Atrioventricular re-entrant tachycardia and atrioventricular node re-entrant tachycardia in a patient with cancer under chemotherapy: a case report and literature review.

Cardio-oncology is a new field of interest in cardiology focusing on the detection and treatment of cardiovascular diseases, such as arrhythmias, myocarditis, and heart failure, as side-effects of chemotherapy and radiotherapy. The association between chemotherapeutic agents and arrhythmias has previously been established. Atrial tachyarrhythmias, particularly atrial fibrillation, are most common, but ventricular arrhythmias, including those related to treatment-induced QT prolongation, and bradyarrhythmias can also occur. However, the association between chemotherapeutic agents and atrioventricular re-entrant tachycardia (AVRT)/atrioventricular node re-entrant tachycardia (AVNRT) remains poorly understood. Here, we report a patient with new-onset AVRT/AVNRT and lung cancer who underwent chemotherapy. We considered that chemotherapy or cancer itself may have been a trigger for the initiation of paroxysmal AVRT/AVNRT, and that radiofrequency catheter ablation was effective in treating this type of tachycardia. Here, possible mechanisms and potential genes (mostly ion channels) involved in AVRT/AVNRT are summarized and the mechanisms underlying the possible regulatory patterns of cancer cells and chemotherapy on ion channels are reviewed. Finally, we considered that ion channel abnormalities may link cancer or chemotherapy to the onset of AVRT/AVNRT. The aim of the present study was to highlight the association between chemotherapeutic agents and AVRT/AVNRT and to provide new insights for future research. Understanding the intermediate mechanisms between chemotherapeutic agents and AVRT/AVNRT may be beneficial in preventing chemotherapy-evoked AVRT/AVNRT (and/or other arrhythmias) in future.

Unleashing the Potential of Nrf2: A Novel Therapeutic Target for Pulmonary Vascular Remodeling.

Pulmonary vascular remodeling, characterized by the thickening of all three layers of the blood vessel wall, plays a central role in the pathogenesis of pulmonary hypertension (PH). Despite the approval of several drugs for PH treatment, their long-term therapeutic effect remains unsatisfactory, as they mainly focus on vasodilation rather than addressing vascular remodeling. Therefore, there is an urgent need for novel therapeutic targets in the treatment of PH. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a vital transcription factor that regulates endogenous antioxidant defense and emerges as a novel regulator of pulmonary vascular remodeling. Growing evidence has suggested an involvement of Nrf2 and its downstream transcriptional target in the process of pulmonary vascular remodeling. Pharmacologically targeting Nrf2 has demonstrated beneficial effects in various diseases, and several Nrf2 inducers are currently undergoing clinical trials. However, the exact potential and mechanism of Nrf2 as a therapeutic target in PH remain unknown. Thus, this review article aims to comprehensively explore the role and mechanism of Nrf2 in pulmonary vascular remodeling associated with PH. Additionally, we provide a summary of Nrf2 inducers that have shown therapeutic potential in addressing the underlying vascular remodeling processes in PH. Although Nrf2-related therapies hold great promise, further research is necessary before their clinical implementation can be fully realized.

Characteristics of Electrocardiogram Findings in Fulminant Myocarditis.

Fulminant myocarditis (FM) is an acute and severe form of myocarditis with rapid progression and poor clinical outcomes in the absence of acute or chronic coronary artery disease. Electrocardiogram (ECG) abnormalities can provide preliminary clues for diagnosis; however, there is a lack of systemic descriptions on ECG changes in FM populations. Thus, a retrospective analysis of 150 consecutive FM patients and 300 healthy controls was performed to determine the characteristic ECG findings in FM. All patients included had markedly abnormal ECG findings. Specifically, 83 (55.33%) patients had significantly lower voltage with remarkably decreased QRS amplitudes in all leads compared with healthy controls (p < 0.01), and 77 (51.33%) patients had a variety of arrhythmias with lethality ventricular tachycardia/ventricular fibrillation in 21 (14.00%) patients and third-degree atrioventricular block in 21 (14.00%) patients, whereas sinus tachycardia was only found in 43 (28.67%) patients with the median heart rate (HR; 88.00 bpm, IQR: 76.00-113.50) higher than that of controls (73.00 bpm, IQR: 68.00-80.00) (p = 0.000). Conduction and repolarization abnormalities were common in patients. A longer QTc interval (452.00 ms, IQR: 419.00-489.50) and QRS duration (94.00 ms, IQR: 84.00-119.00) were observed in patients compared to controls (QTc interval = 399.00 ms, IQR: 386.00-414.00; QRS duration = 90.00 ms, IQR: 86.00-98.00) (p < 0.05). Additionally, HR > 86.50 bpm, QTc > 431.50 ms, and RV5 + SV1 < 1.715 mV can be used to predict FM. Thus, marked and severe ECG abnormalities provide preliminary clues for the diagnosis of FM.

