[Clinical and immunological characteristics of systemic lupus erythematosus with retinopathy].

OBJECTIVE: To investigate the clinical and immunological characteristics of systemic lupus erythematosus (SLE) with retinopathy. METHODS: Fifty SLE patients with retinopathy without hypertension and diabetes (retinopathy group) who were hospitalized in the Peking University People's Hospital from January 2009 to July 2022 were screened. Fifty SLE patients without blurred vision during the course of the SLE and without retinopathy in the fundus examinations (non-retinopathy group) matched for sex and age were selected. Their clinical manifestations, laboratory tests and lymphocyte subsets were statistically analyzed. RESULTS: The most common fundus ocular change of the SLE patients with retinopathy was cotton-wool spots (33/50, 66.0%), followed by intraretinal hemorrhage (31/50, 62.0%). Retinopathy could occur at any stage of SLE duration, with a median of 1 year (20 days to 30 years). The proportion of lupus nephritis (72.0% vs. 46.0%, P=0.008) and serositis (58.0% vs. 28.0%, P=0.002) in the retinopathy group were significantly higher than those in the non-retinopathy group. The proportion of neuropsychiatric systemic lupus erythematosus (NPSLE) in the retinopathy group was higher, but there was no significant difference between the two groups. Compared with the non-retinopathy group, the proportion of positive anti-cardiolipin antibody (30.0% vs. 12.0%, P=0.027), the SLEDAI score (median 22.0 vs. 10.5, P < 0.001), erythrocyte sedimentation rate (P < 0.001), C-reactive protein (P=0.019) and twenty-four hours urine total protein level (P=0.026) in the retinopathy group were significantly higher, and the hemoglobin level was significantly lower [(91.64±25.18) g/L vs. (113.96±18.57) g/L, P < 0.001]. The proportion of CD19+ B cells in peripheral blood of the patients with SLE retinopathy was significantly increased (P=0.010), the proportion of CD4+ T cells was significantly decreased (P=0.025) and the proportion of natural killer (NK) cells was lower (P=0.051) when compared with the non-retinopathy group. CONCLUSION: Retinopathy in SLE suggests a higher activity of SLE disease with more frequent hematologic and retinal involvement. It is recommended to perform fundus examination as soon as a patient is diagnosed with SLE. SLE patients with retinopathy may have stronger abnormal proliferation of B cells, and aggressive treatment should be applied to prevent other important organs involvement.

[Ruxolitinib as an effective treatment for panniculitis associated hemophagocytic syndrome: A report of 2 cases and literature review].

Hemophagocytic syndrome (HPS) is a severe disease characterized by excessive release of inflammatory cytokines caused by abnormal activation of lymphocytes and macrophages, which can cause multiple organ damage and even death. Panniculitis is a disease characterized by inflammation of subcutaneous adipose tissue. We effectively treated 2 patients with panniculitis-associated HPS with ruxolitinib. Case 1: A 70-year-old male started with intermittent plantar swelling and pain, and then developed leukocytosis, mild anemia, multiple red maculopapules with painless subcutaneous nodules on the forehead, neck and bilateral lower legs. The patient was treated with prednisone and leflunomide for improvement. After that, repeated fever and rash occurred again. After admission to our hospital, we found his leukocyte and hemoglobin decreased, ferritin raised, fibrinogen and natural killer (NK) cell activity decreased, and hemophagocytic cells were found in bone marrow aspiration. The skin pathology was consistent with non-suppurative nodular panniculitis. He was diagnosed with nodular panniculitis associa-ted HPS. He was treated with glucocorticoid, cyclosporine, etoposide and gamma globule, but the disease was not completely controlled. After adjusting etoposide to ruxolitinib, his symptoms and abnormal laboratory findings returned to normal. After 2 months he stopped using ruxolitinib due to repeated infections. During the follow-up, though the prednisone dose was tapered, his condition was stable. Case 2: A 46-year-old female patient developed from intermittent fever, erythematous nodular rash with tenderness, leukopenia, and abnormal liver function. antibiotic therapy was ineffective. She improved after glucocorticoid treatment, and relapsed after glucocorticoid reduction. There were fever, limb nodules, erythema with ulcerative necrosis, intermittent abdominal pain when she came to our hospital. Blood examination showed that her white blood cells, red blood cells and platelets were decreased, fibrinogen was decreased, triglyceride was increased, ferritin and soluble interleukin-2 receptor(SIL-2R/sCD25) were significantly raised, and hemophagocytic cells were found in bone marrow aspiration. It was found that Epstein-Barr virus DNA was transiently positive, skin Staphylococcus aureus infection, and pulmonary Aspergillus flavus infection, but C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were normal, and no evidence of tumor and other infection was found. Skin pathology was considered panniculitis. The diagnosis was panniculitis, HPS and complicated infection. Antibiotic therapy and symptomatic blood transfusion were given first, but the disease was not controlled. Later, dexamethasone was given, and the condition improved, but the disease recurred after reducing the dose of dexamethasone. Due to the combination of multiple infections, the application of etoposide had a high risk of infection spread. Ruxolitinib, dexamethasone, and anti-infective therapy were given, and her condition remained stable after dexamethasone withdrawal. After 2 months of medication, she stopped using ruxolitinib. One week after stopping using ruxolitinib, she developed fever and died after 2 weeks of antibiotic therapy treatment in a local hospital. In conclusion, panniculitis and HPS are related in etiology, pathogenic mechanism and clinical manifestations. Abnormal activation of Janus-kinase and signal transduction activator of transcription pathway and abnormal release of inflammatory factors play an important role in the pathogenesis of the two diseases. The report suggests that ruxolitinib is effective and has broad prospects in the treatment of panniculitis associated HPS.

