Left and right ventricular dysfunction in patients with COVID-19-associated myocardial injury.

PURPOSE: SARS-COV-2 infection can develop into a multi-organ disease. Although pathophysiological mechanisms of COVID-19-associated myocardial injury have been studied throughout the pandemic course in 2019, its morphological characterisation is still unclear. With this study, we aimed to characterise echocardiographic patterns of ventricular function in patients with COVID-19-associated myocardial injury. METHODS: We prospectively assessed 32 patients hospitalised with COVID-19 and presence or absence of elevated high sensitive troponin T (hsTNT+ vs. hsTNT-) by comprehensive three-dimensional (3D) and strain echocardiography. RESULTS: A minority (34.3%) of patients had normal ventricular function, whereas 65.7% had left and/or right ventricular dysfunction defined by impaired left and/or right ventricular ejection fraction and strain measurements. Concomitant biventricular dysfunction was common in hsTNT+ patients. We observed impaired left ventricular (LV) global longitudinal strain (GLS) in patients with myocardial injury (-13.9% vs. -17.7% for hsTNT+ vs. hsTNT-, p = 0.005) but preserved LV ejection fraction (52% vs. 59%, p = 0.074). Further, in these patients, right ventricular (RV) systolic function was impaired with lower RV ejection fraction (40% vs. 49%, p = 0.001) and reduced RV free wall strain (-18.5% vs. -28.3%, p = 0.003). Myocardial dysfunction partially recovered in hsTNT + patients after 52 days of follow-up. In particular, LV-GLS and RV-FWS significantly improved from baseline to follow-up (LV-GLS: -13.9% to -16.5%, p = 0.013; RV-FWS: -18.5% to -22.3%, p = 0.037). CONCLUSION: In patients with COVID-19-associated myocardial injury, comprehensive 3D and strain echocardiography revealed LV dysfunction by GLS and RV dysfunction, which partially resolved at 2-month follow-up. TRIAL REGISTRATION: COVID-19 Registry of the LMU University Hospital Munich (CORKUM), WHO trial ID DRKS00021225.

Attenuation of cardiac hypertrophy by G-CSF is associated with enhanced migration of bone marrow-derived cells.

Granulocyte-colony stimulating factor (G-CSF) has been shown to promote mobilization of bone marrow-derived stem cells (BMCs) into the bloodstream associated with improved survival and cardiac function after myocardial infarction. Therefore, the aim of the present study was to investigate whether G-CSF is able to attenuate cardiac remodelling in a mouse model of pressure-induced LV hypertrophy focusing on mobilization and migration of BMCs. LV hypertrophy was induced by transverse aortic constriction (TAC) in C57BL/6J mice. Four weeks after TAC procedure. Mice were treated with G-CSF (100 µg/kg/day; Amgen Biologicals) for 2 weeks. The number of migrated BMCs in the heart was analysed by flow cytometry. mRNA expression and protein level of different growth factors in the myocardium were investigated by RT-PCR and ELISA. Functional analyses assessed by echocardiography and immunohistochemical analysis were performed 8 weeks after TAC procedure. G-CSF-treated animals revealed enhanced homing of VLA-4(+) and c-kit(+) BMCs associated with increased mRNA expression and protein level of the corresponding homing factors Vascular cell adhesion protein 1 and Stem cell factor in the hypertrophic myocardium. Functionally, G-CSF significantly preserved LV function after TAC procedure, which was associated with a significantly reduced area of fibrosis compared to control animals. Furthermore, G-CSF-treated animals revealed a significant improvement of survival after TAC procedure. In summary, G-CSF treatment preserves cardiac function and is able to diminish cardiac fibrosis after induction of LV hypertrophy associated with increased homing of VLA-4(+) and c-kit(+) BMCs and enhanced expression of their respective homing factors VCAM-1 and SCF.

Increased numbers of bone marrow-derived cells in parathyroid adenoma.