Potential Application of Pulsed Field Ablation in Ventricular Arrhythmias.

Pulsed field ablation (PFA) is a new ablative method for the therapy of arrhythmia. Recent preclinical and clinical studies have already demonstrated the feasibility and safety of PFA for the treatment of atrial fibrillation (AF). However, the application of PFA may not be limited to the above fields. There are some data on the application of PFA on ventricular arrhythmias (VAs), such as ventricular fibrillation (VF) and ventricular tachycardia (VT). Further, a case report about PFA has been published recently, in which PFA was successfully applied to the ablation of premature ventricular contractions (PVCs) from the right ventricular outflow tract. Thus, we aimed to review recent research findings of PFA in ventricular ablation and evaluate the possibility of its application in VAs.

Insights Into Platelet-Derived MicroRNAs in Cardiovascular and Oncologic Diseases: Potential Predictor and Therapeutic Target.

Non-communicable diseases (NCDs), represented by cardiovascular diseases and cancer, have been the leading cause of death globally. Improvements in mortality from cardiovascular (CV) diseases (decrease of 14%/100,000, United States) or cancers (increase 7.5%/100,000, United States) seem unsatisfactory during the past two decades, and so the search for innovative and accurate biomarkers of early diagnosis and prevention, and novel treatment strategies is a valuable clinical and economic endeavor. Both tumors and cardiovascular system are rich in angiological systems that maintain material exchange, signal transduction and distant regulation. This pattern determines that they are strongly influenced by circulating substances, such as glycolipid metabolism, inflammatory homeostasis and cyclic non-coding RNA and so forth. Platelets, a group of small anucleated cells, inherit many mature proteins, mRNAs, and non-coding RNAs from their parent megakaryocytes during gradual formation and manifest important roles in inflammation, angiogenesis, atherosclerosis, stroke, myocardial infarction, diabetes, cancer, and many other diseases apart from its classical function in hemostasis. MicroRNAs (miRNAs) are a class of non-coding RNAs containing ∼22 nucleotides that participate in many key cellular processes by pairing with mRNAs at partially complementary binding sites for post-transcriptional regulation of gene expression. Platelets contain fully functional miRNA processors in their microvesicles and are able to transport their miRNAs to neighboring cells and regulate their gene expression. Therefore, the importance of platelet-derived miRNAs for the human health is of increasing interest. Here, we will elaborate systematically the roles of platelet-derived miRNAs in cardiovascular disease and cancer in the hope of providing clinicians with new ideas for early diagnosis and therapeutic strategies.

NLRX1 knockout aggravates lipopolysaccharide (LPS)-induced heart injury and attenuates the anti-LPS cardioprotective effect of CYP2J2/11,12-EET by enhancing activation of NF-κB and NLRP3 inflammasome.