[Comparison of clinical and immunological features between clinically amyopathic dermatomyositis and typical dermatomyositis].

OBJECTIVE: To study the differences between clinically amyopathic dermatomyositis (CADM) and typical dermatomyositis (DM) on clinical and immunological features. METHODS: By collecting clinical data of 106 CADM patients and 158 DM patients from January 2010 to June 2019 in the department of Rheumatology and Immunology, Peking University People's Hospital, the clinical characteristics and immunological features in the two groups were compared, and the distribution characters and the clinical meanings of myositis autoantibodies were discussed in the two groups respectively. Myositis autoantibodies were measured by immunoblotting according to the manufacturers' instructions. RESULTS: In the aspects of clinical manifestations, CADM presented more with onset of interstial lung diseases (ILD) compared with DM (20.7% vs. 7.6%, P=0.002), and CADM-ILD was more likely to be acute ILD (58.3% vs. 26%, P < 0.001), and there were no differences between CADM and DM in cutaneous manifestations, accompanied with connective tissue disease (CTD) and malignancy. In CADM, the positive rate of rheumatoid factors and antinuclear antibodies was lower in DM. The most common myositis specific autoantibodies (MSAs) in CADM were anti-MDA5 (36%), anti-PL-7 (11.2%) and anti-TIF-1γ (10.1%). The most common MSAs in DM were anti-Jo-1 (19.2%), anti-TIF-1γ (11.5%) and anti-MDA5 (11.5%). Anti-MDA5 was correlated with acute ILD and skin ulceration both in CADM and DM; in CADM, skin ulceration was not associated with the titer of anti-MDA5; while in DM, skin ulceration was associated with high titer of anti-MDA5. In DM, anti-TIF-1γ was correlated with heliotrope eruption, V/shawl neck sign, perionychia erythma and malignancy, and higher rate of malignancy was seen in all titers of the anti-TIF-1γ positive patients. In CADM, anti-TIF1-γ showed no correlation with clinical manifestations. The most common myositis associated autoantibody was anti-Ro-52 both in CADM and DM. In CADM, anti-Ro-52 was associated with Raynaud's phenomenon and chronic ILD, while in DM, anti-Ro-52 was associated with mechanic's hands, noninfectious fever and accompanied CTD. CONCLUSION: Compared with DM, ILD is more likely to be acute in CADM. It is different between CADM and DM about the distribution of myositis autoantibodies and the clinical significance of the same myositis antibody, and the clinical significance of some myositis antibodies is related to titers.

[Clinical characteristics and risk factors of cardiovascular disease in patients with elderly-onset rheumatoid arthritis: A large cross-sectional clinical study].

