Cardiac magnetic resonance in histologically proven eosinophilic myocarditis.

BACKGROUND: Eosinophilic myocarditis (EM) is a life-threatening acute heart disease. Cardiac magnetic resonance (CMR) excels in the assessment of myocardial diseases but CMR studies of EM are limited. We aimed to describe CMR findings in histologically proven EM. METHODS: Patients with histologically proven EM seen at an academic center from 2000 through 2020 were identified. Of the 28 patients ascertained, 15 had undergone CMR for diagnosis and constitute our study cohort. RESULTS: The patients, aged 51 ± 17 years, presented with fever (53%), dyspnea (47%), chest pain (53%), heart block (20%), and blood eosinophilia (60%). On CMR, all 15 patients had myocardial edema with 10 of them (67%) having abnormally high left ventricular (LV) mass as well. LV ejection fraction measured < 50% in 11 patients (73%) and < 30% in 2 (13%), but only 6 (40%) had dilated LV size. Eight patients (53%) had pericardial effusion. LV late gadolinium enhancement (LGE) was found in all but one patient (13/14; 93%). LGE was always multifocal and subendocardial but could involve any myocardial layer. Patients with necrotizing EM by histopathology (n = 6) had higher LGE mass (32.1 ± 16.6% vs 14.5 ± 7.7%, p = 0.050) and more LV segments with LGE (15 ± 2 vs 9 ± 3 out of 17, p = 0.003) than patients (n = 9) without myocyte necrosis. Two patients had LV thrombosis accompanying widespread subendocardial LGE. CONCLUSIONS: In EM, CMR shows myocardial edema and LGE that is typically subendocardial but can involve any myocardial layer. The left ventricle is often non-dilated with moderate-to-severe systolic dysfunction. Pericardial effusion is common. Necrotizing EM presents with extensive myocardial LGE on CMR.

Vascular adhesion protein-1-targeted PET imaging in autoimmune myocarditis.

BACKGROUND: Vascular adhesion protein-1 (VAP-1) is an adhesion molecule and primary amine oxidase, and Gallium-68-labeled 1,4,7,10-tetraazacyclododecane-N,N',N″,N‴-tetra-acetic acid conjugated sialic acid-binding immunoglobulin-like lectin 9 motif containing peptide ([68Ga]Ga-DOTA-Siglec-9) is a positron emission tomography (PET) tracer targeting VAP-1. We evaluated the feasibility of PET imaging with [68Ga]Ga-DOTA-Siglec-9 for the detection of myocardial lesions in rats with autoimmune myocarditis. METHODS: Rats (n = 9) were immunized twice with porcine cardiac myosin in complete Freund's adjuvant. Control rats (n = 6) were injected with Freund's adjuvant alone. On day 21, in vivo PET/computed tomography (CT) imaging with [68Ga]Ga-DOTA-Siglec-9 was performed, followed by ex vivo autoradiography, histology, and immunohistochemistry of tissue sections. In addition, myocardial samples from three patients with cardiac sarcoidosis were studied. RESULTS: [68Ga]Ga-DOTA-Siglec-9 PET/CT images of immunized rats showed higher uptake in myocardial lesions than in myocardium outside lesions (SUVmean, 0.5 ± 0.1 vs 0.3 ± 0.1; P = .003) or control rats (SUVmean, 0.2 ± 0.03; P < .0001), which was confirmed by ex vivo autoradiography of tissue sections. Immunohistochemistry showed VAP-1-positive staining in lesions of rats with myocarditis and in patients with cardiac sarcoidosis. CONCLUSION: VAP-1-targeted [68Ga]Ga-DOTA-Siglec-9 PET is a potential novel technique for the detection of myocardial lesions.

An International Survey of Current Clinical Practice in the Treatment of Cardiac Sarcoidosis.