NLRX1 weakens lipopolysaccharide (LPS)-induced NF-κB activation on immune cells. Cytochrome P450 epoxygenase 2J2 (CYP2J2) attenuates LPS-induced cardiac injury by inhibiting NF-κB activation. However, it is still unclear whether NLRX1 could reduce LPS-induced heart damage and whether it is involved in the anti-LPS cardioprotective effect of CYP2J2. In this study, we found that NLRX1 knockout further exacerbated LPS-induced heart injury and up-regulated the proinflammatory cytokines in serum and heart tissue, and weakened the inhibitory effect of CYP2J2 on the harmful effects caused by LPS. We also found that LPS treatment induced ubiquitination of NLRX1 and promoted its binding to IKKα/ß in myocardial tissue, which should theoretically inhibit NF-κB activation. However, LPS eventually leads to activation of NF-κB and NLRP3 inflammasome. Under the action of LPS, CYP2J2 further promoted the ubiquitination of NLRX1 and its binding to IKKα/ß, impaired NF-κB activation and NLRP3 inflammasome activation. NLRX1 knockout notably aggravated LPS-induced NF-κB activation and NLRP3 inflammasome activation, and attenuated the inhibitory effects of CYP2J2 on NF-κB signal and NLRP3 inflammasome. More, CYP2J2 reduced LPS-induced reactive oxygen species (ROS) production and mitochondrial depolarization in heart cells, thereby inhibiting NLRP3 inflammasome activation. NLRX1 knockdown aggravated mitochondrial depolarization induced by LPS and weakened the protective effect of CYP2J2 on mitochondrial potential, although it had no significant effect on reactive oxygen species production. Together, these findings demonstrated that NLRX1 knockout aggravated LPS-induced heart injury and weakened the anti-LPS cardioprotective effect of CYP2J2 by enhancing activation of NF-κB and NLRP3 inflammasome.

Effect of green tea consumption on blood lipids: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Strong epidemiologic evidence indicates that green tea intake is protective against hyperlipidemia; however, randomized controlled studies have presented varying results. In the present study, we aimed to conduct a literature review and meta-analysis to assess the effect of green tea on blood lipids. METHODS: PubMed, Embase, and the Cochrane Library were electronically explored from inception to September 2019 for all relevant studies. Random effect models were used to estimate blood lipid changes between green tea supplementation and control groups by evaluating the weighted mean differences (WMD) with 95% confidence intervals (CIs). The risk of bias for study was assessed using the Cochrane tool. Publication bias was evaluated using funnel plots and Egger's tests. RESULTS: Thirty-one trials with a total of 3321 subjects were included in the meta-analysis. In general, green tea intake significantly lowered the total cholesterol (TC); WMD: - 4.66 mg/dL; 95% CI: - 6.36, - 2.96 mg/dL; P < 0.0001) and low-density lipoprotein (LDL) cholesterol (WMD:- 4.55 mg/dL; 95% CI: - 6.31, - 2.80 mg/dL; P < 0.0001) levels compared with those in the control. Green tea consumption did not affect high-density lipoprotein (HDL) cholesterol; however, it reduced the triglycerides compared with that in the control (WMD: - 3.77 mg/dL; 95% CI: - 8.90, 1.37 mg/dL; P = 0.15). In addition, significant publication bias from funnel plots or Egger's tests was not evident. CONCLUSIONS: Collectively, consumption of green tea lowers LDL cholesterol and TC, but not HDL cholesterol or triglycerides in both normal weight subjects and those who were overweight/obese; however, additional well-designed studies that include more diverse populations and longer duration are warranted.

PPARα ligand, AVE8134, and cyclooxygenase inhibitor therapy synergistically suppress lung cancer growth and metastasis.

BACKGROUND: Lung cancer (LC) is one of the leading causes of death worldwide, which highlights the urgent need for better therapies. Peroxisome proliferator-activated nuclear receptor alpha (PPARα), known as a key nuclear transcription factor involved in glucose and lipid metabolism, has been also implicated in endothelial proliferation and angiogenesis. However, the effects and potential mechanisms of the novel PPARα ligand, AVE8134, on LC growth and progression remain unclear. METHODS: A subcutaneous tumour was established in mice by injecting TC-1 lung tumour cells (~ 1 × 106 cells) into their shaved left flank. These mice were treated with three different PPARα ligands: AVE8134 (0.025% in drinking water), Wyeth-14,643 (0.025%), or Bezafibrate (0.3%). Tumour sizes and metastasis between treated and untreated mice were then compared by morphology and histology, and the metabolites of arachidonic acid (AA) were detected by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Inhibition of either Cyp2c44 expression by genetic disruption or cyclooxygenase (COX) activity by indomethacin was used to test the mechanisms by which AVE8134 affects tumour growth. RESULTS: The pharmacodynamics effects of AVE8134, Wyeth-14,643, and Bezafibrate on lipids control were similar. However, their effects on tumour suppression were different. Eicosanoid profile analysis showed that all PPARα ligands reduced the production of AA-derived epoxyeicosatrienoic acids (EETs) and increased the hydroxyl product, 11-hydroxyeicosatetraenoic acids (11-HETE). Moreover, increased 11-HETE promoted endothelial proliferation, angiogenesis, and subsequent tumour deterioration in a dose-dependent manner possibly via activating the AKT/extracellular signal-regulated kinase (ERK) pathway. The increased 11-HETE partly neutralized the benefits provided by the Cyp2c44-EETs system inhibited by PPARα ligands in tumour-bearing mice. AVE8134 treatment worsened the tumour phenotype in Cyp2c44 knockout mice, indicating that AVE8134 has contradictory effects on tumour growth. The COX inhibitor indomethacin strengthened the inhibitory actions of AVE8134 on tumour growth and metastasis by inhibiting the 11-HETE production in vivo and in vitro. CONCLUSION: In this study, we found that the degrees of inhibition on LC growth and metastasis by PPARα ligands depended on their bidirectional regulation on EETs and 11-HETE. Considering their safety and efficacy, the novel PPARα ligand, AVE8134, is a potentially ideal anti-angiogenesis drug for cancer treatment when jointly applied with the COX inhibitor indomethacin.