OBJECTIVE: To investigate the clinical characteristics of patients with elderly-onset rheumatoid arthritis (EORA), and the risk factors of EORA complicated with cardiovascular disease (CVD). METHODS: A cross-sectional study was conducted in Peking University People's Hospital from July 2009 to December 2014 and 1 116 patients were recruited. The patients' characteristics and CVD, including ischemic heart disease, cerebral and peripheral vascular disease, were recorded. The patients were divided into EORA group (n=212) and younger-onset rheumatoid arthritis (YORA) group (n=904) according to the age of onset ≥60 years and < 60 years. Then, the differences between the groups were analyzed by Student's t test, Mann-Whitney U test or χ2test, and risk influencing CVD were analyzed using Logistic regression. RESULTS: There was no significant difference in the disease activity between the EORA and YORA groups. The proportion of male, pulmonary interstitial disease (ILD), and numbers of deformity joint count (DJC) were significantly higher in the EORA group compared with the YORA group [32.1% vs. 18.5%, χ2=19.11, P < 0.001; 23.6% vs. 13.6%, χ2=16.50, P < 0.001; 6 (2, 12) vs. 3 (2, 7), Z=-3.60, P < 0.001], while the prevalence of Sjögren's syndrome was lower than that of the YORA group (13.5% vs. 5.2%, χ2=11.29, P=0.001). Moreover, there were lower prevalences in the patients treated with disease-modifying antirheumatic drugs (DMARDs) in EORA group (35.4%) than in YORA group (26.7%) (χ2=6.43, P=0.011), especially in methotrexate (MTX), hydroxychloroquine (HCQ) and sulfasalazine (SSZ). In addition, the patients with EORA had a higher prevalence of CVD (27.8%) than the YORA group (11.6%, χ2=40.46, P < 0.001), accompanied with higher prevalence of smoking, hypertension, and hyperlipidemia. Multivariate Logistic regression analysis showed that elder age (OR=1.10, 95%CI: 1.00-1.20), DJC (OR=3.17, 95%CI: 1.04-9.68), rheumatoid nodules (OR=3.56, 95%CI: 1.03-12.23), hypertension (OR=2.37, 95%CI: 1.09-5.13) and hyperlipidemia (OR=8.85, 95%CI: 2.50-31.27) were independent risk factors, while HCQ (OR=0.22, 95%CI: 0.07-0.70) and MTX (OR=0.32, 95%CI: 0.14-0.73) were protective factors of EORA complicated with CVD. CONCLUSION: Compared with YORA, patients with EORA have higher ratio of male, ILD and DJC, which may be attributed to inappropriate therapies. EORA is more likely to be complicated with CVD than YORA. Elder age, DJC, rheumatoid nodules, hypertension, and hyperlipidemia are independent risk factors, while HCQ and MTX are protective factors of EORA complicated with CVD.

[Investigation of sleep disturbance and related factors in patients with primary Sjögren's syndrome].

OBJECTIVE: To investigate the prevalence of sleep disorders and the relevant determinants in a cohort of primary Sjögren' s syndrome (pSS) patients. METHODS: One hundred and eighty-six pSS patients were included in the study, who were admitted to Peking University People' s Hospital and met the criteria of inclusion and exclusion. Sleep quality was assessed using the Pittsburgh sleep quality index(PSQI).Depression, anxiety were evaluated by patient health questionnaire (PHQ)-9, generalized anxiety disorder(GAD)-7, respectively. The demographic and clinical data were also recorded.Disease activity and damage were evaluated with the European League Against Rheumatism Sjögren's syndrome disease activity index (ESSDAI). According to the PSQI score>7, the pSS patients were divided into 152 cases of sleep disorder group and 34 cases of normal sleep group. Mann-Whitney U test, Chi-square test or Fisher' s exact test, independent samples t test, Spearman correlation analysis and Logistic regression were used for statistical analysis. RESULTS: The prevalence of sleep disturbance (PSQI > 7) was 81.7% (152 / 186) in the pSS patients, and 52.7% (98/186) had moderate or severe sleep disorders (PSQI≥ 11). The mean PSQI score of sleep disordered group was (12.29±3.30), while the normal sleep group PSQI score was (5.50±1.20). The PSQI score, PHQ-9 score and GAD-7 score in the sleep-disordered group were significantly higher than those in the normal sleep group (P=0.000, 0.035, 0.031). The PSQI score in the sleep disordered group were significantly higher than those in the normal sleep group in seven aspects: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disorders, hypnotic drug use and daytime dysfunction. All of them had statistical significance. According to the results of Spearman correlation analysis, PSQI had significantly positive correlation with course of disease, anxiety, depression score (r=0.151, 0.240, 0.421, P < 0.05), but negatively correlated with C3, C4 (r=-0.021, -0.235, P < 0.05). Logistic analysis identified the course of disease(OR=2.809, 95%CI: 1.21-6.52)and PHQ-9 score(OR=1.422, 95%CI: 1.04-1.94)as predictors of sleep disorders. CONCLUSION: The incidence of sleep disorder in the pSS patients was higher, which was closely related to the course of disease, anxiety, depression and other factors. It is critical to assess and manage comprehensively the disease.