BACKGROUND: In primary hyperparathyroidism (PHPT), the increased levels of parathyroid hormone (PTH) result in mobilisation of bone-marrow-derived cells (BMCs) into peripheral blood. However, the fate of these cells is still unknown. MATERIALS AND METHODS: In this study, we sought to investigate cells with typical surface markers of BMCs within parathyroid adenomas (PA) of patients with primary hyperparathyroidism. We therefore investigated PA and normal parathyroid glands (NPG) of 15 patients with PHPT by immunohistochemistry and PCR. RESULTS: mRNA levels for CD31, CD34 and CD45 were significantly increased in PA compared to NPG. Immunohistochemical staining for CD31 and CD34 revealed a significantly higher vessel density in PA. Furthermore, scattered single cells expressing CD31, CD34 or CD45 were significantly augmented compared to normal parathyroid glands and directly correlated with vessel density. mRNA levels of SDF-1 was increased whereas its major inhibitor dipeptidylpeptidase IV (DPP IV) is decreased in PA, suggesting that the SDF-1 axis plays a role in the migration of BMCs into PA. CONCLUSION: These data indicate a possible role of BMCs in the pathophysiology of PA of patients with PHPT.

Preconditioning with levosimendan before implantation of left ventricular assist devices.

In this retrospective study, we investigated the impact of preconditioning of the right ventricle with the calcium sensitizer levosimendan immediately before left ventricular assist device (LVAD) implantation on outcome and survival. Nine consecutive LVAD patients (seven suffering from dilative cardiomyopathy and two from ischemic cardiomyopathy) with echocardiographic and invasive evidence of right heart insufficiency received levosimendan with 0.1 µg/kg body weight/min for 24 h before implantation of the assist device (seven HeartWare and two Jarvik 2000). Administration of levosimendan was safe and had not to be discontinued in any patient. We observed no relevant side effects. Twelve-month survival after implantation of the LVAD was 89% representing a superior outcome compared with the fifth INTERMACS registry data with 75% survival. Two temporary extracorporeal membrane-oxygenation implantations were necessary due to intraoperative right ventricular dysfunction. Only one patient died 5 weeks after LVAD implantation of multiorgan failure, five patients were successfully transplanted, and three patients underwent LVAD implantation for destination therapy. Levosimendan might improve clinical outcome and survival when used as pretreatment in patients with right heart insufficiency prior to LVAD implantation. However, we recommend a larger controlled trial in the future to confirm our preliminary results.

Benralizumab Reduces Respiratory Exacerbations and Oral Glucocorticosteroid Dose in Patients with Severe Asthma and Eosinophilic Granulomatosis with Polyangiitis.

Background: Benralizumab reduces exacerbations and long-term oral glucocorticosteroid (OCS) exposure in patients with severe eosinophilic asthma. In patients with eosinophilic granulomatosis with polyangiitis (EGPA), uncontrolled symptoms and exacerbations of asthma and chronic rhinosinusitis (CRS) are important reasons for continued OCS therapies. We aimed to describe outcomes of patients with severe asthma and EGPA treated with benralizumab in real-life. Methods: We retrospectively analyzed adult patients from the Severe Asthma Unit at LMU Munich diagnosed with severe asthma and EGPA treated with benralizumab, differentiating two groups: Group A, patients with a stable daily OCS dose and diagnosis of EGPA >6 months ago; and Group B, patients treated with high-dose daily OCS due to recent diagnosis of EGPA <6 months ago. We compared outcome parameters at baseline and 12 months after initiation of benralizumab, including respiratory exacerbations, daily OCS dose, and lung function. Results: Group A included 17 patients, all receiving OCS therapy and additional immunosuppressants; 15 patients (88%) continued benralizumab for more than 12 months, demonstrating a significant reduction in daily OCS dose and exacerbations while FEV1 increased. Group B included 9 patients, all with high-dose daily OCS and some receiving cyclophosphamide pulse therapy for life-threatening disease. Benralizumab addition during induction was well tolerated. A total of 7/9 (78%) continued benralizumab for more than 12 months and preserved EGPA remission at the 12-month timepoint. Conclusion: In this real-life cohort of patients with severe asthma and EGPA, benralizumab initiation during remission maintenance reduced respiratory exacerbations and daily OCS dose. Benralizumab initiation during remission induction was associated with a high rate of clinical EGPA remission.

Influence of donor age and donor-recipient age difference on intimal hyperplasia in pediatric patients with young and adult donors vs. adult patients after heart transplantation.

