Myocardial Biopsy Research Articles

A rare case of nivolumab-related myasthenia gravis and myocarditis in a patient with metastatic gastric cancer

BackgroundAlthough rare, several immune-related adverse effects can be life-threatening. Here, we describe a metastatic gastric cancer patient presenting with nivolumab-related myasthenia gravis and myocarditis, a previously unreported adverse effect of gastric cancer treatment.Case presentationA 66-year-old man with metastatic gastric cancer visited the emergency department because of dizziness after the first dose of nivolumab. Diagnoses of nivolumab-related myasthenia gravis and myocarditis were established. Myocardial biopsy results and anti-acetylcholine receptor antibody positivity confirmed the diagnoses. Despite plasma exchange and intravenous methylprednisolone and immunoglobulin administration, the patient’s general condition gradually worsened, and he died.ConclusionsStrict monitoring for cardiac and neuromuscular symptoms after nivolumab administration is necessary to rapidly treat these adverse effects.

Neuropeptide Y promotes adipogenesis of human cardiac mesenchymal stromal cells in arrhythmogenic cardiomyopathy

BackgroundArrhythmogenic Cardiomyopathy (AC) is a familial cardiac disease, mainly caused by mutations in desmosomal genes. AC hearts show fibro-fatty myocardial replacement, which favors stress-related life-threatening arrhythmias, predominantly in the young and athletes. AC lacks effective therapies, as its pathogenesis is poorly understood. Recently, we showed that cardiac Mesenchymal Stromal Cells (cMSCs) contribute to adipose tissue in human AC hearts, although the underlying mechanisms are still unclear. PurposeWe hypothesize that the sympathetic neurotransmitter, Neuropeptide Y (NPY), participates to cMSC adipogenesis in human AC. MethodsFor translation of our findings, we combined in vitro cytochemical, molecular and pharmacologic assays on human cMSCs, from myocardial biopsies of healthy controls and AC patients, with the use of existing drugs to interfere with the predicted AC mechanisms. Sympathetic innervation was inspected in human autoptic heart samples, and NPY plasma levels measured in healthy and AC subjects. ResultsAC cMSCs expressed higher levels of pro-adipogenic isotypes of NPY-receptors (i.e. Y1-R, Y5-R). Consistently, NPY enhanced adipogenesis in AC cMSCs, which was blocked by FDA-approved Y1-R and Y5-R antagonists. AC-associated PKP2 reduction directly caused NPY-dependent adipogenesis in cMSCs. In support of the involvement of sympathetic neurons (SNs) and NPY in AC myocardial remodeling, patients had elevated NPY plasma levels and, in human AC hearts, SNs accumulated in fatty areas and were close to cMSCs. ConclusionsIndependently from the disease origin, AC causes in cMSCs a targetable gain of responsiveness to NPY, which leads to increased adipogenesis, thus playing a role in AC myocardial remodeling.

Optimizing the discovery and assessment of therapeutic targets in heart failure with preserved ejection fraction.

There is an urgent need for models that faithfully replicate heart failure with preserved ejection fraction (HFpEF), now recognized as the most common form of heart failure in the world. In vitro approaches have several shortcomings, most notably the immature nature of stem cell‐derived human cardiomyocytes [induced pluripotent stem cells (iPSC)] and the relatively short lifespan of primary cardiomyocytes. Three‐dimensional ‘organoids’ incorporating mature iPSCs with other cell types such as endothelial cells and fibroblasts are a significant advance, but lack the complexity of true myocardium. Animal models can replicate many features of human HFpEF, and rodent models are the most common, and recent attempts to incorporate haemodynamic, metabolic, and ageing contributions are encouraging. Differences relating to species, physiology, heart rate, and heart size are major limitations for rodent models. Porcine models mitigate many of these shortcomings and approximate human physiology more closely, but cost and time considerations limit their potential for widespread use. Ex vivo analysis of failing hearts from animal models offer intriguing possibilities regarding cardiac substrate utilisation, but are ultimately subject to the same constrains as the animal models from which the hearts are obtained. Ex vivo approaches using human myocardial biopsies can uncover new insights into pathobiology leveraging myocardial energetics, substrate turnover, molecular changes, and systolic/diastolic function. In collaboration with a skilled cardiothoracic surgeon, left ventricular endomyocardial biopsies can be obtained at the time of valvular surgery in HFpEF patients. Critically, these tissues maintain their disease phenotype, preserving inter‐relationship of myocardial cells and extracellular matrix. This review highlights a novel approach, where ultra‐thin myocardial tissue slices from human HFpEF hearts can be used to assess changes in myocardial structure and function. We discuss current approaches to modelling HFpEF, describe in detail the novel tissue slice model, expand on exciting opportunities this model provides, and outline ways to improve this model further.