STIL is upregulated in nasopharyngeal carcinoma tissues and promotes nasopharyngeal carcinoma proliferation, migration and invasion.

Nasopharyngeal carcinoma (NPC) is the most common primary malignancy that originates from the nasopharynx. Some regulatory networks involved in nasopharyngeal carcinoma have been reported, but the relevant genes have not been fully identified. We have used mRNA microarray to identify differential expression genes between NPC tissues and adjacent normal tissues. Then high-content shRNA screening was carried out to screen the genes that may control proliferation in nasopharyngeal carcinoma. Cell proliferation was monitored by MTT assays and Celigo image cytometry in vitro and subcutaneous transplantation model in vivo. Flow cytometric analysis was carried out to detect the distribution of cell cycle stages and apoptosis. Transwell assay was performed to measure the migratory and invasive capacities of NPC cells. We identified 20 genes that potentially play an important role in the proliferation of nasopharyngeal carcinoma by mRNA microarray and functional analysis. The result of high-content shRNA screening indicated that STIL had the greatest effect on reducing the proliferation rate of NPC cells. The analysis of The Cancer Genome Atlas (TCGA) data showed that STIL was upregulated in several human cancer tissues, and higher STIL expression level was correlated with shorter survival time. STIL knockdown also inhibited NPC cell migration and invasion, promoted G1/S phase transition and apoptosis. Three genes including ITGA2, SMAD2, JAK1, associated with molecular mechanisms of cancer were influenced by downregulating STIL. Our study confirmed STIL as a key regulator that promotes the proliferation of NPC, providing insight into the molecular mechanisms of nasopharyngeal carcinoma and suggesting a novel therapeutic strategy.

[Changes of serum Krebs von den Lungen-6 levels in interstitial lung disease associated with dermatomyositis and secondary Sjögren's syndrome: a case report].

Interstitial lung diseases (ILDs) are a diverse group of pulmonary disorders characterized by various patterns of inflammation and fibrosis in the interstitium of the lung. The underlying pathogenesis of ILDs is complex and associated with multiple rheumatologic conditions, such as systemic sclerosis, rheumatoid arthritis, pollymyositis and dermatomyositis, Sjögren's syndrome, and systemic lupus erythematosus. As the disease progresses, excessive pulmonary fibrosis impairs alveolar gas exchange and damages pulmonary function. The common methods to diagnose ILDs, such as clinical manifestations, pulmonary function test, and radiological examinations are not specific for ILDs and not able to diagnose ILDs at the early stage due to their low sensitivity. So, the easy way is important to diagnose ILDs. One important biomarker for ILDs is the high-molecular-weight glycoprotein, Krebs von den Lungen-6(KL-6). KL-6 encoded by the MUC1 gene is a mucin-like glycoprotein with high molecular weight and expressed predominantly on the cell surface of type II alveolar epithelial cells, and is detectable in the serum of patients with ILDs. We here report a case of ILDs associated with dermatomyositis and secondary Sjögren's syndrome. A 60-year-old woman was admitted to our hospital with the chief complaints of debilitation, dry mouth, dyspnea and astasia. ILDs associated with dermatomyositis and secondary Sjögren's syndrome was diagnosed clinically when the following criteria were satisfied: (1) development of dyspnea within 2 months of presentation, (2) pulmonary dispersion dysfunction, (3) bilateral infiltrative shadows on chest high resolution computed tomography (HRCT). She was treated with prednisone 50 mg/d prior to admission, but the result of therapy was not good. In our hospital she was treated with intravenous methylprednisolone and cyclophosphamide and oral hydroxychloroquine sulfate. Subsequently, her serum KL-6 levels gradually decreased after treatment, pulmonary diffuse function improved, and the improvement in the clinical manifestation and HRCT findings were observed. Nevertheless, the combination treatment of glucocorticoid and cyclophosphamide had contributed to the favourable outcomes. In conclusion, detection of serum KL-6 levels in ILDs associated with connective tissue diseases may be beneficial to making a definitive diagnosis, predicting the prognosis and monitoring the disease activity, which would be of great help in clinical practice. However, a well-designed clinical study with more patients and a longer follow-up period are required to arrive at a more conclusive judgment on the role of serum KL-6 in patients with ILDs.