Cardiac sarcoidosis (CS) is a potentially serious form of infiltrative cardiomyopathy. Despite scarce evidence, immunosuppressive treatment is generally recommended, but local routines may vary significantly. We sought to survey the clinical practices in the treatment of CS, with the aim that the results may suggest future research priorities. We conducted a web-based survey focused on treatment-naive patients with CS. We subclassified CS according to the presence/absence of overt cardiac presentation (clinically manifest/silent) and to the presence/absence of active inflammation (metabolically active/inactive by fluorodeoxyglucose positron emission tomography). The survey was developed jointly by the authors and administered to expert clinicians (n = 79) involved in CS treatment. An agreement threshold was set at 70%. A total of 62 of 79 respondents (78.5%) from 12 countries completed the survey. The agreement threshold was reached for: (1) always treating clinically manifest, metabolically active CS, 57 of 62 (91.9%), (2) never treating clinically silent, metabolically inactive CS, 44 of 62 (71.0%), (3) not requiring histopathologic confirmation of sarcoidosis before treatment initiation, (49 of 62, 79.0%), (4) using fluorodeoxyglucose positron emission tomography for assessing treatment indication (44 of 62, 71.0%) and treatment response (44 of 62, 71.0%), and (5) using prednisone as a first-line agent (100%), although respondents were divided on monotherapy (69.4%) or combination with methotrexate 25.8%. The approach to particular scenarios, tapering, and duration of treatment showed the greatest variation in response. In conclusion, in this survey of clinical practice, important aspects of CS treatment reached the agreement threshold, whereas others showed a great degree of clinical equipoise.

Gendered Differences in Experiences of Bullying and Mental Health Among Transgender and Cisgender Youth.

Even though previous studies have shown that transgender youth have poorer mental health and more experiences of being bullied than their cisgender counterparts, and that bullying associates with poorer mental health, knowledge on such associations in different gender identity groups is scarce. This study investigated how mental health problems and experiences of being bullied appear across different gender identity groups, and how bullying is associated with mental health among the groups in question. Data from the Finnish School Health Promotion 2021 study (n = 152,880, mean age 16.2 years (standard deviation 1.22)) was used and categorized into four gender identity groups: cisgender girls (n = 76,521), cisgender boys (n = 69,735), transfeminine youth (n = 1317), and transmasculine youth (n = 5307). Transgender youth experienced more bullying and reported poorer mental health than cisgender youth. While transfeminine youth faced the most bullying, transmasculine youth had the most mental health symptoms. In each group, bullying associated with poorer mental health. Compared to cisgender boys without bullying experiences, odds of poorer mental health were dozens-fold among transmasculine youth with weekly bullying experiences. In addition, compared to cisgender boys with bullying experiences, odds of poorer mental health were greater among all other gender identity groups with bullying experiences, and among transmasculine youth in particular (e.g., odds ratio of generalized anxiety = 8.36 (95% confidence interval, 6.59-10.6)). Bullying is associated with poorer mental health in all youth, but transgender youth, and especially transmasculine youth, may be in an even more vulnerable position for its implications. This suggests that there is a need for improving effective measures to decrease bullying in schools and to improve wellbeing of transgender youth.

Virtual Screening Strategy to Identify Retinoic Acid-Related Orphan Receptor γt Modulators.

Molecular docking is a key method used in virtual screening (VS) campaigns to identify small-molecule ligands for drug discovery targets. While docking provides a tangible way to understand and predict the protein-ligand complex formation, the docking algorithms are often unable to separate active ligands from inactive molecules in practical VS usage. Here, a novel docking and shape-focused pharmacophore VS protocol is demonstrated for facilitating effective hit discovery using retinoic acid receptor-related orphan receptor gamma t (RORγt) as a case study. RORγt is a prospective target for treating inflammatory diseases such as psoriasis and multiple sclerosis. First, a commercial molecular database was flexibly docked. Second, the alternative docking poses were rescored against the shape/electrostatic potential of negative image-based (NIB) models that mirror the target's binding cavity. The compositions of the NIB models were optimized via iterative trimming and benchmarking using a greedy search-driven algorithm or brute force NIB optimization. Third, a pharmacophore point-based filtering was performed to focus the hit identification on the known RORγt activity hotspots. Fourth, free energy binding affinity evaluation was performed on the remaining molecules. Finally, twenty-eight compounds were selected for in vitro testing and eight compounds were determined to be low µM range RORγt inhibitors, thereby showing that the introduced VS protocol generated an effective hit rate of ~29%.

Health-related quality of life among transthyretin amyloid cardiomyopathy patients.