Causes of altered ventricular mechanics in hypertrophic cardiomyopathy: an in-silico study

BackgroundHypertrophic cardiomyopathy (HCM) is typically caused by mutations in sarcomeric genes leading to cardiomyocyte disarray, replacement fibrosis, impaired contractility, and elevated filling pressures. These varying tissue properties are associated with certain strain patterns that may allow to establish a diagnosis by means of non-invasive imaging without the necessity of harmful myocardial biopsies or contrast agent application. With a numerical study, we aim to answer: how the variability in each of these mechanisms contributes to altered mechanics of the left ventricle (LV) and if the deformation obtained in in-silico experiments is comparable to values reported from clinical measurements.MethodsWe conducted an in-silico sensitivity study on physiological and pathological mechanisms potentially underlying the clinical HCM phenotype. The deformation of the four-chamber heart models was simulated using a finite-element mechanical solver with a sliding boundary condition to mimic the tissue surrounding the heart. Furthermore, a closed-loop circulatory model delivered the pressure values acting on the endocardium. Deformation measures and mechanical behavior of the heart models were evaluated globally and regionally.ResultsHypertrophy of the LV affected the course of strain, strain rate, and wall thickening—the root-mean-squared difference of the wall thickening between control (mean thickness 10 mm) and hypertrophic geometries (17 mm) was >10%. A reduction of active force development by 40% led to less overall deformation: maximal radial strain reduced from 26 to 21%. A fivefold increase in tissue stiffness caused a more homogeneous distribution of the strain values among 17 heart segments. Fiber disarray led to minor changes in the circumferential and radial strain. A combination of pathological mechanisms led to reduced and slower deformation of the LV and halved the longitudinal shortening of the LA.ConclusionsThis study uses a computer model to determine the changes in LV deformation caused by pathological mechanisms that are presumed to underlay HCM. This knowledge can complement imaging-derived information to obtain a more accurate diagnosis of HCM.

Myocarditis Associated with mRNA COVID-19 Vaccination.

Myocarditis Associated with mRNA COVID-19 Vaccination.

Additional diagnostic value of cardiac magnetic resonance feature tracking in patients with biopsy-proven arrhythmogenic cardiomyopathy

BackgroundWe aim to evaluate the value of Cardiac magnetic resonance (CMR) feature tracking (CMR-FT) in addition to Task Force Criteria(TFC) in patients with (arrhythmogenic cardiomyopathy) AC biopsy-proved. MethodsThirty-five patients with AC histologically proven who performed CMR with late gadolinium enhancement (LGE) acquisition were enrolled. The study population was divided in Group1 (negative CMR TFC and LV ejection fraction≥55%) and Group2 (positive CMR TFC and/or LVEF<55%) and compared to an age and gender-matched control group. CMR datasets of all patients were analyzed to calculate LV indexed end-diastolic (LVEDi) and end-systolic (LVESi) volumes and RV indexed end-diastolic (RVEDi) and end-systolic (RVESi) volumes, both LV ejection fraction (LVEF) and RV ejection fraction (RVEF). Moreover, LV and RV global longitudinal (GLS), circumferential (GCS) and radial (GRS) strain were measured. ResultsThe AC patients showed both higher LVEDi (p:0.002) and RVEDi (p:0.017) and lower LVEF (p: 0.016) as compared to control patients. Moreover, AC patients showed impaired LV-GLS (p < 0.001), LV-GRS (p < 0.001), LV-GCS (p < 0.001) and RV-GRS (p:0.026) as compared to control subjects. Group1 patients showed a significant reduction of LV-GRS (p < 0.05) and LV-GCS p < 0.01) as compared to control subjects. At univariate analysis LV-GCS was the most discriminatory parameter between Group1 vs heathy subjects with an optimal cut-off of −15.8 (Sensitivity: 74%; Specificity: 10%). ConclusionsIn patients with AC biopsy-proven, CMR-FT could improve the diagnostic yield in the subset of patients who results negative for imaging TFC criteria resulting as useful gatekeeper for indication of myocardial biopsy in case of equivocal clinical and imaging presentation.