[Significance of different T follicular helper subsets in rheumatoid arthritis].

OBJECTIVE: To detect the expressions of T follicular helper (Tfh) subsets and T follicular helper effect memory (Tfhem) cells in circulation of patients with rheumatoid arthritis (RA), as well as to examine their roles in providing biomarkers for active RA. METHODS: This study enrolled 41 patients with RA, who were navely-treated or had no application of hormone and disease-modifying anti-rheumatic drugs in recent 3 months, as well as 32 healthy controls. The percentages of Tfhem (CD4+CXCR5+CCR7lowPD1high) cells, Tfh (CD3+CD4+CXCR5+CD45RA-) subsets, Tfh1 (CXCR3+CCR6-Tfh),Tfh2 (CXCR3-CCR6-Tfh),and Tfh17 (CXCR3-CCR6+Tfh), were determined by flow cytometry of peripheral blood from the patients with RA and health controls. Serum levels of cytokines were detected by enzyme-linked immunosorbent (ELISA). The correlations of Tfhem/Tfh subsets with clinical indicators were analyzed. RESULTS: The mean age of the patients was (56.1±14.0) years (range: 20-82 years), the mean disease duration was (8.2±8.1) years. There was no significant difference between the RA patients and the health controls with age and gender. As compared with the health control, the percentage of Tfhem was significantly increased in the peripheral blood of the RA patients (12.8%±5.7% vs. 8.7%±2.0%, P=0.001). Moreover, the increased Tfhem was correlated with the higher disease activity score in 28 joints (DAS28) and erythrocyte sedimentation rate (ESR), but not with other clinical indicators, such as C-reactive protein (CRP), anti-cyclic citrullinated peptide (CCP) antibodies, and rheumatoid factors (RF). In addition, the percentage of Tfh2 subset, but not Tfh1 or Tfh17, was significantly increased in the RA patients (3.002%±0.408% vs. 1.730%±0.160%, P=0.013). As compared with Tfh2-low group, serum levels of Ig (immunoglobulin) A [(3.045±0.261) g/L vs.(3.963±0.815) g/L, P=0.172], IgG [(13.800±0.862) g/L vs.(16.980±0.224) g/L, P=0.161], IgM [(1.135±0.083) g/L vs.(1.731±0.380) g/L, P=0.140], IL (interleukin)-4 [(2.322±0.214) ng/L vs.(3.994±0.751) ng/L, P=0.056] and IL-10[(1.898±0.105) ng/L vs. (3.125±0.880) ng/L, P=0.140] in Tfh2-high group tended to increase with no significant statistical difference. CONCLUSION: Our data suggest that Tfhem is associated with disease activity and is a valuable marker for active RA. It also presents a potential pathogenesis in the development of RA and the target for future therapies. Meanwhile, the increased Tfh2 and associated cytokines might be involved in the development of RA.

Mutual regulation between DNA-PKcs and Snail1 leads to increased genomic instability and aggressive tumor characteristics.

Although the roles of DNA-dependent protein kinase catalytic subunits (DNA-PKcs) in the non-homologous end joining (NHEJ) of DNA repair are well-recognized, the biological mechanisms and regulators by DNA-PKcs besides DNA repair, have not been clearly described. Here, we show that active DNA-PKcs caused by ionizing radiation, phosphorylated Snail1 at serine (Ser) 100, led to increased Snail1 stability. Furthermore, phosphorylated Snail1 at Ser100 reciprocally inhibited the kinase activity of DNA-PKcs, resulting in an inhibition of DNA repair activity. Moreover, Snail1 phosphorylation by DNA-PKcs was involved in genomic instability and aggressive tumor characteristics. Our results describe novel cellular mechanisms that affect genomic instability, sensitivity to DNA-damaging agents, and the migration of tumor cells by reciprocal regulation between DNA-PKcs and Snail1.