AIM: Optimal selection and allocation of donor hearts is a relevant aspect in transplantation medicine. Donor age and cardiac allograft vasculopathy (CAV) affect post-transplant mortality. To what extent donor age impacts intimal hyperplasia (CAVIH) in pediatric and adult patients after heart transplantation (HTx) is understudied. METHODS: In a cohort of 98 HTx patients, 58 pediatric (24.1% with adult donors) and 40 adult patients, we assessed the effect of donor age and donor-recipient age difference (D-R) on the continuous parameter of maximal intima thickness (mIT) in optical coherence tomography. We evaluated their predictive value regarding higher mIT and the prevalence of CAVIH, defined as mIT > 0.3 mm, and compared it to established CAV risk factors. RESULTS: In the overall population, donor age correlated with mIT (p < 0.001), while in the pediatric subpopulation, both donor age and D-R correlated with mIT (p < 0.001 and p = 0.002, respectively). In the overall population, donor age was a main predictor of higher mIT and CAVIH (p = 0.001 and p = 0.01, respectively) in addition to post-transplant interval, arterial hypertension, and dyslipidemia. In the pediatric patients, dyslipidemia remained a main predictor of both higher mIT and CAVIH (p = 0.004 and p = 0.040, respectively), while donor age and D-R were not. CONCLUSION: While there was an effect of the non-modifiable parameter of donor age regarding maximal intimal thickness, a stronger association was seen between the modifiable risk factor dyslipidemia and higher maximal intimal thickness and CAVIH in both the overall population and the pediatric subpopulation.

Stringent monitoring can decrease mortality of immune checkpoint inhibitor induced cardiotoxicity.

Background: Immune checkpoint inhibitor (ICI)-induced myocarditis is a rare immune-related adverse event (irAE) with a fatality rate of 40%-46%. However, irMyocarditis can be asymptomatic. Thus, improved monitoring, detection and therapy are needed. This study aims to generate knowledge on pathogenesis and assess outcomes in cancer centers with intensified patient management. Methods: Patients with cardiac irAEs from the SERIO registry (www.serio-registry.org) were analyzed for demographics, ICI-related information (type of ICI, therapy line, combination with other drugs, onset of irAE, and tumor response), examination results, irAE treatment and outcome, as well as oncological endpoints. Cardiac biopsies of irMyocarditis cases (n = 12) were analyzed by Nanostring and compared to healthy heart muscle (n = 5) and longitudinal blood sampling was performed for immunophenotyping of irMyocarditis-patients (n = 4 baseline and n = 8 during irAE) in comparison to patients without toxicity under ICI-therapy (n = 4 baseline and n = 7 during ICI-therapy) using flow cytometry. Results: A total of 51 patients with 53 cardiac irAEs induced by 4 different ICIs (anti-PD1, anti-PD-L1, anti-CTLA4) were included from 12 centers in 3 countries. Altogether, 83.0% of cardiac irAEs were graded as severe or life-threatening, and 11.3% were fatal (6/53). Thus, in centers with established consequent troponin monitoring, work-up upon the rise in troponin and consequent treatment of irMyocarditis with corticosteroids and -if required-second-line therapy mortality rate is much lower than previously reported. The median time to irMyocarditis was 36 days (range 4-1,074 days) after ICI initiation, whereas other cardiotoxicities, e.g. asystolia or myocardiopathy, occurred much later. The cytokine-mediated signaling pathway was differentially regulated in myocardial biopsies as compared to healthy heart based on enrichment Gene Ontology analysis. Additionally, longitudinal peripheral blood mononuclear cell (PBMC) samples from irMyocarditis-patients indicated ICI-driven enhanced CD4+ Treg cells and reduced CD4+ T cells. Immunophenotypes, particularly effector memory T cells of irMyocarditis-patients differed from those of ICI-treated patients without side effects. LAG3 expression on T cells and PD-L1 expression on dendritic cells could serve as predictive indicators for the development of irMyocarditis. Conclusion: Interestingly, our cohort shows a very low mortality rate of irMyocarditis-patients. Our data indicate so far unknown local and systemic immunological patterns in cardiotoxicity.

Enhanced stem cell migration mediated by VCAM-1/VLA-4 interaction improves cardiac function in virus-induced dilated cardiomyopathy.