Cyclosporine A-enhanced cardioplegia preserves mitochondrial basal respiration after ischemic arrest.

Mitochondrial permeability transition pore (mPTP) opening plays a crucial role in cell death during ischemia-reperfusion injury (IRI). Cyclosporine A (CsA) inhibits mPTP opening. This study aimed to investigate the effects of CsA treatment during cardioplegia on the mitochondrial function and cardiac IRI. Landrace pigs (52.9 ± 3.7 kg) were subjected to midline sternotomy, cardiopulmonary bypass at 34°C and 90 minutes of cardiac arrest. They received either a single shot of standard 4°C cold histidine-tryptophan-α-ketoglutarate (HTK)-Bretschneider solution (n = 11) or HTK-Bretschneider plus 1.2 mg/L CsA (histidine-tryptophan-α-ketoglutarate plus cyclosporine A (HTK/CsA); n = 11). During reperfusion global left-ventricular function was assessed and myocardial biopsies were harvested at baseline, during ischemia and 45 minutes following reperfusion. High-resolution respirometry and hydrogen peroxide production were measured. Immunohistochemical stainings for apoptosis-inducing factor and hypoxia-inducible factor-1α as well as a flow cytometry-based JC-1 mitochondrial membrane potential assay were performed. Hemodynamic parameters were comparable between both groups. The cytochrome C release (HTK: 930.3 ± 804.4 pg/mg, HTK/CsA: 699.7 ± 394.0 pg/mg, p = 0.457) as well as PGC1α content (HTK: 66.7%, HTK/CsA: 33.3%, p = 0.284) was lower in the HTK/CsA group. Respiratory measurements revealed that the oxygen flux under basal respiration was higher in the HTK/CsA group (8.2 ± 1.3 pmol·O2·s-1·mg-1·ww) than in the HTK group (3.8 ± 1.4 pmol·O2·s-1·mg-1·ww, p = 0.045). There were no significant differences regarding histological surrogates of apoptosis and necrosis. Supplementing cardioplegic solutions with CsA enhances the basal mitochondrial respiration thereby exerting a cardioprotective effect and diminishing IRI-induced damage. CsA seems to preserve mitochondrial function via non-ROS related pathways.

Pulmonary Hypertension Independently Shortens Survival of Patients with Myeloproliferative Neoplasms