The immune-metabolic regulatory roles of epoxyeicosatrienoic acids on macrophages phenotypic plasticity in obesity-related insulin resistance.

Macrophages in adipose tissue are associated with obesity-induced low-grade inflammation, which contributed to insulin resistance and the related metabolic diseases. Macrophages display phenotypic plasticity, and polarize under the condition of obesity. Epoxyeicosatrienoic Acids (EETs) are lipid mediators that are involved in the regulation of inflammatory cascades and glucose homeostasis. In this mini-review, we briefly summarize the macrophages recruitment, infiltration and polarization in obese mice, and also discuss the immune-metabolic regulatory role of EETs in this process (See Fig. 1).

P2y12 Receptor Promotes Pressure Overload-Induced Cardiac Remodeling via Platelet-Driven Inflammation in Mice.

Inflammation plays a critical role in adverse cardiac remodeling and heart failure. The P2y12 receptor is one of the predominant activating receptors for platelets, thus initiating inflammatory responses under various diseases. In this study, we investigated the functional significance of P2y12-mediated platelet activation in pressure overload-induced cardiac remodeling. Notably, P2y12 knockout (P2y12-/-) mice exhibited suppressed transverse aortic constriction-induced changes in cardiac hypertrophy, collagen synthesis, inflammatory cell recruitment, and cardiac dysfunction. Activated platelets and platelet-leukocyte aggregates were markedly downregulated in P2y12 knockout mice compared with wild-type counterparts after transverse aortic constriction. Moreover, bone marrow chimera experiments revealed that wild-type recipients of P2y12 knockout bone marrow markedly improved cardiac function and attenuated cardiac remodeling, reversed by wild-type platelets reinjection. Platelet depletion and P-selectin inhibition mimicked these protective effects by limiting the interaction between activated platelets and leukocytes. Furthermore, activated wild-type platelets directly induced cardiomyocyte hypertrophy and collagen synthesis via α-granule exocytosis, vanished in P2y12 knockout platelets or those administered anti-NSF (N-ethlymalimide-sensitive factor) antibodies. The results suggest that P2y12-mediated platelet activation promotes cardiac remodeling by triggering a series of inflammatory changes and interacting with leukocytes and endotheliocytes.

CYP2J2 and Its Metabolites EETs Attenuate Insulin Resistance via Regulating Macrophage Polarization in Adipose Tissue.