Endogenous circulation of bone marrow-derived cells (BMCs) was observed in patients with dilated cardiomyopathy (DCM) who showed cardiac upregulation of Vascular Cell Adhesion Protein-1 (VCAM-1). However, the underlying pathophysiology is currently unknown. Thus, we aimed to analyze circulation, migration and G-CSF-based mobilization of BMCs in a murine model of virus-induced DCM. Mice with coxsackievirus B3 (CVB3) induced DCM and healthy controls were analyzed regarding their myocardial homing factors by PCR. To determine cardiac VCAM-1 expression ELISA and immunohistochemistry were applied. Flow cytometry was performed to analyze BMCs. Cardiac diameters and function were evaluated by echocardiography before and 4 weeks after G-CSF treatment. In murine CVB3-induced DCM an increase of BMCs in peripheral blood and a decrease of BMCs in bone marrow was observed. We found an enhanced migration of Very Late Antigen-4 (VLA-4⁺) BMCs to the diseased heart overexpressing VCAM-1 and higher numbers of CD45⁻CD34⁻Sca-1⁺ and CD45⁻CD34⁻c-kit⁺ cells. Mobilization of BMCs by G-CSF boosted migration along the VCAM-1/VLA-4 axis and reduced apoptosis of cardiomyocytes. Significant improvement of cardiac function was detected by echocardiography in G-CSF-treated mice. Blocking VCAM-1 by a neutralizing antibody reduced the G-CSF-dependent effects on stem cell migration and cardiac function. This is the first study showing that in virus-induced DCM VCAM-1/VLA-4 interaction is crucial for recruitment of circulating BMCs leading to beneficial anti-apoptotic effects resulting in improved cardiac function after G-CSF-induced mobilization.

Domestic Parasitic Infections in Patients with Asthma and Eosinophilia in Germany - Three Cases with Learnings in the Era of Anti- IL5 Treatments.

Eosinophilic inflammation is a hallmark of asthma, and blood eosinophilia has been established as a biomarker for phenotyping asthma and predicting the response to anti-IL5 treatments. Although parasitic infections are rare in European adults, they remain an important differential diagnosis for blood eosinophilia. We present three patients with both domestic parasitic infections and asthma to raise awareness of the potential challenge of eosinophilia and to provide experience in the management of parasitic infections in the setting of planned or ongoing anti-IL5 treatment. One, a patient from Croatia with moderate asthma but severe blood eosinophilia had an underlying Strongyloides stercoralis infection, with positive stool cultures. Second, a patient with severe allergic asthma and gastrointestinal symptoms had a positive S. stercoralis titer in serology with a clinical response to treatment with ivermectin. Third, a patient with severe nonallergic eosinophilic asthma and eosinophilic granulomatosis with polyangiitis (EGPA) showed an increasing hepatic tumour under anti-IL5-receptor therapy. Positive serology confirmed the diagnosis of Echinococcus multilocularis, and albendazole therapy was initiated. Anti-IL5 therapies were safely started (Patient 2) or resumed (Patient 3) after the initiation of antiparasitic treatment. Screening for parasitic infections is useful in cases of hypereosinophilia, extrapulmonary symptoms or stay in endemic regions.

The DZHK research platform: maximisation of scientific value by enabling access to health data and biological samples collected in cardiovascular clinical studies.

The German Centre for Cardiovascular Research (DZHK) is one of the German Centres for Health Research and aims to conduct early and guideline-relevant studies to develop new therapies and diagnostics that impact the lives of people with cardiovascular disease. Therefore, DZHK members designed a collaboratively organised and integrated research platform connecting all sites and partners. The overarching objectives of the research platform are the standardisation of prospective data and biological sample collections among all studies and the development of a sustainable centrally standardised storage in compliance with general legal regulations and the FAIR principles. The main elements of the DZHK infrastructure are web-based and central units for data management, LIMS, IDMS, and transfer office, embedded in a framework consisting of the DZHK Use and Access Policy, and the Ethics and Data Protection Concept. This framework is characterised by a modular design allowing a high standardisation across all studies. For studies that require even tighter criteria additional quality levels are defined. In addition, the Public Open Data strategy is an important focus of DZHK. The DZHK operates as one legal entity holding all rights of data and biological sample usage, according to the DZHK Use and Access Policy. All DZHK studies collect a basic set of data and biosamples, accompanied by specific clinical and imaging data and biobanking. The DZHK infrastructure was constructed by scientists with the focus on the needs of scientists conducting clinical studies. Through this, the DZHK enables the interdisciplinary and multiple use of data and biological samples by scientists inside and outside the DZHK. So far, 27 DZHK studies recruited well over 11,200 participants suffering from major cardiovascular disorders such as myocardial infarction or heart failure. Currently, data and samples of five DZHK studies of the DZHK Heart Bank can be applied for.