Introduction: Myeloproliferative neoplasms (MPN) are frequently associated with symptoms of fatigue, poor sleep, mood disorders, lightheadedness and shortness of breath. The cause of these symptoms is not well understood and is often attributed to blood count abnormalities or elevated inflammatory cytokines common in these disorders. There is a high degree of overlap between clinical manifestations of MPN and symptoms reported by pts with pulmonary hypertension (PH). Small studies have shown that pts with MPNs are at risk for PH but the extent to which PH contributes to clinical symptoms and prognosis in MPN pts is unknown.Methods: 300 sequential MPN pts undergoing transthoracic echocardiography (echo) between January, 2011 and April, 2017 were studied (Table 1). A second MPN cohort of 287 patients (NoEcho) was matched for age and diagnosis to the MPN Echo+ (Echo) cohort. Baseline demographics including age, gender, diagnosis, date of diagnosis, mutation profile, transformation, BMT, bleeding or thrombosis history, symptoms, cardiovascular risk factors, echo indication and survival were collected for all pts. To ensure accurate echo assessment of PH sequelae, RV assessment via both tricuspid annular plane systolic excursion (TAPSE) and peak tricuspid annular systolic velocity (S‘) were required for study inclusion. RV dysfunction (RVDYS) was defined by impairment of both TAPSE and S’. RV global longitudinal strain (GLS) was quantified as a secondary means of assessing RV function as a continuous variable. Pulmonary artery systolic pressure (PASP) was calculated based on tricuspid regurgitant velocity and inferior vena cava caliber; PH (PASP³35 mmHg) and advanced PH (PASP³50 mmHg) were defined via established criteria. LV systolic and diastolic function, geometry, and mass were quantified based on linear dimensions in parasternal long axis, consistent with quantitative methods previously validated. Echoes were interpreted in a high-volume laboratory, for which expertise and reproducibility have been documented. All cause mortality was assessed following echo.Results: PH was identified in the majority (56%; 135/239) of MPN pts who underwent echo (Table 2). PH was common among all MPN subtypes (46% CML, 58% ET, 57% PV, 63% MF, 100% CEL, 42% MPN/MDS and 79% MPN-NOS). Advanced PH was identified in 20% of all MPN pts and within each subtype (15% CML, 13% ET, 16% PV, 29% MF, 33% CEL, 25% MPN/MDS and 43% MPN-NOS). RVDYS was 8-fold more common (24% vs 3%; p=<0.001) among MPN pts with PH and the magnitude of RVDYS increased stepwise in relation to PASP (p<0.001), suggesting that PH was causally related to RV failure. Although impaired LV systolic function (LVEF<50%) was no more common in MPN pts with PH (17% vs 10%; p=0.10), LV hypertrophy (38% vs 14%, p=<0.001), LV mass (99 ± 31 vs 83 ± 23 g/m2, p<0.001), LV filling pressure (E/e': 14±6 vs 11±4; p<0.001), and frequency of LV diastolic dysfunction (any grade: 71 vs 52%; p=0.003) were all increased in pts with PH. Left atrium (LA) area was also increased in MPN pts with PH (24 vs 19 cm2; p=0.001), further suggesting a post-capillary cause for PH in this MPN population. Myocardial biopsy of an MPN patient with advanced PH demonstrated interstitial fibrosis in non-infarcted myocardium suggesting that fibrosis could play a role in LV diastolic dysfunction and PH in pts with MPNs.During median follow-up of 6.2 yrs (0.1 to 43 yrs), likelihood of death was higher for pts with advanced PH (odds ratio 3.1, p=0.004), or with RVDYS whether quantified by GLS (odds ratio 2.4, p=0.04) or TAPSE/S' (odds ratio 2.3, p=0.048). Cox Proportional Hazards model (parameterized for age, gender, MPN diagnosis, transformation and BMT) indicated that the Echo cohort was similar to the NoEcho control group. Pts with PH were more likely to experience fatigue than pts with a normal estimated PASP. Whereas dyspnea was no more common in pts with PH as a whole, pts with advanced PH were more likely to experience both fatigue and dyspnea compared to those with less severe PH or normal PASP. Cox proportional hazards modeling identified Advanced PH as an independent predictor of death in models that included Age, Gender, MPN Diagnosis, Transformation and BMT.Conclusions : PH with post-capillary hemodynamics is extremely common in pts with MPN and is associated with frequently reported symptoms such as fatigue. When advanced or when associated with RVDYS, PH independently confers increased mortality risk for MPN pts. [Display omitted] DisclosuresRitchie:Bristol-Myers Squibb: Other: Research funding to my institution; Astellas Pharma: Other: Research funding to my institution; Celgene: Consultancy, Other: Travel, Speakers Bureau; Pfizer: Consultancy, Other: Research funding to my institution; NS Pharma: Other: Research funding to my institution; Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy, Other: Research funding to my institution, and travel, Speakers Bureau.

Glucosylceramide synthase deficiency in the heart compromises β1-adrenergic receptor trafficking.

Aims Cardiac injury and remodelling are associated with the rearrangement of cardiac lipids. Glycosphingolipids are membrane lipids that are important for cellular structure and function, and cardiac dysfunction is a characteristic of rare monogenic diseases with defects in glycosphingolipid synthesis and turnover. However, it is not known how cardiac glycosphingolipids regulate cellular processes in the heart. The aim of this study is to determine the role of cardiac glycosphingolipids in heart function.Methods and results Using human myocardial biopsies, we showed that the glycosphingolipids glucosylceramide and lactosylceramide are present at very low levels in non-ischaemic human heart with normal function and are elevated during remodelling. Similar results were observed in mouse models of cardiac remodelling. We also generated mice with cardiomyocyte-specific deficiency in Ugcg, the gene encoding glucosylceramide synthase (hUgcg –/– mice). In 9- to 10-week-old hUgcg –/– mice, contractile capacity in response to dobutamine stress was reduced. Older hUgcg –/– mice developed severe heart failure and left ventricular dilatation even under baseline conditions and died prematurely. Using RNA-seq and cell culture models, we showed defective endolysosomal retrograde trafficking and autophagy in Ugcg-deficient cardiomyocytes. We also showed that responsiveness to β-adrenergic stimulation was reduced in cardiomyocytes from hUgcg –/– mice and that Ugcg knockdown suppressed the internalization and trafficking of β1-adrenergic receptors.Conclusions Our findings suggest that cardiac glycosphingolipids are required to maintain β-adrenergic signalling and contractile capacity in cardiomyocytes and to preserve normal heart function.

