Myocardial PD-L1 Expression in Patients With Ischemic and Non-ischemic Heart Failure

Objective: Immune checkpoints inhibitors are promising and wide-spread agents in anti-cancer therapy. However, despite their efficacy, these agents could cause cardiotoxicity, a rare but life-threatening event. In addition, there are still no well-described predictive factors for the development of immune-related adverse events and information on high risk groups. According to known experimental studies we hypothesized that cardiovascular diseases may increase myocardial PD-L1 expression, which could be an extra target for Checkpoint inhibitors and a potential basis for complications development.Methods: We studied patterns of myocardial PD-L1 expression in non-cancer-related cardiovascular diseases, particularly ischemic heart disease (n = 12) and dilated cardiomyopathy (n = 7), compared to patients without known cardiovascular diseases (n = 10) using mouse monoclonal anti-PD-L1 antibody (clone 22C3, 1:50, Dako). Correlation between immunohistochemical data and echocardiographic parameters was assessed. Statistical analyses were performed using R Statistical Software—R studio version 1.3.1093.Results: In the myocardium of cardiac patients, we found membranous, cytoplasmic, and endothelial expression of PD-L1 compared to control group. In samples from patients with a history of myocardial infarction, PD-L1 membrane and endothelial expression was more prominent and frequent, and cytoplasmic and intercalated discs staining was more localized. In contrast, samples from patients with dilated cardiomyopathy displayed very faint endothelial staining, negative membrane staining, and more diffuse PD-L1 expression in the cytoplasm and intercalated discs. In samples from the non-cardiac patients, no convincing PD-L1 expression was observed. Moreover, we discovered a significant negative correlation between PD-L1 expression level and left ventricular ejection fraction and a positive correlation between PD-L1 expression level and left ventricular end-diastolic volume.Conclusions: The present findings lay the groundwork for future experimental and clinical studies of the role of the PD-1/PD-L1 pathway in cardiovascular diseases. Further studies are required to find patients at potentially high risk of cardiovascular adverse events associated with immune checkpoint inhibitors therapy.

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Disorganization of intercalated discs in dilated cardiomyopathy

Scientific Reports ◽

10.1038/s41598-021-90502-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Yukinobu Ito ◽

Makoto Yoshida ◽

Hirotake Masuda ◽

Daichi Maeda ◽

Yukitsugu Kudo-Asabe ◽

...

Keyword(s):

Dilated Cardiomyopathy ◽

Interstitial Fibrosis ◽

Left Ventricular ◽

Pathological Diagnosis ◽

Control Group ◽

Failure Group ◽

Intercalated Discs ◽

Group Reduction ◽

Group A ◽

Morphological Differences

AbstractDilated cardiomyopathy (DCM) is a primary myocardial disease, the pathology of which is left ventricular or biventricular dilation and impaired myocardial contractility. The clinical and pathological diagnosis of DCM is difficult, and other cardiac diseases must be ruled out. Several studies have reported pathological findings that are characteristic of DCM, including cardiomyocyte atrophy, nuclear pleomorphism, and interstitial fibrosis, but none of these findings are DCM-specific. In this study, we examined the morphological differences in the intercalated discs (ICDs) between three groups of patients, a DCM group, a chronic heart failure group, and a control group. A total of 22 autopsy cases, including five DCM cases, nine CHF cases and eight control cases, were retrieved from the archives of the Department of Pathology at Akita University, Japan. The morphological differences were examined using multiple methods: macroscopic examination, light microscopy, immunohistochemistry, electron microscopy, and gene expression analyses. We observed disorganized ICDs, clearly illustrated by N-cadherin immunostaining in the DCM group. “Reduction of N-cadherin immunostaining intensity” and “ICD scattering” was DCM-specific. The results suggest that disorganized ICDs contribute to the development of DCM, and that N-cadherin immunostaining is useful for determining the presence of disorganized ICDs and for the pathological diagnosis of DCM.

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Late cardiac adverse events in patients with cancer treated with immune checkpoint inhibitors

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2019-000261 ◽

2020 ◽

Vol 8 (1) ◽

pp. e000261 ◽

Cited By ~ 5

Author(s):

Charles Dolladille ◽

Stephane Ederhy ◽

Stéphane Allouche ◽

Querntin Dupas ◽

Radj Gervais ◽

...

