Transcriptional and functional analysis of plasma exosomal microRNAs in acute viral myocarditis.

AIM: To assess the differential expression profiles of exosome-derived microRNA (miRNA) and reveal their potential functions in patients with acute viral myocarditis (AVMC). MATERIALS & METHODS: Peripheral blood samples were collected from 9 patients diagnosed with AVMC and 9 healthy controls (HC) in the Affiliated Hospital of Qingdao University from July 2021 to September 2022. The exosomal miRNA expression were tested using RNA high-throughput sequencing. We conducted the GO and KEGG functional analysis to predict the potential molecular, biological functions and related signaling pathways of miRNAs in exosomes. Target genes of exosomal miRNAs were predicted and miRNA-target gene network was mapped using gene databases. Differentially expressed exosomal miRNAs were selected and their expression levels were detected by quantitative real-time polymerase chain reaction (qRT-PCR) to verify the sequencing results. RESULTS: P < 0.05 and Fold Change>2 were considered as cut-off value to screen miRNAs that were differently expressed. This study identified 14 upregulated and 14 downregulated exosome-derived miRNAs. GO and KEGG analysis showed that differentially expressed miRNAs may be related to ß-catenin binding, DNA transcription activities, ubiquitin ligase, PI3K-Akt, FoxO, P53, MAPK, and etc.. The target genes of differentially expressed miRNAs were predicted using gene databases. Real-time PCR confirmed the upregulation of hsa-miR-548a-3p and downregulation of hsa-miR-500b-5p in AVMC. CONCLUSIONS: Hsa-miR-548a-3p and hsa-miR-500b-5p could serve as a promising biomarker of AVMC. Exosomal miRNAs may have substantial roles in the mechanisms of AVMC.

Factors predicting resolution of left ventricular thrombus in different time windows after myocardial infarction.

BACKGROUND: Left ventricular thrombus (LVT) is a serious complication after myocardial infarction. However, due to its asymptomatic nature, early detection is challenging. We aimed to explore the differences in clinical correlates of LVT found in acute to subacute and chronic phases of myocardial infarction. METHODS: We collected data from 153 patients who were diagnosed with LVT after myocardial infarction at the Affiliated Hospital of Qingdao University from January 2013 to December 2022. Baseline information, inflammatory markers, transthoracic echocardiograph (TTE) data and other clinical correlates were collected. Patients were categorized into acute to subacute phase group (< 30 days) and chronic phase group (30 days and after) according to the time at which echocardiograph was performed. The resolution of thrombus within 90 days is regarded as the primary endpoint event. We fitted logistic regression models to relating clinical correlates with phase-specific thrombus resolution. RESULTS: For acute to subacute phase thrombus patients: C-reactive protein levels (OR: 0.95, 95% CI: 0.918-0.983, p = 0.003) were significantly associated with thrombus resolution. For chronic phase thrombus patients: anticoagulant treatment was associated with 5.717-fold odds of thrombus resolution (OR: 5.717, 95% CI: 1.543-21.18, p = 0.009). CONCLUSIONS: Higher levels of CRP were associated with lower likelihood of LVT resolution in acute phase myocardial infarction; Anticoagulant therapy is still needed for thrombus in the chronic stage of myocardial infarction.

Computed Tomography-Based Radiomics Analysis for Prediction of Response to Neoadjuvant Chemotherapy in Breast Cancer Patients.