AIMS: Transthyretin amyloid cardiomyopathy (ATTR CM) is a progressive and severe heart disease with physical and psychological implications. The Nordic PROACT study was conducted to investigate the health-related quality of life (HRQoL) in ATTR CM patients. METHODS AND RESULTS: The Nordic PROACT study was a cross-sectional non-interventional study conducted in 12 cardiology hospital clinics across Norway, Sweden, Finland and Denmark. Men and women aged ≥18 years diagnosed with symptomatic ATTR CM were included. The investigator provided information on medical history, biomarkers, current treatment, co-morbidities and disease severity according to the New York Heart Association (NYHA) class and the National Amyloidosis Centre (NAC) staging. Patients completed the HRQoL questionnaires in the form of the Kansas City Cardiomyopathy Questionnaire (KCCQ), the EQ-5D-5L index with Visual Analog Scale (VAS), and the Major Depression Inventory (MDI). A total of 169 patients (mean ± SD age 77.7 ± 6.2 years) were included. Ninety-two per cent were men. Seventy-six per cent had wildtype ATTR CM (ATTRwt CM) and 15% had a hereditary form of ATTR CM (ATTRv CM) while 9% were genetically unclassified. Most patients were in NYHA class II (54%) and NAC stage 1 (53%). Participation in randomized clinical trials (RCT) was noted in 58% of the patients. The 169 ATTR CM patients had a mean ± SD KCCQ score of 64.3 ± 23.1 for total symptom score, 64.8 ± 20.9 for overall summary score (OSS) and 65.1 ± 21.5 for clinical summary score. The EQ-5D-5L total utility score was 0.8 ± 0.2 and the EQ-5D-5L VAS score was 62.9 ± 20.6. The vast majority (89%) did not report any signs of depression. Patients with ATTRv CM had a higher KCCQ OSS as compared with ATTRwt CM, while EQ-5D-5L utility score, EQ-5D-5L VAS and MDI were similar. Non-RCT participants had a poorer HRQoL as compared with RCT participants as reflected in lower KCCQ OSS and EQ-5D-5L VAS scores and a higher MDI score. Patients with higher NYHA classes and NAC disease stages had a poorer HRQoL as demonstrated by lower KCCQ and EQ-5D-5L scores and higher MDI scores. Correlation between KCCQ, EQ-5D-5L and MDI and the covariate NYHA class remained significant (P < 0.05) after adjusting for multiple testing. CONCLUSIONS: KCCQ scores were lower than previously reported for patients with other heart diseases of non-ATTR CM origin. The HRQoL measures correlated well to NYHA class and NAC disease stage. The prevalence of depression appeared to be low.

Cardiac sarcoidosis: phenotypes, diagnosis, treatment, and prognosis.

Cardiac sarcoidosis (CS) results from epithelioid cell granulomas infiltrating the myocardium and predisposing to conduction disturbances, ventricular tachyarrhythmias, and heart failure. Manifest CS, however, constitutes only the top of an iceberg as advanced imaging uncovers cardiac involvement 4 to 5 times more commonly than what is clinically detectable. Definite diagnosis of CS requires myocardial biopsy and histopathology, but a sufficient diagnostic likelihood can be achieved by combining extracardiac histology of sarcoidosis with clinical manifestations and findings on cardiac imaging. CS can appear as the first or only organ manifestation of sarcoidosis or on top of pre-existing extracardiac disease. Due to the lack of controlled trials, the care of CS is based on observational evidence of low quality. Currently, the treatment involves corticosteroid-based, tiered immunosuppression to control myocardial inflammation with medical and device-based therapy for symptomatic atrioventricular block, ventricular tachyarrhythmias, and heart failure. Recent outcome data indicate 90% to 96% 5-year survival in manifest CS with the 10-year figures ranging from 80% to 90%. Major progress in the care of CS awaits the key to its molecular-genetic pathogenesis and large-scale controlled clinical trials.

Cardiac magnetic resonance in giant cell myocarditis: a matched comparison with cardiac sarcoidosis.