Association of Complement and MAPK Activation With SARS-CoV-2-Associated Myocardial Inflammation.

IMPORTANCE: Myocardial injury is a common feature of patients with SARS-CoV-2 infection. However, the cardiac inflammatory processes associated with SARS-CoV-2 infection are not completely understood. OBJECTIVE: To investigate the inflammatory cardiac phenotype associated with SARS-CoV-2 infection compared with viral myocarditis, immune-mediated myocarditis, and noninflammatory cardiomyopathy by integrating histologic, transcriptomic, and proteomic profiling. DESIGN, SETTING, AND PARTICIPANTS: This case series was a cooperative study between the Ludwig Maximilian University Hospital Munich and the Cardiopathology Referral Center at the University of Tübingen in Germany. A cohort of 19 patients with suspected myocarditis was examined; of those, 5 patients were hospitalized with SARS-CoV-2 infection between March and May 2020. Cardiac tissue specimens from those 5 patients were compared with specimens from 5 patients with immune-mediated myocarditis, 4 patients with non-SARS-CoV-2 viral myocarditis, and 5 patients with noninflammatory cardiomyopathy, collected from January to August 2019. EXPOSURES: Endomyocardial biopsy. MAIN OUTCOMES AND MEASURES: The inflammatory cardiac phenotypes were measured by immunohistologic analysis, RNA exome capture sequencing, and mass spectrometry-based proteomic analysis of endomyocardial biopsy specimens. RESULTS: Among 19 participants, the median age was 58 years (range, 37-76 years), and 15 individuals (79%) were male. Data on race and ethnicity were not collected. The abundance of CD163+ macrophages was generally higher in the cardiac tissue of patients with myocarditis, whereas lymphocyte counts were lower in the tissue of patients with SARS-CoV-2 infection vs patients with non-SARS-CoV-2 virus-associated and immune-mediated myocarditis. Among those with SARS-CoV-2 infection, components of the complement cascade, including C1q subunits (transcriptomic analysis: 2.5-fold to 3.6-fold increase; proteomic analysis: 2.0-fold to 3.4-fold increase) and serine/cysteine proteinase inhibitor clade G member 1 (transcriptomic analysis: 1.7-fold increase; proteomic analysis: 2.6-fold increase), belonged to the most commonly upregulated transcripts and differentially abundant proteins. In cardiac macrophages, the abundance of C1q was highest in SARS-CoV-2 infection. Assessment of important signaling cascades identified an upregulation of the serine/threonine mitogen-activated protein kinase pathways. CONCLUSIONS AND RELEVANCE: This case series found that the cardiac immune signature varied in inflammatory conditions with different etiologic characteristics. Future studies are needed to examine the role of these immune pathways in myocardial inflammation.

Pembrolizumab-induced myocarditis in a patient with malignant mesothelioma: plasma exchange as a successful emerging therapy-case report.

Malignant mesothelioma is an aggressive cancer associated with prior exposure to asbestos and dismal prognosis. Immune checkpoint inhibitor therapy is currently approved by the Food and Drug Administration for pre-treated malignant pleural mesothelioma. We describe a 75-year-old patient with disseminated, progressive malignant mesothelioma receiving 2 cycles of pembrolizumab who presented with generalized muscle weakness, shortness of breath, double vision and ptosis. There was no previous history of cardiovascular disease. The clinical picture, supported by the detection of anti-titin autoantibodies suggested myasthenia gravis (MG). Also, cardiac biomarkers were elevated. Echocardiography showed new severely reduced ejection fraction. A 12-lead resting electrocardiogram (ECG) revealed ST segment elevation in the posterior leads with polymorphic ventricular extrasystoles. Because cardiac catheterization revealed no relevant coronary lesions, immune checkpoint inhibitor-associated myocarditis and MG were suspected. Management and Outcome: The patient was started on steroids. Within a few days of presentation respiratory failure set in and the patient was intubated. Recurrent arrhythmias followed, which were treated by repeated emergency electrical cardioversion. In order to relieve myasthenic symptoms, plasma exchange was initiated and 10 cycles were carried out. This consequently also led to an improvement of myocarditis. Upon discharge, the ejection fraction recovered. The patient recovered and was alive at 1-year follow-up, without relevant limitations to his quality of life. Discussion and Conclusion: The article further discusses the use of plasma exchange for immune checkpoint inhibitor-associated myocarditis based on a review of literature. We conclude that patients showing no improvement after steroid therapy for immune checkpoint inhibitor-related myocarditis should be evaluated for plasma exchange, which appears to be an effective treatment option.