PURPOSE: Previous studies have pointed out that magnetic resonance- and fluorodeoxyglucose positron emission tomography-based radiomics had a high predictive value for the response of the neoadjuvant chemotherapy (NAC) in breast cancer by respectively characterizing tumor heterogeneity of the relaxation time and the glucose metabolism. However, it is unclear whether computed tomography (CT)-based radiomics based on density heterogeneity can predict the response of NAC. This study aimed to develop and validate a CT-based radiomics nomogram to predict the response of NAC in breast cancer. METHODS: A total of 162 breast cancer patients (110 in the training cohort and 52 in the validation cohort) who underwent CT scans before receiving NAC and had pathological response results were retrospectively enrolled. Grades 4 to 5 cases were classified as response to NAC. According to the Miller-Payne grading system, grades 1 to 3 cases were classified as nonresponse to NAC. Radiomics features were extracted, and the optimal radiomics features were obtained to construct a radiomics signature. Multivariate logistic regression was used to develop the clinical prediction model and the radiomics nomogram that incorporated clinical characteristics and radiomics score. We assessed the performance of different models, including calibration and clinical usefulness. RESULTS: Eight optimal radiomics features were obtained. Human epidermal growth factor receptor 2 status and molecular subtype showed statistical differences between the response group and the nonresponse group. The radiomics nomogram had more favorable predictive efficacy than the clinical prediction model (areas under the curve, 0.82 vs 0.70 in the training cohort; 0.79 vs 0.71 in the validation cohort). The Delong test showed that there are statistical differences between the clinical prediction model and the radiomics nomogram ( z = 2.811, P = 0.005 in the training cohort). The decision curve analysis showed that the radiomics nomogram had higher overall net benefit than the clinical prediction model. CONCLUSION: The radiomics nomogram based on CT radiomics signature and clinical characteristics has favorable predictive efficacy for the response of NAC in breast cancer.

The Molecular Mechanisms of Cardiotoxicity Induced by HER2, VEGF, and Tyrosine Kinase Inhibitors: an Updated Review.

AIM: In recent decades, there has been a revolutionary decrease in cancer-related mortality and an increase in survival due to the introduction of novel targeted drugs. Nevertheless, drugs targeting human epidermal growth factor receptor 2 (HER-2), angiogenesis, and other tyrosine kinases also come with unexpected cardiac side effects, including heart failure, hypertension, arterial thrombosis, and arrhythmias, and have mechanisms that are unlike those of classic chemotherapeutic agents. In addition, it is challenging to address some problems, as the existing guidelines need to be more specific, and further large-scale clinical trials and experimental studies are required to confirm the benefit of administering cardioprotective agents to patients treated with targeted therapies. Therefore, an improved understanding of cardiotoxicity becomes increasingly important to minimize the pernicious effects and maximize the beneficial effects of targeted agents. METHODS: "Cardiotoxicity", "targeted drugs", "HER2", "trastuzumab", "angiogenesis inhibitor", "VEGF inhibitor" and "tyrosine kinase inhibitors" are used as keywords for article searches. RESULTS: In this article, we report several targeted therapies that induce cardiotoxicity and update knowledge of the clinical evidence, molecular mechanisms, and management measures.

U-shaped association between plasma sphingosine-1-phosphate levels and mortality in patients with chronic systolic heart failure: a prospective cohort study.

BACKGROUND: The endogenous lipid molecule sphingosine-1-phosphate (S1P) has received attention in the cardiovascular field due to its significant cardioprotective effects, as revealed in animal studies. The purpose of our study was to identify the distribution characteristics of S1P in systolic heart failure patients and the prognostic value of S1P for long-term prognosis. METHODS: We recruited 210 chronic systolic heart failure patients from June 2014 to December 2015. Meanwhile 54 healthy people in the same area were selected as controls. Plasma S1P was measured by liquid chromatography-tandem mass spectrometry. Patients were grouped according to the baseline S1P level quartiles, and restricted cubic spline plots described the association between S1P and all-cause death. Cox proportional hazard analysis was used to determine the relationship between category of S1P and all-cause death. RESULTS: Compared with the control group, the plasma S1P in chronic heart failure patients demonstrated a higher mean level (1.269 µmol/L vs 1.122 µmol/L, P = 0.006) and a larger standard deviation (0.441 vs 0.316, P = 0.022). Based on multivariable Cox regression with restricted cubic spline analysis, a non-linear and U-shaped association between S1P levels and the risk of all-cause death was observed. After a follow-up period of 31.7 ± 10.3 months, the second quartile (0.967-1.192 µml/L) with largely normal S1P levels had the lowest all-cause mortality and either an increase (adjusted HR = 2.368, 95%CI 1.006-5.572, P = 0.048) or a decrease (adjusted HR = 0.041, 95%CI 0.002-0.808, P = 0.036) predicted a worse prognosis. The survival curves showed that patients in the lowest quartile and highest quartile were at a higher risk of death. CONCLUSIONS: Plasma S1P levels in systolic heart failure patients are related to the long-term all-cause mortality with a U-shaped correlation. TRIAL REGISTRATION: CHiCTR, ChiCTR-ONC-14004463. Registered 20 March 2014.