AIMS: Giant cell myocarditis (GCM) is an inflammatory cardiomyopathy akin to cardiac sarcoidosis (CS). We decided to study the findings of GCM on cardiac magnetic resonance (CMR) imaging and to compare GCM with CS. METHODS AND RESULTS: CMR studies of 18 GCM patients were analyzed and compared with 18 CS controls matched for age, sex, left ventricular (LV) ejection fraction and presenting cardiac manifestations. The analysts were blinded to clinical data. On admission, the duration of symptoms (median) was 0.2 months in GCM vs. 2.4 months in CS (P = 0.002), cardiac troponin T was elevated (>50 ng/L) in 16/17 patients with GCM and in 2/16 with CS (P < 0.001), their respective median plasma B-type natriuretic propeptides measuring 4488 ng/L and 1223 ng/L (P = 0.011). On CMR imaging, LV diastolic volume was smaller in GCM (177 ± 32 mL vs. 211 ± 58 mL, P = 0.014) without other volumetric or wall thickness measurements differing between the groups. Every GCM patient had multifocal late gadolinium enhancement (LGE) in a distribution indistinguishable from CS both longitudinally, circumferentially, and radially across the LV segments. LGE mass averaged 17.4 ± 6.3% of LV mass in GCM vs 25.0 ± 13.4% in CS (P = 0.037). Involvement of insertion points extending across the septum into the right ventricular wall, the "hook sign" of CS, was present in 53% of GCM and 50% of CS. CONCLUSION: In GCM, CMR findings are qualitatively indistinguishable from CS despite myocardial inflammation being clinically more acute and injurious. When matched for LV dysfunction and presenting features, LV size and LGE mass are smaller in GCM.

Incidence and Predictors of Atrial Fibrillation in Cardiac Sarcoidosis: A Multimodality Imaging Study.

BACKGROUND: In cardiac sarcoidosis (CS), the risk and predictors of new-onset atrial fibrillation (AF) are poorly known. OBJECTIVES: The authors evaluated the incidence and characteristics of AF in newly diagnosed CS. METHODS: The authors studied 118 patients (78 women, mean age 50 years) with AF-naive CS having undergone cardiac 18F-fluorodexoyglucose positron emission tomography (18F-FDG PET) at the time of diagnosis. Details of patient characteristics and medical or device therapy were collected from hospital charts. The PET scans were re-analyzed for presence of atrial and ventricular inflammation, and coincident cardiac magnetic resonance (CMR) studies and single-photon emission computed tomography (SPECT) perfusions were analyzed for cardiac structure and function, including the presence and extent of myocardial scarring. Detection of AF was based on interrogation of intracardiac devices and on ambulatory or 12-lead electrocardiograms. RESULTS: Altogether 34 patients (29%) suffered paroxysms of AF during follow-up (median, 3 years) with persistent AF developing in 7 patients and permanent AF in 4. The estimated 5-year incidence of AF was 55% (95% CI: 34%-72%) in the 39 patients with atrial 18F-FDG uptake at the time of diagnosis vs 18% (95% CI: 10%-28%) in the 79 patients without atrial uptake (P < 0.001). In cause-specific Cox regression analysis, atrial uptake was an independent predictor of AF (P < 0.001) with HR of 6.01 (95% CI: 2.64-13.66). Other independent predictors were an increased left atrial maximum volume (P < 0.01) and history of sleep apnea (P < 0.01). Ventricular involvement by PET, SPECT, or CMR was nonpredictive. Symptoms of AF prompted electrical cardioversion in 12 patients (35%). Three of the 34 patients (9%) experiencing AF suffered a stroke versus none of those remaining free of AF. CONCLUSIONS: In newly diagnosed CS, future AF is relatively common and associated with atrial inflammation and enlargement on multimodality cardiac imaging.

Cardiac sarcoidosis and giant cell myocarditis after COVID-19 infection.

Patients infected with SARS-CoV-2 have varying manifestations of cardiac involvement. We report four patients presenting with symptomatic cardiac sarcoidosis (CS) or giant cell myocarditis (GCM) 1-8 months after mild COVID-19. All patients received immunosuppressive therapy and improved gradually within the following months. The possible temporal association between the CS/GCM and COVID-19 infection might suggest that COVID-19 could be a trigger for granulomatous myocarditis.

Incidence of Sudden Cardiac Death and Life-Threatening Arrhythmias in Clinically Manifest Cardiac Sarcoidosis With and Without Current Indications for an Implantable Cardioverter Defibrillator.