SLE strikes the heart! A rare presentation of SLE myocarditis presenting as cardiogenic shock

BackgroundAlthough systemic lupus erythematosus (SLE) can affect the cardiovascular system in many ways with diverse presentations, a severe cardiogenic shock secondary to SLE myocarditis is infrequently described in the medical literature. Variable presenting features of SLE myocarditis can also make the diagnosis challenging. This case report will allow learners to consider SLE myocarditis in the differential and appreciate the diagnostic uncertainty.Case presentationA 20-year-old Filipino male presented with acute dyspnea, pleuritic chest pain, fevers, and diffuse rash after being diagnosed with SLE six months ago and treated with hydroxychloroquine. Labs were notable for leukopenia, non-nephrotic range proteinuria, elevated cardiac biomarkers, inflammatory markers, low complements, and serologies suggestive of active SLE. Broad-spectrum IV antibiotics and corticosteroids were initiated for sepsis and SLE activity. Blood cultures were positive for MSSA with likely skin source. An electrocardiogram showed diffuse ST-segment elevations without ischemic changes. CT chest demonstrated bilateral pleural and pericardial effusions with dense consolidations. Transthoracic and transesophageal echocardiogram demonstrated reduced left ventricular ejection fraction (LVEF) 45% with no valvular pathology suggestive of endocarditis. Although MSSA bacteremia resolved, the patient rapidly developed cardiopulmonary decline with a repeat echocardiogram demonstrating LVEF < 10%. A Cardiac MRI was a nondiagnostic study to elucidate an etiology of decompensation given inability to perform late gadolinium enhancement. Later, cardiac catheterization revealed normal cardiac output with non-obstructive coronary artery disease. As there was no clear etiology explaining his dramatic heart failure, endomyocardial biopsy was obtained demonstrating diffuse myofiber degeneration and inflammation. These pathological findings, in addition to skin biopsy demonstrating lichenoid dermatitis with a granular “full house” pattern was most consistent with SLE myocarditis. Furthermore, aggressive SLE-directed therapy demonstrated near full recovery of his heart failure.ConclusionAlthough myocarditis during SLE flare is a well-described cardiac manifestation, progression to cardiogenic shock is infrequent and fatal. As such, SLE myocarditis should be promptly considered. Given the heterogenous presentation of SLE, combination of serologic evaluation, advanced imaging, and myocardial biopsies can be helpful when diagnostic uncertainty exists. Our case highlights diagnostic methods and clinical course of a de novo presentation of cardiogenic shock from SLE myocarditis, then rapid improvement.

Left atrial strain by speckle tracking predicts atrial fibrosis in patients undergoing heart transplantation.

In patients with heart failure (HF), chronically raised left ventricular (LV) filling pressures lead to progressive left atrial (LA) dysfunction and fibrosis. We aimed to assess the correlation of LA reservoir strain (peak atrial longitudinal strain, PALS) by speckle tracking echocardiography (STE) and LA fibrosis assessed by myocardial biopsy in patients undergoing heart transplantation (HTx). Forty-eight patients with advanced HF [mean age 51.2 ± 8.1 years, 29% females; LV ejection fraction ≤25% and New York Heart Association (NYHA) class III-IV] referred for HTx were enrolled and underwent pre-operative echocardiographic evaluation, right heart catheterization, and cardiopulmonary exercise testing. Exclusion criteria were non-sinus rhythm, mechanical ventilation, severe mitral/tricuspid regurgitation, or other valvular disease and poor acoustic window. After HTx, LA bioptic samples were collected and analysed to determine the extent of myocardial fibrosis (%). LA fibrosis showed correlation with PALS (R = -0.88, P < 0.0001), VO2max (R = -0.68, P < 0.0001), NYHA class (R = 0.66, P < 0.0001), LA stiffness (R = 0.58, P = 0.0002), and E/e' (R = 0.44, P = 0.005), while poorly correlated with E/A ratio (R = 0.23, P = 0.21). PALS had a good correlation with NYHA class (R = -0.64, P < 0.0001), PAoP (R = -0.61, P = 0.03) and VO2max (R = 0.57, P = 0.0001). Multivariate regression analysis identified PALS (beta = -0.91, P < 0.001) and LA Volume (beta = -0.19, P = 0.03) as predictors of LA Fibrosis, while E/e' was not a significant predictor (beta = 0.15, P = 0.08). Emerging as a possible index of myocardial fibrosis in patients with advanced HF, PALS could help to optimize the management and the selection of those patients with irreversible LA structural damage for advanced therapeutic strategies.