Keyword(s):

Adverse Events ◽

Immune Checkpoint ◽

Checkpoint Inhibitors ◽

Left Ventricular Systolic Dysfunction ◽

Left Ventricular ◽

Fulminant Myocarditis ◽

Link Type ◽

Therapy Initiation ◽

First 90 Days ◽

Cardiac Adverse Events

BackgroundImmune checkpoint inhibitor (ICI)-associated early cardiac adverse events (CAEs), mostly acute and fulminant myocarditis, have been well characterized and mainly occur during the first 90 days after ICI therapy initiation. ICI-associated late CAEs (occurring after the first 90 days of treatment) have not yet been described.MethodsFirst, we compared characteristics of a cohort involving early (defined as a CAE time to onset (TTO) of <90 days after ICI therapy initiation) and late (defined as a CAE TTO of ≥90 days after ICI therapy initiation) ICI-associated CAE consecutive cases who were referred to three French cardio-oncology units. Second, ICI-associated CAE cases were searched in VigiBase, the WHO global individual case safety report database, and early and late ICI-associated CAEs were compared.ResultsIn the cohort study, compared with early CAE cases (n=19, median TTO of 14 days), late ICI-associated CAE cases (n=19, median TTO of 304 days) exhibited significantly more left ventricular systolic dysfunction (LVSD) and heart failure (HF) and less frequent supraventricular arrhythmias. In VigiBase, compared with early cases (n=437, 73.3%, median TTO 21 days), the late ICI-associated CAE reports (n=159, 26.7%, median TTO 178 days) had significantly more frequent HF (21.1% vs 31.4%, respectively, p=0.01). Early and late ICI-associated CAE cases had similarly high mortality rates (40.0% vs 44.4% in the cohort and 30.0% vs 27.0% in VigiBase, respectively).ConclusionsLate CAEs could occur with ICI therapy and were mainly revealed to be HF with LVSD.Trial registration numbersNCT03678337,NCT03882580, andNCT03492528.

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Disorganization of Intercalated Discs in Dilated Cardiomyopathy

10.21203/rs.3.rs-153597/v1 ◽

2021 ◽

Author(s):

Yukinobu Ito ◽

Makoto Yoshida ◽

Hirotake Masuda ◽

Daichi Maeda ◽

Yukitsugu Kudo-Asabe ◽

...

Keyword(s):

Dilated Cardiomyopathy ◽

Interstitial Fibrosis ◽

Left Ventricular ◽

Pathological Diagnosis ◽

Control Group ◽

Failure Group ◽

Intercalated Discs ◽

Group Reduction ◽

Group A ◽

Morphological Differences

Abstract Dilated cardiomyopathy (DCM) is a primary myocardial disease, the pathology of which is left ventricular or biventricular dilation and impaired myocardial contractility. The clinical and pathological diagnosis of DCM is difficult, and other cardiac diseases must be ruled out. Several studies have reported pathological findings that are characteristic of DCM, including cardiomyocyte atrophy, nuclear pleomorphism, and interstitial fibrosis, but none of these findings are DCM-specific. In this study, we examined the morphological differences in ICDs between three groups of patients, a DCM group, a chronic heart failure group, and a control group. A total of 21 autopsy cases, including five DCM cases, eight CHF cases and eight control cases, were retrieved from the archives of the Department of Pathology at Akita University, Japan. The morphological differences were examined using multiple methods: macroscopic examination, light microscopy, immunohistochemistry, electron microscopy, and gene expression analyses. We observed disorganized intercalated discs (ICDs), clearly illustrated by N-cadherin immunostaining in the DCM group. “Reduction of N-cadherin immunostaining intensity” and “ICD scattering” was DCM-specific. The results suggest that disorganized ICDs contribute to the development of DCM, and that N-cadherin immunostaining is useful for determining the presence of disorganized ICDs and for the pathological diagnosis of DCM.

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Immune Checkpoint Myocarditis from Adjuvant Treatment of Melanoma

10.31487/j.gccr.2020.01.05 ◽

2020 ◽

pp. 1-2

Author(s):

Carrie Lenneman ◽

John Dasher ◽

Lavanya Kondapalli ◽

Carrie Lenneman

Keyword(s):

T Cells ◽

High Risk ◽

Adverse Events ◽

Adjuvant Treatment ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Effective Therapy ◽

Stage Iii

Immune checkpoint inhibitors (ICIs) are effective therapy for many metastatic cancers and are now being used as adjuvant treatment for many stage III cancers to reduce the high risk of reoccurrence. ICIs activate a patient’s own T-cells to fight cancer, but in some cases, immune-related adverse events (irAEs) with inflammation of many organs can occur. Rare cases of myocarditis have been reported. More data is needed to improve our ability to monitor, diagnose and treat irAEs.