BACKGROUND: Cardiac sarcoidosis (CS) predisposes to sudden cardiac death (SCD). Guidelines for implantable cardioverter defibrillators (ICDs) in CS have been issued by the Heart Rhythm Society in 2014 and the American College of Cardiology/American Heart Association/Heart Rhythm Society consortium in 2017. How well they discriminate high from low risk remains unknown. METHODS: We analyzed the data of 398 patients with CS detected in Finland from 1988 through 2017. All had clinical cardiac manifestations. Histological diagnosis was myocardial in 193 patients (definite CS) and extracardiac in 205 (probable CS). Patients with and without Class I or IIa ICD indications at presentation were identified, and subsequent occurrences of SCD (fatal or aborted) and sustained ventricular tachycardia were recorded, as were ICD indications emerging first on follow-up. RESULTS: Over a median of 4.8 years, 41 patients (10.3%) had fatal (n=8) or aborted (n=33) SCD, and 98 (24.6%) experienced SCD or sustained ventricular tachycardia as the first event. By the Heart Rhythm Society guideline, Class I or IIa ICD indications were present in 339 patients (85%) and absent in 59 (15%), of whom 264 (78%) and 30 (51%), respectively, received an ICD. Cumulative 5-year incidence of SCD was 10.7% (95% CI, 7.4%-15.4%) in patients with ICD indications versus 4.8% (95% CI, 1.2%-19.1%) in those without (χ2=1.834, P=0.176). The corresponding rates of SCD were 13.8% (95% CI, 9.1%-21.0%) versus 6.3% (95% CI, 0.7%-54.0%; χ2=0.814, P=0.367) in definite CS and 7.6% (95% CI, 3.8%-15.1%) versus 3.3% (95% CI, 0.5%-22.9%; χ2=0.680, P=0.410) in probable CS. In multivariable regression analysis, SCD was predicted by definite histological diagnosis (P=0.033) but not by Class I or IIa ICD indications (P=0.210). In patients without ICD indications at presentation, 5-year incidence of SCD, sustained ventricular tachycardia, and emerging Class I or IIa indications was 53% (95% CI, 40%-71%). By the American College of Cardiology/American Heart Association/Heart Rhythm Society guideline, all patients with complete data (n=245) had Class I or IIa indications for ICD implantation. CONCLUSIONS: Current ICD guidelines fail to distinguish a truly low-risk group of patients with clinically manifest CS, the 5-year risk of SCD approaching 5% despite absent ICD indications. Further research is needed on prognostic factors, including the role of diagnostic histology. Meanwhile, all patients with CS presenting with clinical cardiac manifestations should be considered for an ICD implantation.

Ligand-Enhanced Negative Images Optimized for Docking Rescoring.

Despite the pivotal role of molecular docking in modern drug discovery, the default docking scoring functions often fail to recognize active ligands in virtual screening campaigns. Negative image-based rescoring improves docking enrichment by comparing the shape/electrostatic potential (ESP) of the flexible docking poses against the target protein's inverted cavity volume. By optimizing these negative image-based (NIB) models using a greedy search, the docking rescoring yield can be improved massively and consistently. Here, a fundamental modification is implemented to this shape-focused pharmacophore modelling approach-actual ligand 3D coordinates are incorporated into the NIB models for the optimization. This hybrid approach, labelled as ligand-enhanced brute-force negative image-based optimization (LBR-NiB), takes the best from both worlds, i.e., the all-roundedness of the NIB models and the difficult to emulate atomic arrangements of actual protein-bound small-molecule ligands. Thorough benchmarking, focused on proinflammatory targets, shows that the LBR-NiB routinely improves the docking enrichment over prior iterations of the R-NiB methodology. This boost can be massive, if the added ligand information provides truly essential binding information that was lacking or completely missing from the cavity-based NIB model. On a practical level, the results indicate that the LBR-NiB typically works well when the added ligand 3D data originates from a high-quality source, such as X-ray crystallography, and, yet, the NIB model compositions can also sometimes be improved by fusing into them, for example, with flexibly docked solvent molecules. In short, the study demonstrates that the protein-bound ligands can be used to improve the shape/ESP features of the negative images for effective docking rescoring use in virtual screening.

Cardiac Magnetic Resonance Imaging-Based Screening for Cardiac Sarcoidosis in Patients With Atrioventricular Block Requiring Temporary Pacing.