A systematic review of myasthenia gravis complicated with myocarditis.

Among many of the autoimmune diseases observed in patients with myasthenia gravis (MG), myocarditis is one of the most critical. The goal of this review is to systematically describe and investigate the characteristics of MG complicated with myocarditis. We identified 183 records in PubMed (MEDLINE), Web of Science, and EMBASE from 1948 to September 10, 2020. Studies were included if they presented clinical data on MG complicated with myocarditis. Of the 35 patients from 28 studies in this review, 57.14% (20/35) were males, with a mean age of 59.11 ± 15.87. Dyspnea was the most common cardiac symptom accounting for over 60% in the study. Among the 35 patients, 13 cases of myocarditis occurred concomitantly with MG and the longest interval between MG and myocarditis was 7 years. Forty percent of patients developed myocarditis caused by immune checkpoint inhibitors (ICI). Among the patients with myocarditis, over half of the patients were diagnosed by myocardial biopsy. After active immune regulation and symptomatic treatment, only 15 of 35 patients with MG complicated with myocarditis improved, 18 patients died during hospitalization, one patient died due to tumor progression and 1patient died 5 years later. The prognosis of patients with MG complicated with myocarditis is poor, and myocardial enzymes and other indexes need to be monitored for patients taking ICI drugs. Patients with dyspnea who are still not ideally treated by mechanical ventilation should be vigilant against the occurrence of MG complicated with myocarditis.

Diagnosing Myocarditis with MicroRNAs

Acute myocarditis remains a challenging diagnosis to make, even with use of magnetic resonance imaging (MRI) and myocardial biopsy (MB). In a mouse

DOSE EVALUATION AND PROPOSAL OF LOCAL DIAGNOSTIC REFERENCE LEVELS FOR PAEDIATRIC CARDIAC CATHETERIZATIONS PERFORMED ON A HIGH-SENSITIVITY ANGIOGRAPHIC SYSTEM ALLOWING LOW-DOSE IMAGING.

Radiation doses from paediatric cardiac catheterizations were analysed based on procedure type and patient weight, and local diagnostic reference levels (LDRLs) were proposed. The procedures were performed on a Siemens Artis Q.zen biplane system with high-sensitivity detectors allowing low-dose imaging. Good radiological practice, e.g. adapting dose level and frame rate continuously and minimizing the x-ray field with collimators, was routine during procedures. The median total dose-area-product (DAP) value was 58 μGym2 for diagnostic catheterizations, 48 μGym2 for interventional catheterizations and 33 μGym2 for myocardial biopsies. The median DAP per body weight was 4.0 μGym2 kg-1. The median total fluoroscopy time varied from 6.0min for myocardial biopsies, to 9.7 and 10.5min, respectively, for diagnostic and interventional catheterizations. The third quartile of the DAP values in each weight group was proposed as LDRL. LDRLs for fluoroscopy time were determined solely based on procedure type, due to the absence of weight dependence.

Daytime and outcomes after cardiac surgery: Systematic review and metaanalysis, insights from a large UK database review and post-hoc trial analysis.

BackgroundSeveral studies have suggested a variation of myocardial tolerance to ischaemia depending on the daytime of surgery. To test this hypothesis, we conducted a three-level analysis: metaanalysis, national patient-level dataset analysis and a post-hoc trial analysis.MethodsWe first performed a systematic review and metaanalysis of available studies comparing clinical outcomes following cardiac surgery performed in the morning (am) versus afternoon (pm). Then, we interrogated the UK national adult cardiac surgery audit database (NACSA) and analysed the am or pm outcomes of patients undergoing non-emergency aortic valve replacement (AVR) or coronary artery bypass grafting (CABG). In a post-hoc analysis, we further investigated the effect of time of surgery on serum troponin release and ventricular myocardial biopsy adenine nucleotide metabolism.ResultsA total of 18377 patients undergoing uncomplicated isolated CABG or isolated AVR on the same day am or pm were included in the metaanalysis. Meta-analytic estimates showed no difference in the risk of MI between patients operated in pm vs am (OR 1.02, 95% CI:0.79–1.32) and in the risk of mortality (OR 1.1, 95% CI:0.85-1.42). Outcomes of 91248 patients from the NACSA dataset were analysed according to the daytime of the procedure. Patient-level analysis showed no significant effect of daytime for both isolated AVR (p=0.094) and isolated CABG (p=0.425). Finally, we performed a post-hoc trial database analysis in 124 patients undergoing isolated AVR or CABG of serial cardiac troponin and nucleotides metabolism on ventricular myocardial biopsies. We found no significant diurnal changes in the perioperative cardiac troponin release or nucleotide metabolism in the AVR (p=0.30) or the CABG cohort (p=0.97).ConclusionThe present three-level analysis found no evidence that daytime influences clinical outcomes and myocardial injury in patients undergoing cardiac surgery.