RNA sequencing and anthocyanin synthesis-related genes expression analyses in white-fruited Vaccinium uliginosum.

BACKGROUND: Vaccinium uliginosum (Ericaceae) is an important wild berry having high economic value. The white-fruited V. uliginosum variety found in the wild lacks anthocyanin and bears silvery white fruits. Hence, it is a good resource for investigating the mechanism of fruit color development. This study aimed to verify the differences in the expression levels of some structural genes and transcription factors affecting the anthocyanin biosynthesis pathway by conducting high-throughput transcriptome sequencing and real-time PCR analysis by using the ripening fruits of V. uliginosum and the white-fruited variety. RESULTS: We annotated 42,837 unigenes. Of the 325 differentially expressed genes, 41 were up-regulated and 284 were down-regulated. Further, 11 structural genes of the flavonoid pathway were up-regulated, whereas two were down-regulated. Of the seven genes encoding transcription factors, five were up-regulated and two were down-regulated. The structural genes VuCHS, VuF3'H, VuFHT, VuDFR, VuANS, VuANR, and VuUFGT and the transcription factors VubHLH92, VuMYB6, VuMYBPA1, VuMYB11, and VuMYB12 were significantly down-regulated. However, the expression of only VuMYB6 and VuMYBPA1 rapidly increased during the last two stages of V. uliginosum when the fruit was ripening, consistent with anthocyanin accumulation. CONCLUSIONS: VuMYB6 was annotated as MYB1 by the BLAST tool. Thus, the white fruit color in the V. uliginosum variant can be attributed to the down-regulation of transcription factors VuMYB1 and VuMYBPA1, which leads to the down-regulation of structural genes associated with the anthocyanin synthesis pathway.

Correlations between MTP and ROS Levels of Peripheral Blood Lymphocytes and Readmission in Patients with Chronic Heart Failure.

BACKGROUND: Peripheral blood lymphocytes exhibit changes that parallel those in failing cardiomyocytes. We hypothesised that mitochondrial transmembrane potential (MTP) and reactive oxygen species (ROS) levels of lymphocytes are associated with serum NT-proBNP and short-term prognosis in patients with chronic heart failure (CHF). METHODS: Fifty-four CHF patients and 30 controls were enrolled in this prospective study. Mitochondrial transmembrane potential and ROS levels of lymphocytes were evaluated by flow cytometry and reported as the JC-1 fluorescence ratio and DCF fluorescence intensity, respectively. Serum NT-proBNP levels and biochemical parameters were also examined. All the participants received follow-up to evaluate clinical end-points after eight months. RESULTS: Chronic heart failure patients had higher levels of DCF fluorescence intensity of lymphocytes and serum NT-proBNP, as well as lower levels of JC-1 fluorescence ratios compared with those of controls (all P<0.05). A closer relationship was found between Lg(DCF fluorescence intensity of lymphocytes) or JC-1 fluorescence ratio of lymphocytes and Lg(NT-proBNP) (both P<0.05) in CHF patients. During the eight-month follow-up period, 14 CHF patients (25.9%) were readmitted for severe HF, but none died. A logistic regression analysis showed that both ROS level and MTP of the lymphocytes were independent predictors (B=7.03, P=0.006; B= - 0.32, P=0.029, respectively) of readmission of CHF patients. CONCLUSIONS: In CHF patients at low risk, MTP and ROS levels of the lymphocytes showed a significant change that is associated with serum NT-proBNP and patient readmission.

Apamin-Sensitive K+ Current Upregulation in Volume-Overload Heart Failure is Associated with the Decreased Interaction of CK2 with SK2.