Background Some myocardial diseases, such as cardiac sarcoidosis, predispose to complete atrioventricular block. The European Society of Cardiology Guidelines on cardiac pacing in 2021 recommend myocardial disease screening in patients with conduction disorder requiring pacemaker with multimodality imaging, including cardiac magnetic resonance (CMR) imaging. The ability of CMR imaging to detect myocardial disease in patients with a temporary pacing wire is not well documented. Methods and Results Our myocardial disease screening protocol is based on using an active fixation pacing lead connected to a reusable extracorporeal pacing generator (temporary permanent pacemaker) as a bridge to a permanent pacemaker. From 2011 to 2019, we identified 17 patients from our CMR database who underwent CMR imaging with a temporary permanent pacemaker for atrioventricular block. We analyzed their clinical presentations, CMR data, and pacemaker therapy. All CMRs were performed without adverse events. Pacing leads induced minor artifacts to the septal myocardial segments. The extent of late gadolinium enhancement in CMR imaging was used to screen patients for the presence of myocardial disease. Patients with evidence of late gadolinium enhancement underwent endomyocardial biopsy. If considered clinically indicated, also 18-F-fluorodeoxyglucose positron emission tomography and extracardiac tissue biopsy were performed if sarcoidosis was suspected. Eventually, 8 of 17 patients (47.1%) were diagnosed with histologically confirmed granulomatous inflammatory cardiac disease. Importantly, only 1 had a previously diagnosed extracardiac sarcoidosis at the time of presentation with high-degree atrioventricular block. Conclusions CMR imaging with temporary permanent pacemaker protocol is an effective and safe early screening tool for myocardial disease in patients presenting with atrioventricular block requiring immediate, continuous pacing for bradycardia.

Prevalence, Characteristics, and Outcomes of COVID-19-Associated Acute Myocarditis.

BACKGROUND: Acute myocarditis (AM) is thought to be a rare cardiovascular complication of COVID-19, although minimal data are available beyond case reports. We aim to report the prevalence, baseline characteristics, in-hospital management, and outcomes for patients with COVID-19-associated AM on the basis of a retrospective cohort from 23 hospitals in the United States and Europe. METHODS: A total of 112 patients with suspected AM from 56 963 hospitalized patients with COVID-19 were evaluated between February 1, 2020, and April 30, 2021. Inclusion criteria were hospitalization for COVID-19 and a diagnosis of AM on the basis of endomyocardial biopsy or increased troponin level plus typical signs of AM on cardiac magnetic resonance imaging. We identified 97 patients with possible AM, and among them, 54 patients with definite/probable AM supported by endomyocardial biopsy in 17 (31.5%) patients or magnetic resonance imaging in 50 (92.6%). We analyzed patient characteristics, treatments, and outcomes among all COVID-19-associated AM. RESULTS: AM prevalence among hospitalized patients with COVID-19 was 2.4 per 1000 hospitalizations considering definite/probable and 4.1 per 1000 considering also possible AM. The median age of definite/probable cases was 38 years, and 38.9% were female. On admission, chest pain and dyspnea were the most frequent symptoms (55.5% and 53.7%, respectively). Thirty-one cases (57.4%) occurred in the absence of COVID-19-associated pneumonia. Twenty-one (38.9%) had a fulminant presentation requiring inotropic support or temporary mechanical circulatory support. The composite of in-hospital mortality or temporary mechanical circulatory support occurred in 20.4%. At 120 days, estimated mortality was 6.6%, 15.1% in patients with associated pneumonia versus 0% in patients without pneumonia (P=0.044). During hospitalization, left ventricular ejection fraction, assessed by echocardiography, improved from a median of 40% on admission to 55% at discharge (n=47; P<0.0001) similarly in patients with or without pneumonia. Corticosteroids were frequently administered (55.5%). CONCLUSIONS: AM occurrence is estimated between 2.4 and 4.1 out of 1000 patients hospitalized for COVID-19. The majority of AM occurs in the absence of pneumonia and is often complicated by hemodynamic instability. AM is a rare complication in patients hospitalized for COVID-19, with an outcome that differs on the basis of the presence of concomitant pneumonia.

Immunomodulating Therapies in Acute Myocarditis and Recurrent/Acute Pericarditis.