Histopathological changes of myocytes in restrictive cardiomyopathy.

Restrictive cardiomyopathy (RCM) is a rare primary myocardial disease, and its pathological features are yet to be determined. Restrictive cardiomyopathy with MHY7 mutation was diagnosed in a 65-year-old Japanese woman. Electron microscopy of a myocardial biopsy revealed electron-dense materials resulting from focal myocyte degeneration and necrosis as well as tubular structures and pseudo-inclusion bodies in some nuclei. These features may be associated with the pathogenesis of RCM.

Comparative Transcriptomics of Immune Checkpoint Inhibitor Myocarditis Identifies Guanylate Binding Protein 5 and 6 Dysregulation.

Simple SummaryImmune checkpoint inhibitors are revolutionizing cancer treatment, but lead to the occurrence of immune related adverse events including ICI-associated myocarditis (ICIM). To date, transcriptional alterations of this rare phenomenon with a high mortality rate are not characterized. 19 ICIM patients at the University Hospitals Heidelberg and Kiel showed diverse clinical presentations. Comparative transcriptomics was able to distinguish ICIM patients from patients with dilated cardiomyopathy or virus-induced myocarditis in the upregulation of 3784 genes. The RNA-based analyses and immunohistology revealed a potential role of an inflammasome-regulating protein, GBP5, as a potential pathomechanism in cardiomyocytes. These alterations may help to diagnose ICIM and potentially enable to identify patients at risk in an early stage.Immune checkpoint inhibitors (ICIs) are revolutionizing cancer treatment. Nevertheless, their increasing use leads to an increase of immune-related adverse events (irAEs). Among them, ICI-associated myocarditis (ICIM) is a rare irAE with a high mortality rate. We aimed to characterize the transcriptional changes of ICIM myocardial biopsies and their possible implications. Patients suspected for ICIM were assessed in the cardio-oncology units of University Hospitals Heidelberg and Kiel. Via RNA sequencing of myocardial biopsies, we compared transcriptional changes of ICIM (n = 9) with samples from dilated cardiomyopathy (DCM, n = 11), virus-induced myocarditis (VIM, n = 5), and with samples of patients receiving ICIs without any evidence of myocarditis (n = 4). Patients with ICIM (n = 19) showed an inconsistent clinical presentation, e.g., asymptomatic elevation of cardiac biomarkers (hs-cTnT, NT-proBNP, CK), a drop in left ventricular ejection fraction, or late gadolinium enhancement in cMRI. We found 3784 upregulated genes in ICIM (FDR < 0.05). In the overrepresented pathway ‘response to interferon-gamma’, we found guanylate binding protein 5 and 6 (compared with VIM: GBP5 (log2 fc 3.21), GBP6 (log2 fc 5.37)) to be significantly increased in ICIM on RNA- and protein-level. We conclude that interferon-gamma and inflammasome-regulating proteins, such as GBP5, may be of unrecognized significance in the pathophysiology of ICIM.