Recent studies have shown that the sensitivity of apamin-sensitive K(+) current (I KAS, mediated by apamin-sensitive small conductance calcium-activated potassium channels subunits) to intracellular Ca(2+) is increased in heart failure (HF), leading to I KAS upregulation, action potential duration shortening, early after depolarization, and recurrent spontaneous ventricular fibrillation. We hypothesized that casein kinase 2 (CK2) interacted with small conductance calcium-activated potassium channels (SK) is decreased in HF, and protein phosphatase 2A (PP2A) is increased on the opposite, upregulating the sensitivity of I KAS to intracellular Ca(2+) in HF. Rat model of volume-overload HF was established by an abdominal arteriovenous fistula procedure. The expression of SK channels, PP2A and CK2 was detected by Western blot analysis. Interaction and colocalization of CK2 with SK channel were detected by co-immunoprecipitation analysis and double immunofluorescence staining. In HF rat left ventricle, SK3 was increased by 100 % (P < 0.05), and SK2 was not significantly changed. PP2A protein was increased by 94.7 % in HF rats (P < 0.05), whereas the level of CK2 was almost unchanged. We found that CK2 colocalized with SK2 and SK3 in rat left ventricle. With anti-CK2α antibody, SK2 and SK3 were immunoprecipitated, the level of precipitated SK2 decreased by half, whereas precipitated SK3 was almost unchanged. In conclusion, the increased expression of total PP2A and decreased interaction of CK2 with SK2 may underlie enhanced sensitivity of I KAS to intracellular Ca(2+) in volume-overload HF rat.

Bisoprolol reversed small conductance calcium-activated potassium channel (SK) remodeling in a volume-overload rat model.

A recent study indicated that apamin-sensitive current (I KAS, mediated by apamin-sensitive small conductance calcium-activated potassium channels subunits) density significantly increased in heart failure and led to recurrent spontaneous ventricular fibrillation. While the underlying molecular correlation with SK channels is still undetermined, we hypothesized that they are remodeled in HF and that bisoprolol could reverse the remodeling. Volume-overload models were created on male Sprague-Dawley rats by producing an abdominal arteriovenous fistula. Confocal microscopy, quantitative real-time PCR, and western blot were performed to investigate the expression of SK channels and observe the influence of ß-blocker bisoprolol on the expression of SK channels I KAS, and the effect of bisoprolol on I KAS and the sensitivity of I KAS to [Ca(2+)]i at single isolated cells were also explored using whole-cell patch clamp techniques. SK channels were remodeled in HF rats, displaying the significant increase of SK1 and SK3 channel expression. After the treatment of HF rats with bisoprolol, the expression of SK1 and SK3 channels was significantly downregulated, and bisoprolol effectively downregulated I KAS density as well as the sensitivity of I KAS to [Ca(2+)]i. Our data indicated that the expression of SK1 and SK3 increased in HF. Bisoprolol effectively attenuated the change and downregulated I KAS density as well as the sensitivity of I KAS to [Ca(2+)]i.

Left bundle branch pacing in a ventricular pacing dependent patient with heart failure: A case report.

BACKGROUND: Left bundle branch pacing (LBBP) is a physiological pacing method that has emerged in recent years. It is an ideal choice for patients with complete left bundle branch block who are in need of cardiac resynchronization therapy (CRT). Moreover, LBBP is superior in maintaining physiological ventricular activation and can effectively improve heart function and quality of life in patients with pacemaker-induced cardiomyopathy. However, LBBP in pacing-dependent patients who already have cardiac dysfunction has not been well assessed. CASE SUMMARY: A 69-year-old male patient presented with symptoms of chest tightness, palpitation and systolic heart failure with New York Heart Association class III for 1 mo. The 12-lead electrocardiogram showed atrial fibrillation with third-degree atrioventricular block and ventricular premature beat. Holter revealed a right bundle branch block, atrial fibrillation with third-degree atrioventricular block, frequent multifocal ventricular premature beats, Ron-T and ventricular tachycardia. The echocardiogram documented an enlarged left atrium and left ventricle and a low left ventricular ejection fraction. Coronary angiography indicated a stenosis of 30% in the middle left anterior descending artery. Apparently, a CRT-D pacemaker was the best choice for this patient according to previous findings. However, the patient was worried about the financial burden. A single-chamber pacemaker with LBBP was selected, with the plan to take amiodarone and upgrade with dual-chamber implantable cardioverter-defibrillator or CRT-D at an appropriate time. During the follow-up at 3 mo after LBBP, the patient showed an improvement in cardiac function with slight improvement in echocardiography parameters, and the New York Heart Association functional class was maintained at I. Moreover, the patient no longer suffered from chest tightness and palpitation. Holter showed decreased ventricular arrhythmia of less than 5%. CONCLUSION: LBBP might be used in patients with heart failure and a high-degree atrioventricular block as an alternative to conventional CRT.