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The natural history of myocardial disease in dialysis patients.

Journal of the American Society of Nephrology ◽

10.1681/asn.v212 ◽

1991 ◽

Vol 2 (1) ◽

pp. 2-12 ◽

Cited By ~ 2

Author(s):

P S Parfrey ◽

J D Harnett ◽

P E Barre

Keyword(s):

Risk Factors ◽

Heart Failure ◽

Congestive Heart Failure ◽

Heart Disease ◽

Natural History ◽

Ischemic Heart Disease ◽

Dilated Cardiomyopathy ◽

Left Ventricular ◽

Ischemic Heart ◽

Dialysis Patients

Among dialysis patients, only 23% have a normal echocardiogram, about 10% have recurrent or chronic congestive heart failure, and 17% have asymptomatic ischemic heart disease. The predisposing factors for congestive heart failure are dilated cardiomyopathy, hypertrophic hyperkinetic disease, and ischemic heart disease. Dilated cardiomyopathy, a disorder of systolic function, includes among its risk factors age, hyperparathyroidism, and smoking. Hypertrophic disease results in diastolic dysfunction, and its predictors include age, hypertension, aluminum accumulation, anemia, and, perhaps, hyperparathyroidism. Ischemic heart disease is due to the presence of coronary artery disease and also to nonatherosclerotic disease caused by the reduction in coronary vasodilator reserve and altered myocardial oxygen delivery and use. The clinical outcome of congestive heart failure is comparable to that of nonrenal patients with medically refractory heart failure. Left ventricular hypertrophy is an important independent determinant of survival. A subset have hyperkinetic disease with severe hypertrophy and have a bad survival, as low as 43% have a 2-yr survival after the first admission to hospital with cardiac failure. The prognosis for those with dilated cardiomyopathy is less severe but is worse than those with normal echocardiogram. The survival of patients with symptomatic ischemic heart disease was little different from that of patients without symptoms, suggesting that the underlying cardiomyopathies had an adverse impact on survival independent of ischemic disease. Much research needs to be undertaken on the risk factors, natural history, and therapy of the various types of cardiac disease prevalent in dialysis patients.

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P1113Patchy localisation of late gadolinium enhancement associated with ventricular arrhythmia in dilated cardiomyopathy

EP Europace ◽

10.1093/europace/euaa162.043 ◽

2020 ◽

Vol 22 (Supplement_1) ◽

Author(s):

V Pooranachandran ◽

A Mistry ◽

Z Vali ◽

X Li ◽

B Sidhu ◽

...

Keyword(s):

Late Gadolinium Enhancement ◽

High Risk ◽

Ventricular Arrhythmia ◽

Dilated Cardiomyopathy ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Lv Function ◽

