawing endocardial and epicardial borders on the short-axis cine images from basal slice to apical segment . It was where the LV stroke volume (LVSV) was calculated by LVEDV-LVESV, and the LV global volume (LVGV) was defined as the sum of the mean LV cavity volume (LVEDV+LVESV)/2 and the myocardium volume. The LV myocardial volume was calculated as the LV myocardial mass divided by the specific myocardial density (1.05 g/mL). Further details regarding CMR data assessment are described previously .The selection of covariates is based on our previous studies , 9, 15, The attending physician of the patients had to fill out clinical information, and the biochemical and imaging data were obtained using the Empower DataWeb data collection management system . The patients were followed up at a 3-month interval with the clinical outpatient visit or by contact with the patient's family members. The status of the events was updated on the Empower DataWeb each time.The main outcome was the composite of major adverse cardiac events (MACEs), including cardiovascular death and cardiac transplantation. Cardiovascular death was defined as HF, fatal MI, sudden death, and ischemic or hemorrhagic stroke. The causes of death were based on the physician's judgment. The patients were followed up until the beginning of May 2020.www.empowerstats.com, X&Y Solutions, Inc. Boston MA) and R software version 3.6.1 (http://www.R-project.org). The two-side alpha level was set at 0.05. Continuous variables are presented as mean ± SD or medians and interquartile ranges (IQRs), while categorical variables are presented as frequencies and percentages. Box-Cox transformation was used to assess the skewed distribution variable. We used multiple imputations based on five replications and a chained equation approach method in the R approach to account for missing data. We also performed sensitivity analyses to compare the distributions of variables with missing data at observed complete case data and the pooling datasets with variables from multiple imputations.All statistical analyses were performed using EmpowerStats  were used to identify the LVGFI and outcome correlations after adjusting the most covariates because LVGFI was a continuous variable . GAM alsTime-dependent receiver operating characteristic curves (ROCs) were plotted to set the optimal cutoff of CMR-LVGFI for the primary composite endpoint based on the Youden index. The optimal cutoff values of LVGFI for the analyzed events were based on the highest sum of sensitivity and specificity. The event-free curves were based on Kaplan–Meier analysis stratified by LVGFI optimal cutoffs and compared using the log-rank test.Between January 1, 2015 and April 30, 2020, a total of 493 patients with stage C or D HF who met the above inclusion criteria were enrolled in this study. However, 159 patients did not complete the CMR examination, and the final analysis included 334 patients  with DCMA total of 43 patients developed MACEs in the median follow-up period of 565 days, consisting of 41 patient deaths and two heart transplantation patients. In the present study, we established a linear inverse correlation between LVGFI and Log RR for MACEs after adjusting for sex, age, BMI, ischemia cardiomyopathy, LBBB on EKG, QRS duration, RBBB on EKG, intraventricular block on EKG, AF on EKG; Na+, Cl–, BNP, Hb, creatinine, WBC, LV-LGE, RVEDV, and RVEF, respectively .P = 0.0013) after adjusting for age, sex, and BMI. This was also true in Model II  after adjusting for sex, age, BMI, and ischemia cardiomyopathy, LBBB on EKG, QRS duration, RBBB on EKG, intraventricular block on EKG, and AF on EKG; Model III  after adjusting for sex, age, BMI, Na+, Cl–, BNP, Hb, creatinine, white blood cell; Model IV , after adjusting for sex, age, BMI, LV-LGE, RVEDV, RVEF; Model V  was obtained after adjusting for ischemia cardiomyopathy, LBBB on EKG, QRS duration, RBBB on EKG, intraventricular block on EKG, AF on EKG, Na+, Cl–, BNP, Hb, creatinine, white blood cell, LV-LGE, RVEDV, and RVEF.The results of univariate analyses of MACEs are summarized in P = 0.0021).The time-dependent ROC curves that we used for bootstrap resampling (times = 500) were constructed to determine the optimal cutoff of CMR-LVGFI for the primary composite with a 15.73% endpoint . The dicTo evaluate the potential influence of other factors, the subgroup analysis was conducted after stratifying the patients by age, BMI, and SBP, sex, diabetes mellitus, LBBB on EKG, ischemia cardiomyopathy, AF on EKG, and CMR-LV-LGE . NotablyThis large prospective cohort study investigated the association between CMR-derived LVGFI and outcomes in patients with stage C or D HF with DCM in China. The current findings demonstrated that the long-term risk of the composite endpoint in patients with DCM over a median follow-up period of 565 days was significantly negatively associated with CMR-LVGFI integrating LV structure with global function. For every 1 SD increase in CMR-LVGFI, a HR of the composite endpoint after adjusting the clinical, laboratory, electrocardiogram, and CMR routine variables decreased by 46%, which was evident in all the subgroups after adjustments.The changes in LV structure and geometry, termed cardiac remodeling, involve chamber dilation and/or hypertrophy. The patterns of LV remodeling were classified as concentric hypertrophy and remodeling, physiological hypertrophy, and eccentric hypertrophy and remodeling. Fifty years ago, Linzbach  proposedP = 0.6) in our study . Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.LX and JD are the guarantors of integrity of the entire study. TL, JD, and LX are responsible for the study concepts and design. TL, ZZ, KB, YG, HW, RW, WL, SC, YL, and YS performed the experimental studies and prepared the first draft of the manuscript, which was critically revised by GY, DF, JD, and LX. TL, ZZ, KB, YG, and HW analyzed and interpreted the data. TL and ZZ performed statistical analysis and all the results were checked by JD and LX. All authors contributed to the article and approved the submitted version.This study was supported by a grant from the National Natural Science Foundation of China (U1908211), the National Key Research and Development Program of China (2016YFC1300300 and 2016YFC1301002), and the Capital's Funds for Health Improvement and Research Foundation of China (2020-1-1052). This study was also supported in part by the British Heart Foundation , the European Research Council Innovative Medicines Initiative , the AI for Health Imaging Award , and the UK Research and Innovation Future Leaders Fellowship (MR/V023799/1).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. 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