Effectiveness of myocarditis therapy depending on the diagnosis approach (with or without myocardial biopsy)

Aim. To evaluate the effectiveness of myocarditis therapy depending on the diagnosis approach (with or without myocardial biopsy).Material and methods. The study included 83 patients ≥18 years old with severe and moderate myocarditis (25 women and 58 men; mean age, 45,7±11,7 years), established by myocardial biopsy (group 1, n=36) or by a non-invasive diagnostic algorithm (group 2, n=47), for which immunosuppressive therapy (IST) was carried out. Inclusion criteria were left ventricular (LV) end-diastolic dimension &gt;5,5 cm and ejection fraction (EF) &lt;50%. An endomyocardial (n=31) or intraoperative (n=5) biopsy with a study of the viral genome and level of anticardiac antibodies were performed. Coronary angiography (29%), cardiac multislice computed tomography (75%), cardiac magnetic resonance imaging (41%), and 99mTc-MIBI scintigraphy (35%) were also carried out. The mean follow-up period was 3 years (36 [12; 65] months). The study was approved by the Intercollegiate Ethics Committee.Results. The groups were completely comparable in age, baseline parameters (class III [2,25; 3] and III [2; 3] heart failure (HF); end-diastolic LV dimension, 6,7±0,7 and 6,4±0,7 cm; EF, 29,9±8,7 and 31,4±9,3%), the extent of cardiac therapy (excluding the administration rate of в-blockers — 94,4 and 78,7%, p&lt;0,05) and 1ST (methylprednisolone in 91,7 and 89,4% of patients at a mean dose of 24 [16; 32] and 20 [15; 32] mg/day, azathioprine in 50,0 and 46,8% of patients at a mean dose of 150 mg/day or mycophenolate mofetil 2,0 g/day in 30,6% in group 1, hydroxychloroquine 0,2 g/day in 27,8 and 23,4%). Biopsy in group 1 revealed active/borderline (61/39%) myocarditis, in 8 patients — viral genome in the myocardium, including parvovirus B19 in 7 of them. Both groups showed a comparable significant increase in EF after 6 months up to 37,6±8,1 and 42,6±11,5% (p&lt;0,001) and after 27 [12; 54] months up to 43,4±9,6 and 45,5±12,3% (p&lt;0,001), as well as a significant decrease in HF class to 2 [1; 2] in both groups. An increase in EF by ≥10% was recorded in 70 and 72% of patients, respectively. The mortality rate was 13,9 and 12,8%. Taking into account the only transplantation in group 2, the death+transplantation endpoints reached 13,9 and 14,9% of patients (without significant differences between the groups).Conclusion. In patients with severe and moderate myocarditis diagnosed with and without myocardial biopsy, the effectiveness of combined therapy, including IST, was comparable. If it is impossible to perform a biopsy, complex non-invasive strategy makes it possible to diagnose myocarditis with different probability rate and conduct an effective IST, the refusal of which mostly is not justified.

THE IMPACT OF SIROLIMUS AS A PRIMARY IMMUNOSUPPRESSANT ON MYOCARDIAL FIBROSIS AND DIASTOLIC FUNCTION FOLLOWING HEART TRANSPLANTATION

Purpose Myocardial fibrosis is an important contributor for development of diastolic dysfunction (DD) following heart transplantation (HT). Small studies have reported superiority of sirolimus (SRL) over calcineurin inhibitor (CNI) in mitigating DD assessed by echocardiography. However, data on invasive hemodynamic assessment is lacking, and the impact of SRL on myocardial fibrosis progression remains unclear. We aimed to investigate the impact of SRL on DD and fibrosis progression among HT recipients. Methods A cohort of 100 HT recipients who were either treated with CNI alone (n =51) or converted from CNI to SRL (n=49) as primary immunosuppression was analyzed. Diastolic function parameters were assessed using serial echocardiograms and right heart catheterizations (RHC). Myocardial fibrosis was quantified on serial myocardial biopsies by automated digital analysis, blinded to the type of therapy. Results After 3 years, left ventricular end diastolic diameter (LVEDD) increased in the SRL group (45.7 ± 5.1 to 48.3 ± 5.5 mm, paired p Conclusion Early conversion to SRL is associated with improvement in DD and LV filling pressures which can be partially explained by attenuation of myocardial fibrosis progression as compared to CNI therapy.

Post-COVID-19 Kawasaki-Like Syndrome.

A 42-year-old man was referred for a week history of severe dysphagia, odynophagia, fever (39 °C), fatigue, abdominal pain, pharyngeal swelling, and multiple neck lymphadenopathies. The medical history reported a mild form of COVID-19 one month ago. The biology reported an unspecified inflammatory syndrome. The patient developed peritonitis, myocarditis, and hepatitis. A myocardium biopsy was performed. A diagnosis of Kawasaki-like disease (KLD) was performed. The occurrence of KLD in adults is rare but has to be known by otolaryngologists regarding the otolaryngological clinical presentation that may precede the multiple organ failure.