Macrophages in adipose tissue are associated with obesity-induced low-grade inflammation, which contributed to insulin resistance and the related metabolic diseases. Previous studies demonstrated the beneficial effects of epoxyeicosatrienoic acids (EETs) on metabolic disorders and inflammation. Here we investigated the effects of CYP2J2-EETs-sEH metabolic pathway on insulin resistance in mice and the potential mechanisms. High fat diet (HFD)-induced obesity caused metabolic dysfunction with more weight gain, elevated glucose and lipids levels, impaired glucose tolerance and insulin sensitivity, while increase in EETs level by rAAV-mediated CYP2J2 overexpression, administration of sEH inhibit TUPS or EETs infusion significantly attenuated these metabolic disorders. EETs inhibited macrophages recruitment to adipose tissue and their switch to classically activated macrophage (M1) phenotype, while preserved the alternatively activated macrophage (M2) phenotype, which was accompanied by substantially reduced adipose tissue and systemic inflammation and insulin resistance. In vitro studies further clarified the effects of EETs on macrophage infiltration and polarization, and microarray assays showed that cAMP-EPAC signaling pathway was involved in these processes. Collectively, these results described key beneficial immune-regulatory properties and metabolic regulation of CYP2J2-EETs-sEH metabolic pathway, and indicated therapeutic potential of EETs in obesity-induced insulin resistance and related inflammatory diseases through modulating macrophage polarization targeting cAMP-EPAC signaling pathway.

CYP2J2 overexpression ameliorates hyperlipidemia via increased fatty acid oxidation mediated by the AMPK pathway.

OBJECTIVE: The study aims to investigate the effect of cytochrome P450 2J2 (CYP2J2) overexpression on hyperlipidemia in mice and further to explore its effect on fatty acid oxidation in vivo and in vitro. METHODS: The effects and mechanisms of endothelial-specific CYP2J2 transgene (Tie2-CYP2J2-Tr) on lipid and fatty acid metabolism were investigated in high-fat diet (HFD) -treated mice. HepG2, LO2 cells, and HUVECs were exposed to 0.4 mM free fatty acid (FFA) for 24 h and used as a model to investigate the roles of CYP2J2 overexpression and epoxyeicosatrienoic acids (EETs) on fatty acid ß-oxidation in vitro. RESULTS: Tie2-CYP2J2-Tr mice had significantly lower plasma and liver triglycerides, lower liver cholesterol and fatty acids, and reduced HFD-induced lipid accumulation. CYP2J2 overexpression resulted in activation of the hepatic and endothelial AMPKα, increased ACC phosphorylation, and increased expression of CPT-1 and PPARα, which were all reduced by HFD treatment. In FFA-treated HepG2, LO2, and HUVECs, both CYP2J2 overexpression and EETs significantly decreased lipid accumulation and increased fatty acid oxidation via activating the AMPK and PPARα pathways. CONCLUSIONS: Endothelial-specific CYP2J2 overexpression alleviates HFD-induced hyperlipidemia in vivo. CYP2J2 ameliorates FFA-induced dyslipidemia via increased fatty acid oxidation mediated by the AMPK and PPARα pathways.

Epoxyeicosatrienoic acids regulate macrophage polarization and prevent LPS-induced cardiac dysfunction.

Macrophages, owning tremendous phenotypic plasticity and diverse functions, were becoming the target cells in various inflammatory, metabolic and immune diseases. Cytochrome P450 epoxygenase 2J2 (CYP2J2) metabolizes arachidonic acid to form epoxyeicosatrienoic acids (EETs), which possess various beneficial effects on cardiovascular system. In the present study, we evaluated the effects of EETs treatment on macrophage polarization and recombinant adeno-associated virus (rAAV)-mediated CYP2J2 expression on lipopolysaccharide (LPS)-induced cardiac dysfunction, and sought to investigate the underlying mechanisms. In vitro studies showed that EETs (1µmol/L) significantly inhibited LPS-induced M1 macrophage polarization and diminished the proinflammatory cytokines at transcriptional and post-transcriptional level; meanwhile it preserved M2 macrophage related molecules expression and upregulated anti-inflammatory cytokine IL-10. Furthermore, EETs down-regulated NF-κB activation and up-regulated peroxisome proliferator-activated receptors (PPARα/γ) and heme oxygenase 1 (HO-1) expression, which play important roles in regulating M1 and M2 polarization. In addition, LPS treatment in mice induced cardiac dysfunction, heart tissue damage and infiltration of M1 macrophages, as well as the increase of inflammatory cytokines in serum and heart tissue, but rAAV-mediated CYP2J2 expression increased EETs generation in heart and significantly attenuated the LPS-induced harmful effects, which mechanisms were similar as the in vitro study. Taken together, the results indicate that CYP2J2/EETs regulates macrophage polarization by attenuating NF-κB signaling pathway via PPARα/γ and HO-1 activation and its potential use in treatment of inflammatory diseases.