A new antiallergic agent that binds to dimerized translationally controlled tumor protein and inhibits allergic symptoms is nontoxic.

Dimerized translationally controlled tumor protein (dTCTP) plays a role in allergic diseases. A 7-mer peptide, dimerized translationally binding protein 2 (dTBP2), binds to dTCTP and inhibits dTCTP, suggesting that the 7-mer peptide may have therapeutic potential. We assessed the safety of dTBP2 by examining its cytotoxicity to both human bronchial epithelial cells and mice. dTBP2 did not cause cytotoxicity to the epithelial cells in concentrations up to 100 µg/ml. Also, dTBP2 caused no adverse effects upon repeated administration of 50 mg/kg over 24 h to mice. Hence, we conclude that dTBP2 is a safe candidate drug for use in the therapy of allergic diseases.

Upregulation of CXCR4 is functionally crucial for maintenance of stemness in drug-resistant non-small cell lung cancer cells.

The hypothesis of cancer stem cells has been proposed to explain the therapeutic failure in a variety of cancers including lung cancers. Previously, we demonstrated acquisition of epithelial-mesenchymal transition, a feature highly reminiscent of cancer stem-like cells, in gefitinib-resistant A549 cells (A549/GR). Here, we show that A549/GR cells contain a high proportion of CXCR4+ cells that are responsible for having high potential of self-renewal activity in vitro and tumorigenicity in vivo. A549/GR cells exhibited strong sphere-forming activity and high CXCR4 expression and SDF-1α secretion compared with parent cells. Pharmacological inhibition (AMD3100) and/or siRNA transfection targeting CXCR4 significantly suppressed sphere-forming activity in A549 and A549/GR cells, and in various non-small cell lung cancer (NSCLC) cell lines. A549/GR cells showed enhanced Akt, mTOR and STAT3 (Y705) phosphorylation. Pharmacological inhibition of phosphatidyl inositol 3-kinase or transfection with wild-type PTEN suppressed phosphorylation of Akt, mTOR and STAT3 (Y705), sphere formation, and CXCR4 expression in A549/GR cells, whereas mutant PTEN enhanced these events. Inhibition of STAT3 by WP1066 or siSTAT3 significantly suppressed the sphere formation, but not CXCR4 expression, indicating that STAT3 is a downstream effector of CXCR4-mediated signaling. FACS-sorted CXCR4+ A549/GR cells formed many large spheres, had self-renewal capacity, demonstrated radiation resistance in vitro and exhibited stronger tumorigenic potential in vivo than CXCR4- cells. Lentiviral-transduction of CXCR4 enhanced sphere formation and tumorigenicity in H460 and A549 cells, whereas introduction of siCXCR4 suppressed these activities in A549/GR cells. Our data indicate that CXCR4+ NSCLC cells are strong candidates for tumorigenic stem-like cancer cells that maintain stemness through a CXCR4-medated STAT3 pathway and provide a potential therapeutic target for eliminating these malignant cells in NSCLC.

Relevance of ventricular electrical dispersion to arrhythmogenesis in ischemic myocardium--a simulation study.

A computer simulation method was used to study the possible role of electrical dispersion induced by regional ischemia in the mechanisms underlying cardiac arrhythmias. Ischemic cells were simulated by considering the three major component conditions of acute ischemia (elevated extracellular K+ concentration, acidosis and anoxia) at the level of ionic currents and ionic concentrations. An ischemic area was introduced into a homogeneous healthy tissue to create a localized inhomogeneity. The constructed models were solved using the operator splitting and adaptive time step methods. The numerical experiments showed that action potential durations (APDs) of ischemic cells did not change with beats of shorter or longer cycle length. The smaller percentage increase of slow component of the delayed rectifier K+ current, I(ks), and smaller outward Na+-Ca2+ exchange current were found to be the ionic mechanisms underlying the decreased rate dependence in ischemic cells. The results suggest that ischemia flattens the APD restitution curve; however, the dispersion of refractory period can be greatly increased by a premature beat in the constructed inhomogeneous sheet. This demonstrates that the dispersion of refractoriness rather than APD by a premature beat contributes to reentrant tachyarrhythmias in the locally ischemic tissue.