Impact of serum uric acid levels on the clinical prognosis and severity of coronary artery disease in patients with acute coronary syndrome and hypertension after percutaneous coronary intervention: a prospective cohort study.

OBJECTIVE: The impact of serum uric acid (sUA) levels on the clinical prognosis and severity of coronary artery disease in patients with acute coronary syndrome (ACS) and hypertension after percutaneous coronary intervention (PCI) is not fully clear. This study aimed to assess the association among sUA levels, clinical prognosis and severity of coronary artery disease in patients with ACS and hypertension after PCI. DESIGN: In this prospective cohort study, we followed-up patients with ACS and hypertension after PCI for 1 year to explore the risk factors for 1 year total major adverse cardiovascular events (MACEs) and multivessel coronary artery disease, the dose-effect relationship among sUA levels, MACEs and severity of coronary artery disease and correlation between sUA levels and severity of coronary artery disease (Gensini score). SETTING/PATIENTS: Several Chinese internists followed-up 422 patients who were diagnosed with ACS and hypertension after PCI in a large tertiary hospital of Qingdao during the period from 1 June 2019 to 1 December 2019. OUTCOME MEASURES: One-year follow-up MACEs results and coronary angiography results. RESULTS: In the coronary angiography results, multivessel coronary artery disease (28.5% vs 21.4%, p=0.006) and non-culprit lesion vascular occlusion (11.7% vs 5.3%, p=0.042) were more common in the hyperuricaemia group, and the Gensini score (26.69±13.46 vs 17.66±10.57, p<0.001) was also higher. In the results of 1-year MACEs, the incidence of all-cause mortality (3.5% vs 2.5%, p=0.037), PCI or coronary artery bypass grafting therapy due to myocardial infarction or angina pectoris (15.1% vs 7.6%, p=0.027), medication conservative therapy in hospital due to myocardial infarction or angina pectoris (12.9% vs 6.7%, p=0.041) and total MACEs (31.8% vs 16.9%, p=0.001) were higher in patients with hyperuricaemia. Univariate and multivariate logistic regression analysis models showed that hyperuricaemia was still an independent risk factor for total MACEs within 1 year (OR=2.618, 95% CI 1.656 to 4.139, p<0.001; OR=1.920, 95% CI 1.158 to 3.183, p=0.011, respectively) and multivessel coronary artery disease (OR=2.140, 95% CI 1.371 to 3.342, p=0.001; OR=1.688, 95% CI 1.051 to 2.710, p=0.030, respectively) after adjusting for confounding factors. The severity of coronary artery disease (non-culprit lesion vascular occlusion (4.7% vs 8.4% vs 9.6% vs 16.2%, p=0.041); multivessel coronary artery disease (17.9% vs 22.4% vs 29.8% vs 35.2%, p=0.022); Gensini score (16.96±10.35 vs 19.31±10.63 vs 26.12±11.48 vs 33.33±14.01, p<0.001)) and the incidence of total MACEs (13.2% vs 14.2% vs 34.6% vs 41%, p<0.001) increased significantly with the sUA levels increasing. Further, the Gensini score was positively correlated with uric acid levels (r=0.515, p<0.001). CONCLUSIONS: Hyperuricaemia is an independent risk factor for 1-year total MACEs and multivessel coronary artery disease in patients with ACS and hypertension after PCI.

Glucose control independent mechanisms involved in the cardiovascular benefits of glucagon-like peptide-1 receptor agonists.