The field of inflammatory disease of the heart or "cardio-immunology" is rapidly evolving due to the wider use of non-invasive diagnostic tools able to detect and monitor myocardial inflammation. In acute myocarditis, recent data on the use of immunomodulating therapies have been reported both in the setting of systemic autoimmune disorders and in the setting of isolated forms, especially in patients with specific histology (e.g., eosinophilic myocarditis) or with an arrhythmicburden. A role for immunosuppressive therapies has been also shown in severe cases of coronavirus disease 2019 (COVID-19), a condition that can be associated with cardiac injury and acute myocarditis. Furthermore, ongoing clinical trials are assessing the role of high dosage methylprednisolone in the context of acute myocarditis complicated by heart failure or fulminant presentation or the role of anakinra to treat patients with acute myocarditis excluding patients with hemodynamically unstable conditions. In addition, the explosion of immune-mediated therapies in oncology has introduced new pathophysiological entities, such as immune-checkpoint inhibitor-associated myocarditis and new basic research models to understand the interaction between the cardiac and immune systems. Here we provide a broad overview of evolving areas in cardio-immunology. We summarize the use of new imaging tools in combination with endomyocardial biopsy and laboratory parameters such as high sensitivity troponin to monitor the response to immunomodulating therapies based on recent evidence and clinical experience. Concerning pericarditis, the normal composition of pericardial fluid has been recently elucidated, allowing to assess the actual presence of inflammation; indeed, normal pericardial fluid is rich in nucleated cells, protein, albumin, LDH, at levels consistent with inflammatory exudates in other biological fluids. Importantly, recent findings showed how innate immunity plays a pivotal role in the pathogenesis of recurrent pericarditis with raised C-reactive protein, with inflammasome and IL-1 overproduction as drivers for systemic inflammatory response. In the era of tailored medicine, anti-IL-1 agents such as anakinra and rilonacept have been demonstrated highly effective in patients with recurrent pericarditis associated with an inflammatory phenotype.

Optimization of Cavity-Based Negative Images to Boost Docking Enrichment in Virtual Screening.

Molecular docking is a key in silico method used routinely in modern drug discovery projects. Although docking provides high-quality ligand binding predictions, it regularly fails to separate the active compounds from the inactive ones. In negative image-based rescoring (R-NiB), the shape/electrostatic potential (ESP) of docking poses is compared to the negative image of the protein's ligand binding cavity. While R-NiB often improves the docking yield considerably, the cavity-based models do not reach their full potential without expert editing. Accordingly, a greedy search-driven methodology, brute force negative image-based optimization (BR-NiB), is presented for optimizing the models via iterative editing and benchmarking. Thorough and unbiased training, testing and stringent validation with a multitude of drug targets, and alternative docking software show that BR-NiB ensures excellent docking efficacy. BR-NiB can be considered as a new type of shape-focused pharmacophore modeling, where the optimized models contain only the most vital cavity information needed for effectively filtering docked actives from the inactive or decoy compounds. Finally, the BR-NiB code for performing the automated optimization is provided free-of-charge under MIT license via GitHub (https://github.com/jvlehtonen/brutenib) for boosting the success rates of docking-based virtual screening campaigns.

Short- and long-term outcomes after heart transplantation in cardiac sarcoidosis and giant-cell myocarditis: a systematic review and meta-analysis.

Heart transplantation (HTx) is a valid therapeutic option for end-stage heart failure secondary to cardiac sarcoidosis (CS) or giant-cell myocarditis (GCM). However, post-HTx outcomes in patients with inflammatory cardiomyopathy (ICM) have been poorly investigated. We searched PubMed, Scopus, Science Citation Index, EMBASE, and Google Scholar, screened the gray literature, and contacted experts in the field. We included studies comparing post-HTx survival, acute cellular rejection, and disease recurrence in patients with and without ICM. Data were synthesized by a random-effects meta-analysis. We screened 11,933 articles, of which 14 were considered eligible. In a pooled analysis, post-HTx survival was higher in CS than non-CS patients after 1 year (risk ratio [RR] 0.88, 95% confidence interval [CI] 0.60-1.17; I2 = 0%) and 5 years (RR 0.72, 95% CI 0.52-0.91; I2 = 0%), but statistically significant only after 5 years. During the first-year post-HTx, the risk of acute cellular rejection was similar for patients with and without CS, but after 5 years, it was lower in those with CS (RR 0.38, 95% CI 0.03-0.72; I2 = 0%). No difference in post-HTx survival was observed between patients with and without GCM after 1 year (RR 1.16, 95% CI 0.05-2.28; I2 = 0%) or 5 years (RR 0.98, 95% CI 0.42-1.54; I2 = 0%). During post-HTx follow-up, recurrence of CS and GCM occurred in 5% and 8% of patients, respectively. Post-HTx outcomes in patients with CS and GCM are comparable with cardiac recipients with other heart failure etiologies. Patients with ICM should not be disqualified from HTx.