Cardiac manifestation is evident in chorea-acanthocytosis but different from McLeod syndrome.

INTRODUCTION: We aimed to study the various cardiac manifestations of the two core neuroacanthocytosis (NA) syndromes, namely chorea-acanthocytosis (ChAc) and McLeod syndrome (MLS). So far, cardiac involvement has been described as specific feature only for MLS. METHODS: We studied six patients with ChAc (mean age 44.5 years, five men, one woman) and six patients with MLS (mean age 57.1 years, all men). Cardiac evaluation included echocardiography and/or cardiac magnetic resonance imaging (cardiac MRI), 24-h ECG-recording and examination of cardiac biomarkers. RESULTS: Cardiac involvement of ChAc was found in four of six patients. Two patients showed mildly reduced left ventricular ejection fraction (LVEF), two other patients mild to moderate left ventricular (LV) dilatation. Neither an increase in ventricular ectopic beats nor ventricular tachycardia were evident in ChAc. Four of five MLS patients showed left ventricle dilatation and reduced left ventricular ejection fraction (LVEF). Two of these, in addition, had critical ventricular tachycardia. High sensitive troponin T was elevated in all patients, for whom data were available (n = 10). In contrast, elevation of high sensitive troponin I was found in one of six ChAc and one of two MLS patients. CONCLUSION: For the first time, we reveal cardiac involvement in a cohort of six ChAc patients, while the risk to develop heart failure seems lower than in MLS. Our study confirms the malignant nature of MLS in terms of ventricular arrhythmias and progression to advanced heart failure. Herein, we define disease-specific recommendations for cardiac assessment in both conditions.

Differences in Cardiac Magnetic Resonance Imaging Markers Between Patients With COVID-19-associated Myocardial Injury and Patients With Clinically Suspected Myocarditis.

PURPOSE: Coronavirus 2019 disease (COVID-19) has been shown to affect the myocardium, resulting in a worse clinical outcome. In this registry study, we aimed to identify differences in cardiac magnetic resonance imaging (CMRI) between COVID-19 and all-cause myocarditis. MATERIALS AND METHODS: We examined CMRI of patients with COVID-19 and elevated high-sensitivity serum troponin levels performed between March 31st and May 5th and compared them to CMRI of patients without SARS-CoV-2 infection with suspected myocarditis in the same time period. For this purpose, we evaluated Lake-Louise Criteria for myocarditis by determining nonischemic myocardial injury via T1-mapping, extracellular volume, late gadolinium enhancement, and myocardial edema (ME) by T2-mapping and fat-saturated T2w imaging (T2Q). RESULTS: A total of 15 of 18 (89%) patients with COVID-19 had abnormal findings. The control group consisted of 18 individuals. There were significantly fewer individuals with COVID-19 who had increased T2 (5 vs. 10; P=0.038) and all-cause ME (7 vs. 15; P=0.015); thus, significantly fewer patients with COVID-19 fulfilled Lake-Louise Criteria (6 vs. 17; P<0.001). In contrast, nonischemic myocardial injury was not significantly different. In the COVID-19 group, indexed end-diastolic volume of the left ventricle showed a significant correlation to the extent of abnormal T1 (R2=0.571; P=0.017) and extracellular volume (R2=0.605; P=0.013) and absolute T1, T2, and T2Q (R2=0.644; P=0.005, R2=0.513; P=0.035 and R2=0.629; P=0.038, respectively); in the control group, only extracellular volume showed a weak correlation (R2=0.490; P=0.046). CONCLUSIONS: Cardiac involvement in COVID-19 seems to show less ME than all-cause myocarditis. Abnormal CMRI markers correlated to left ventricle dilation only in the COVID-19 group. Larger comparative studies are needed to verify our findings.

Myocardial Inflammation and Dysfunction in COVID-19-Associated Myocardial Injury.