Gadolinium Enhancement ◽

Ventricular Ejection Fraction ◽

Significant Difference

Abstract Funding Acknowledgements None Introduction Myocardial fibrosis detected using late gadolinium enhancement(LGE) on cardiac magnetic resonance(CMR) imaging holds prognostic value in dilated cardiomyopathy(DCM). Recent reports have demonstrated the localisation of LGE to be promising predictors of ventricular arrhythmic (VA).Aim: To determine the localisation of LGE associated with high risk of VA in DCM patients. Methods: Retrospective review of consecutive DCM patients(n = 85) implanted with an implantable cardioverter defibrillator(ICD) at a single tertiary centre between 2011-2018. All patients with insufficient follow-up data, cardiac channelopathies, primary valvular pathology and congenital heart disease were excluded from analysis(n = 11). Details of VA occurrence were obtained from medical and pacing notes. VA was defined as VA causing haemodynamic compromise or appropriate device therapy (anti-tachycardia pacing/shock). Localisation of LGE was defined as midwall, patchy, subepicardial or transmural. Left ventricular ejection fraction(LVEF) <35% was defined as severely impaired function. Results:74 DCM patients implanted with an ICD were identified for analysis; LGE was observed in 18(60%) VA and 29(66%) non-VA patients(p = 0.6). There was no observed difference in mean age for patients with and without LGE (68 ± 10 vs. 65 ± 10 years,p = 0.07). A significant difference was seen between localisation and VA (p = 0.04), with patchy LGE demonstrating a higher arrhythmic risk(p = 0.005). There was no association between LVEF and LGE(p = 0.2) however, a significant difference was seen in LVEF and arrhythmic risk, with a more severely impaired LV function seen in patients without VA(p = 0.01). Conclusion:This study has demonstrated a patchy LGE localisation to be strongly associated with ventricular arrhythmia in DCM. Whilst this is a valuable tool in risk stratification, a prospective study with a larger population is required to confirm the validity of this finding. Moreover, an additional method will need to be considered to identify high risk patients without LGE. Ventricular Arrhythmia (n = 30) No Ventricular Arrhythmia (n = 44) P Value Male(%) 20(67%) 24(55%) p = 0.29 Age(Mean ± SD) 65 ± 12 65 ± 10 p = 0.36 LGE Midwall 10(56%) 24(83%) p = 0.04 Subepicardial 1(5.5%) 2(7%) p = 0.85 Transmural 1(5.5%) 2(7%) p = 0.85 Patchy 6(33%) 1(3%) p = 0.005 LVEF <35% 23(77%) 42(95%) p = 0.01

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P6453Activation of necroptotic pathway by downregulated caspase-8 expression is associated with progression of left ventricular remodeling in nonischemic dilated cardiomyopathy

European Heart Journal ◽

10.1093/eurheartj/ehz746.1046 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

Y Fujita ◽

T Yano ◽

K Abe ◽

N Nagano ◽

N Kamiyama ◽

...

Keyword(s):

Regression Analysis ◽

Dilated Cardiomyopathy ◽

Linear Regression Analysis ◽

Left Ventricular ◽

Expression Level ◽

Diastolic Filling ◽

Caspase 8 ◽

Image Analyzer ◽

Nonischemic Dilated Cardiomyopathy ◽

Intercalated Disks

Abstract Background Necroptosis, a form of programmed necrosis, has been suggested to be involved in the pathogenesis of various pathological conditions including heart failure. Protein expression of caspase-8, an endogenous inhibitor of necroptosis, is reported to be downregulated in human failing hearts, but its clinical significance remains unclear. Methods Endomyocardial biopsy specimens were obtained from patients with nonischemic dilated cardiomyopathy (n=57, 56.2±14.5 years old, 70% male). The area stained with antibodies against caspase-8 and phospho-MLKL-Ser358 was calculated using an image analyzer, and fibrotic and cardiomyocyte areas were determined by Masson's Trichrome staining. Using a level of median caspase-8 expression (6.04% of the area of the myocardium with caspase-8 signal), patients were classified into a high caspase-8 expression group (H-cas8) and a low caspase-8 expression group (L-cas8). Results Caspase-8 signals were detected in cytoplasm and intercalated disks of cardiomyocytes. Patients in the L-cas8 group was younger (51.3±13.1 vs. 61.2±14.3 years old) and had larger left ventricular end-diastolic volume (LVEDV: 174±49 vs. 131±41 ml), larger left ventricular end-systolic volume (LVESV: 123±51 vs. 87±39 ml), and higher ratio of mitral peak velocity of early filling to late diastolic filling (E/A: 1.94±1.48 vs. 1.12±0.66) compared with the H-cas8 group. Caspase-8 expression level was positively correlated with age (r=0.34, p=0.01) and negatively correlated with LVEDV (r=−0.47, p<0.01), LVESV (r=−0.40, p<0.01), and E/A (r=−0.39, p<0.01) in simple linear regression analysis. The extent of myocardial fibrosis was not correlated with caspase-8 expression level. Multiple regression analysis indicated that LVEDV, LVESV, and E/A were independent explanatory factors of caspase-8 expression level after adjusting age and sex. Phospho-MLKL signals, an index of activation of necroptotic pathway, were frequently observed in cytoplasm, intercalated disks, and nuclei in the L-cas8 group but not in the H-cas8 group. Conclusion Lower caspase-8 expression in cardiomyocytes was associated with increased phosphorylation of MLKL and larger left ventricular volume, suggesting that downregulated caspase-8 may contribute to progression of myocardial remodeling via activation of MLKL in human dilated cardiomyopathy.