Patients with type 2 diabetes mellitus (T2DM) face a high risk of developing cardiovascular diseases. However, traditional hypoglycemic drugs have limited effects on macrovascular complications of the disease. Clinical trials have confirmed that glucagon-like peptide-1 receptor agonists (GLP-1RAs), in addition to their capability of controlling blood glucose, can also decrease the risk of cardiovascular events in T2DM. The protective influence of GLP-1RAs on coronary heart disease and heart failure has been proven in recent clinical studies. Therefore, the international guidelines recommend GLP-1 RAs as the first-line therapy for patients with T2DM having cardiovascular disease. Notwithstanding the widespread clinical application of GLP-1RAs, the underlying mechanisms through which GLP-1RAs exert cardiovascular benefits in patients with DM remain unclear. In this review, we systematically summarize the mechanisms of action of GLP-1RAs responsible for producing favorable effects on the cardiovascular system, beyond their capability of blood glucose regulation. GLP-1RA-mediated cardiovascular protection is manifested through multiple mechanisms, including oxidative stress, inflammation, endoplasmic reticulum stress, apoptosis, and vascular/cardiac remodeling. The understanding of these mechanisms will facilitate the development of new and promising therapeutic modalities for T2DM. Furthermore, we have identified several promising targets for future research in this area.

Resection of a giant sternal chondrosarcoma and chest wall reconstruction: a case report.

Chondrosarcomas are common bone carcinomas; however, they are uncommon in the sternum, and giant sternal tumors have rarely been reported in advanced-age patients. This study aimed to describe the clinical presentation, method of preoperative planning and surgery, and perioperative management of a giant sternal chondrosarcoma in an advanced-age patient. We describe the case of an 80-year-old woman who presented with a rare giant sternal chondrosarcoma. The patient's symptoms included significant painful swelling and limited activity. The mass was firm and fixed, and the boundary was unclear. We first performed a simulated surgery on a three-dimensional (3D) model using the mimics system for preoperative planning. An extensive resection of the tumor was then performed. Due to the financial status of the patient, the huge chest wall defect was reconstructed with simple ordinary metal locking bone plates and polyester surgical mesh, and good results were achieved. The patient was discharged without any complications 12 days after surgery. The postoperative pathological examination confirmed the diagnosis of primary grade I-II chondrosarcoma. At the 12-month follow-up examination, the patient was completely rehabilitated, and there was no evidence of recurrence. Giant, low-grade sternal chondrosarcoma is an extremely rare disease in elderly women. 3D modeling and simulated surgery are effective approaches for the preoperative planning of surgery. Postoperative ventilators, antibiotics, and nutritional support are also necessary. Using our reconstructive techniques, chest wall reconstruction with polyester patches and orthopedic steel plates could be a safe, reliable and affordable surgery procedure. It may be an appropriate option for similar cases.

Effects of Guanfu total base on Bcl-2 and Bax expression and correlation with atrial fibrillation.

OBJECTIVE: This study sought to investigate the effects of Guanfu total base on Bcl-2 and Bax expression and the correlation of Bcl-2 and Bax expression with atrial fibrillation. METHODS: Twenty-four male Sprague-Dawley rats were randomly divided into control, model, and treatment groups (n = 8 each). A combined intravenous injection of CaCl2 (10 mg/mL) and acetylcholine (Ach; 66 µg/mL) was administered to the model and treatment groups for 7 consecutive days to induce atrial fibrillation. After 3 days, the treatment group was administered orally with Aconitum coreanum. Controls received saline for 7 consecutive days. Atrial fibrillation duration was monitored by using an electrocardiogram. Immunohistochemical analysis was used to measure the expression and distribution of Bcl-2 and Bax in the atrial myocardial tissues, RT-PCR was used to measure the Bcl-2 and Bax mRNA expression, and western blot was used to measure Bcl-2 and Bax expression in the atrial myocardial tissue. RESULTS: The model group showed prolonged atrial fibrillation, but this was absent in the control and treatment groups, indicating that treatment with A. coreanum effectively reduced atrial fibrillation duration. Immunohistochemical analysis showed that Bcl-2 expression in the atrial muscle tissue was significantly lower, but Bax expression was significantly higher in the model group compared to that in the control group. After treatment, Bcl-2 expression increased and Bax expression decreased (P < 0.01) in the treatment group compared to those in the model group. RT-PCR and western blot presented the same trends. CONCLUSION: Bcl-2 and Bax expression was correlated with atrial fibrillation. Guanfu total base was effective in treating atrial fibrillation, upregulating Bcl-2 expression, and downregulating Bax expression.