BACKGROUND: Myocardial injury, defined by elevated troponin levels, is associated with adverse outcome in patients with coronavirus disease 2019 (COVID-19). The frequency of cardiac injury remains highly uncertain and confounded in current publications; myocarditis is one of several mechanisms that have been proposed. METHODS: We prospectively assessed patients with myocardial injury hospitalized for COVID-19 using transthoracic echocardiography, cardiac magnetic resonance imaging, and endomyocardial biopsy. RESULTS: Eighteen patients with COVID-19 and myocardial injury were included in this study. Echocardiography revealed normal to mildly reduced left ventricular ejection fraction of 52.5% (46.5%-60.5%) but moderately to severely reduced left ventricular global longitudinal strain of -11.2% (-7.6% to -15.1%). Cardiac magnetic resonance showed any myocardial tissue injury defined by elevated T1, extracellular volume, or late gadolinium enhancement with a nonischemic pattern in 16 patients (83.3%). Seven patients (38.9%) demonstrated myocardial edema in addition to tissue injury fulfilling the Lake-Louise criteria for myocarditis. Combining cardiac magnetic resonance with speckle tracking echocardiography demonstrated functional or morphological cardiac changes in 100% of investigated patients. Endomyocardial biopsy was conducted in 5 patients and revealed enhanced macrophage numbers in all 5 patients in addition to lymphocytic myocarditis in 1 patient. SARS-CoV-2 RNA was not detected in any biopsy by quantitative real-time polymerase chain reaction. Finally, follow-up measurements of left ventricular global longitudinal strain revealed significant improvement after a median of 52.0 days (-11.2% [-9.2% to -14.7%] versus -15.6% [-12.5% to -19.6%] at follow-up; P=0.041). CONCLUSIONS: In this small cohort of COVID-19 patients with elevated troponin levels, myocardial injury was evidenced by reduced echocardiographic left ventricular strain, myocarditis patterns on cardiac magnetic resonance, and enhanced macrophage numbers but not predominantly lymphocytic myocarditis in endomyocardial biopsies.

Dilative cardiomyopathy displaying double trouble etiology: Myocarditis and Mcleod syndrome?

Herein we report on a patient acutely admitted to the emergency room due to malaise and effort intolerance. A heart ultrasound, a cardiovascular MRI and an endomyocardial biopsy were suggestive of myocarditis. With appropriate medications the ejection fraction (EF) slowly improved but follow-up blood examinations revealed a hyperckemia. A neuromuscular examination revealed bilateral atrophy of medial gastrocnemius muscle and absent deep tendon reflexes at lower limbs . Genetic analysis revealed the presence of the hemizygous novel mutation c.757delT (p.Trp253fs) in XK gene thus confirming the diagnosis of McLeod Syndrome (MLS). In this patient an overlap of two conditions, dilative cardiomyopathy (DCMi) due to myocarditis and MLS, might have occurred. Patients with DCMi and hyperckemia should undergo a careful neuromuscular examination as some subclinical signs (calves-hypotrophy, areflexia) might go overlooked. We therefore suggest including the search for acanthocytes in patients with DCMi and hyperCKemia as it is a quick and cheap test that might unravel the MLS diagnosis.

Cardioprotective Potential of Human Endothelial-Colony Forming Cells from Diabetic and Nondiabetic Donors.