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Case Report: Successful revascularization in massive pulmonary embolism with a large protruding thrombus and dilated cardiomyopathy

F1000Research ◽

10.12688/f1000research.28311.2 ◽

2021 ◽

Vol 10 ◽

pp. 13

Author(s):

Hendri Susilo ◽

Rerdin Julario ◽

Citrawati Dyah Kencono Wungu

Keyword(s):

Pulmonary Embolism ◽

High Risk ◽

Right Ventricular ◽

Dilated Cardiomyopathy ◽

Acute Pulmonary Embolism ◽

Systolic Function ◽

Vena Cava ◽

Massive Pulmonary Embolism ◽

Left Ventricular ◽

Ventricular Afterload

Pulmonary embolism is a potentially life-threatening condition. Despite advances in diagnostics, lack of consensus and delays in determining the diagnosis of pulmonary embolism are still important problems. We report the diagnosis and management of a 37-year-old man suffering from massive pulmonary embolism, a large protruding thrombus, and dilated cardiomyopathy. Echocardiography showed dilatation of all cardiac chambers, a large protruding thrombus in the right atrium to the inferior vena cava, impaired left and right ventricular systolic function, and global hypokinetic of the left ventricle with eccentric left ventricular hypertrophy. A thoracic computerized tomography scan showed pulmonary embolism with infarction. The patient’s blood pressure was 60/40 mmHg and heart rate was 110 bpm. The patient was diagnosed with high-risk acute pulmonary embolism. We gave him hemodynamic support and reperfusion therapy with a loading dose of 250,000 units of Streptokinase followed by 100,000 units/hour for 24 hours. After revascularization, the patient's hemodynamic condition improved. The diagnosis of acute pulmonary embolism is based on clinical symptoms, hemodynamic changes, or radiological examination. Unstable hemodynamic underlies high-risk stratification. Hypotension or shock results from obstruction of the pulmonary artery which causes increased right ventricular afterload and acute right ventricular dysfunction. Reperfusion with thrombolysis therapy could provide good outcomes in this patient. Prolonged anticoagulation should be given to prevent the recurrence of venous thromboembolism.

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A machine-learning-based method to predict adverse events in patients with dilated cardiomyopathy and severely reduced ejection fractions

British Journal of Radiology ◽

10.1259/bjr.20210259 ◽

2021 ◽

pp. 20210259

Author(s):

Shengeli Shu ◽

Ziming Hong ◽

Qinmu Peng ◽

Xiaoyue Zhou ◽

Tianjng Zhang ◽

...

Keyword(s):

Machine Learning ◽

Adverse Events ◽

Risk Stratification ◽

Heart Transplantation ◽

Dilated Cardiomyopathy ◽

Systolic Function ◽

Laboratory Data ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Support Vector

Objective: Patients with dilated cardiomyopathy (DCM) and severely reduced left ventricular ejection fractions (LVEFs) are at very high risks of experiencing adverse cardiac events. A machine learning (ML) method could enable more effective risk stratification for these high-risk patients by incorporating various types of data. The aim of this study was to build an ML model to predict adverse events including all-cause deaths and heart transplantation in DCM patients with severely impaired LV systolic function. Methods: One hundred and eighteen patients with DCM and severely reduced LVEFs (<35%) were included. The baseline clinical characteristics, laboratory data, electrocardiographic, and cardiac magnetic resonance (CMR) features were collected. Various feature selection processes and classifiers were performed to select an ML model with the best performance. The predictive performance of tested ML models was evaluated using the area under the curve (AUC) of the receiver operating characteristic curve using 10-fold cross-validation. Results: Twelve patients died, and 17 patients underwent heart transplantation during the median follow-up of 508 days. The ML model included systolic blood pressure, left ventricular end-systolic and end-diastolic volume indices, and late gadolinium enhancement (LGE) extents on CMR imaging, and a support vector machine was selected as a classifier. The model showed excellent performance in predicting adverse events in DCM patients with severely reduced LVEF (the AUC and accuracy values were 0.873 and 0.763, respectively). Conclusions: This ML technique could effectively predict adverse events in DCM patients with severely reduced LVEF. Advances in knowledge: The ML method has superior ability in risk stratification in severe DCM patients.

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