OBJECTIVE: The potential therapeutic role of endothelial progenitor cells (EPCs) in ischemic heart disease for myocardial repair and regeneration is subject to intense investigation. The aim of the study was to investigate the proregenerative potential of human endothelial colony-forming cells (huECFCs), a very homogenous and highly proliferative endothelial progenitor cell subpopulation, in a myocardial infarction (MI) model of severe combined immunodeficiency (SCID) mice. METHODS: CD34+ peripheral blood mononuclear cells were isolated from patient blood samples using immunomagnetic beads. For generating ECFCs, CD34+ cells were plated on fibronectin-coated dishes and were expanded by culture in endothelial-specific cell medium. Either huECFCs (5 × 105) or control medium were injected into the peri-infarct region after surgical MI induction in SCID/beige mice. Hemodynamic function was assessed invasively by conductance micromanometry 30 days post-MI. Hearts of sacrificed animals were analyzed by immunohistochemistry to assess cell fate, infarct size, and neovascularization (huECFCs n = 15 vs. control n = 10). Flow-cytometric analysis of enzymatically digested whole heart tissue was used to analyze different subsets of migrated CD34+ /CD45+ peripheral mononuclear cells as well as CD34-/CD45- cardiac-resident stem cells two days post-MI (huECFCs n = 10 vs. control n = 6). RESULTS: Transplantation of human ECFCs after MI improved left ventricular (LV) function at day 30 post-MI (LVEF: 30.43 ± 1.20% vs. 22.61 ± 1.73%, p < 0.001; ΔP/ΔTmax 5202.28 ± 316.68 mmHg/s vs. 3896.24 ± 534.95 mmHg/s, p < 0.05) when compared to controls. In addition, a significantly reduced infarct size (50.3 ± 4.5% vs. 66.1 ± 4.3%, p < 0.05) was seen in huECFC treated animals compared to controls. Immunohistochemistry failed to show integration and survival of transplanted cells. However, anti-CD31 immunohistochemistry demonstrated an increased vascular density within the infarct border zone (8.6 ± 0.4 CD31+ capillaries per HPF vs. 6.2 ± 0.5 CD31+ capillaries per HPF, p < 0.001). Flow cytometry at day two post-MI showed a trend towards increased myocardial homing of CD45+ /CD34+ mononuclear cells (1.1 ± 0.3% vs. 0.7 ± 0.1%, p = 0.2). Interestingly, we detected a significant increase in the population of CD34-/CD45-/Sca1+ cardiac resident stem cells (11.7 ± 1.7% vs. 4.7 ± 1.7%, p < 0.01). In a subgroup analysis no significant differences were seen in the cardioprotective effects of huECFCs derived from diabetic or nondiabetic patients. CONCLUSIONS: In a murine model of myocardial infarction in SCID mice, transplantation of huECFCs ameliorated myocardial function by attenuation of adverse post-MI remodeling, presumably through paracrine effects. Cardiac repair is enhanced by increasing myocardial neovascularization and the pool of Sca1+ cardiac resident stem cells. The use of huECFCs for treating ischemic heart disease warrants further investigation.

Blocking LFA-1 Aggravates Cardiac Inflammation in Experimental Autoimmune Myocarditis.

The lymphocyte function-associated antigen 1 (LFA-1) is a member of the beta2-integrin family and plays a pivotal role for T cell activation and leukocyte trafficking under inflammatory conditions. Blocking LFA-1 has reduced or aggravated inflammation depending on the inflammation model. To investigate the effect of LFA-1 in myocarditis, mice with experimental autoimmune myocarditis (EAM) were treated with a function blocking anti-LFA-1 antibody from day 1 of disease until day 21, the peak of inflammation. Cardiac inflammation was evaluated by measuring infiltration of leukocytes into the inflamed cardiac tissue using histology and flow cytometry and was assessed by analysis of the heart weight/body weight ratio. LFA-1 antibody treatment severely enhanced leukocyte infiltration, in particular infiltration of CD11b+ monocytes, F4/80+ macrophages, CD4+ T cells, Ly6G+ neutrophils, and CD133+ progenitor cells at peak of inflammation which was accompanied by an increased heart weight/body weight ratio. Thus, blocking LFA-1 starting at the time of immunization severely aggravated acute cardiac inflammation in the EAM model.

Midkine drives cardiac inflammation by promoting neutrophil trafficking and NETosis in myocarditis.

Heart failure due to dilated cardiomyopathy is frequently caused by myocarditis. However, the pathogenesis of myocarditis remains incompletely understood. Here, we report the presence of neutrophil extracellular traps (NETs) in cardiac tissue of patients and mice with myocarditis. Inhibition of NET formation in experimental autoimmune myocarditis (EAM) of mice substantially reduces inflammation in the acute phase of the disease. Targeting the cytokine midkine (MK), which mediates NET formation in vitro, not only attenuates NET formation in vivo and the infiltration of polymorphonuclear neutrophils (PMNs) but also reduces fibrosis and preserves systolic function during EAM. Low-density lipoprotein receptor-related protein 1 (LRP1) acts as the functionally relevant receptor for MK-induced PMN recruitment as well as NET formation. In summary, NETosis substantially contributes to the pathogenesis of myocarditis and drives cardiac inflammation, probably via MK, which promotes PMN trafficking and NETosis. Thus, MK as well as NETs may represent novel therapeutic targets for the treatment of cardiac inflammation.