PD-1 Inhibitor-Induced Thyrotoxicosis Associated with Coronary Artery Spasm and Ventricular Tachycardia.

Programmed cell death protein 1 (PD-1) inhibitors open a new era of cancer immunotherapy, but they are associated with immune-related adverse events (irAEs) involving multiple endocrine organs of which thyroid dysfunction is the most common An uncommon condition of coronary artery spasm and ventricular tachycardia associated with thyrotoxicosis, induced by a PD-1 inhibitor, is discussed in this case. A 60-year-old male patient with a 1-week history of chest tightness and palpitation at rest was referred to us in July 2021. No obvious abnormalities were noted on physical examination and electrocardiography. He was being treated with a PD-1 inhibitor (camrelizumab, 200 mg) for lung metastasis of liver cancer; treatment stopped because he was found to have hyperthyroidism. Holter recorded intermittent STsegment arch back raised 0.5-14 mm upward lasting for 1-5 min, accompanied by ventricular tachycardia. He was treated with antivasospasm drugs (isosorbide mononitrate and diltiazem). Thyroid function was reexamined and revealed elevated FT3 and FT4 levels, decreased TSH levels, and negative thyroid-associated antibodies. After antivasospasm treatment and iodine taboo diet, his symptoms were relieved, and ST-segment elevation and ventricular tachycardia were disappeared. This case adds to our knowledge of the association between coronary artery spasms and thyrotoxicosis, which is an irAE induced by a PD-1 inhibitor. Patients treated with PD-1 inhibitors need regular follow-ups for cardiac complications, especially those with a history of heart disease.

Reduction of Activin Receptor-Like Kinase 4 Expression Ameliorates Myocardial Ischemia/Reperfusion Injury through Inhibiting TGFß Signaling Pathway.

The activation of activin receptor-like kinase 4 (ALK4) signaling plays a pivotal role in the pressure-overloaded heart, and haplodeficiency of ALK4 can alleviate cardiac fibrosis secondary to myocardial infarction and preserve cardiac function through partially inactivating the Smad3/4 pathway. However, whether transforming growth factor (TGF) ß signaling is involved in the beneficial effects of ALK4 knockdown on the ischemic heart is still unclear. This study was undertaken to investigate the change in the TGFß signaling after ALK4 knockdown in vivo and in vitro. Forty C57BL/6J mice were randomized into ALK4+/- ischemia/reperfusion (I/R) group (ALK4+/-+I/R, n = 10), ALK4+/- sham group (ALK4+/-+sham, n = 10), wild-type sham group (WT+sham, n = 10), and WT I/R group (WT+I/R, n = 10). Heart histology and the levels of cytokines related to antioxidant and inflammation, as well as protein and mRNA expressions of molecules associated with TGFß pathway, were examined in different groups. Our results showed that the reduction of ALK4 expression ameliorated myocardial I/R injury through inhibiting TGFß signaling pathway. Our findings indicate that ALK4 may become a novel target for the therapy of myocardial I/R injury.

Rotundic Acid Regulates the Effects of Let-7f-5p on Caco2 Cell Proliferation.

BACKGROUND & OBJECTIVE: Nowadays, the interaction between natural products and microRNAs provides a promising field for exploring the chemopreventive agents for various cancers. As a member of microRNAs, the expression of let-7f-5p is universally downregulated in Colorectal Cancer (CRC). The present study aimed to uncover the function of let-7f-5p in the proliferation of human colon cancer cell line Caco2 and explored chemopreventive agents from natural resources that can prevent the development of CRC. METHODS: Herein, Caco2 cells were transfected with let-7f-5p mimic and inhibitor to manipulate let-7f-5p levels, and the expression of let-7f-5p was performed by RT-qPCR. Next, we determined how let-7f-5p regulates Caco2 cell proliferation by using MTT, wound-healing, cell cycle, and colony formation assays. Besides, to further understand the effect of let-7f-5p, we evaluated the protein level of AMER3 and SLC9A9 by using western blotting assays. RESULTS: The results showed a suppressive function of let-7f-5p on Caco2 cell proliferation and then put forward a triterpenoid (Rotundic Acid, RA) which significant antagonized the effect of cell proliferation, restitution after wounding, and colony formation caused by let-7f-5p. Moreover, the western blot results further indicated that the inhibitory effect of RA might be due to its suppressive role in let-7f-5p-targeted AMER3 and SLC9A9 regulation. CONCLUSION: Our validation study results confirmed that let-7f-5p was a potent tumor suppressor gene of Caco2 cell proliferation, and RA showed as a regulator of the effect of let-7f-5p on cell proliferation and then could be a potential chemopreventive agent for CRC treatment.

The proatherosclerotic function of indoleamine 2, 3-dioxygenase 1 in the developmental stage of atherosclerosis.

The discrepancy of indoleamine 2, 3-dioxygenase 1 (IDO1) function in atherosclerosis has been noted. Compared to the protective effect of IDO1 against established atherogenesis, the role of IDO1 in the developmental process of atherosclerosis is still unclear. Here, the expression patterns and activities of IDO1 and its isoenzyme tryptophan 2,3-dioxygenase (TDO) in aortas and blood samples of patients with atherosclerosis were investigated. IDO1 and TDO were colocalized with CD3-positive lymphocytes and CD68-positive macrophages in atherosclerotic lesions. The expression and activity of IDO1 and TDO increased with the grade of the histological classification in early atherosclerosis (grade I, II), but the increase did not continue in advanced atherosclerosis (grade III). Treatment of THP-1 macrophages (THP-M) with oxidized low-density lipoprotein (oxLDL) induced the expression of IDO1 via the PI3K/Akt/NF-κB pathway, indicating the potential function of IDO1 in foam cells. Before and after treatment with oxLDL on THP-M, IFN-γ-induced IDO1 exhibited different degrees of promotion on foaming, inflammatory factor production and cell apoptosis. Finally, we found that the IDO1 inhibitor 1-methyl-tryptophan could elevate the high-density lipoprotein cholesterol level in serum and reduce the area of the aortic atherosclerotic lesions in high-fat diet-fed ApoE-/- mice. Our study indicated that IDO1 played a complicated and unfixed role in the entire process of atherogenesis, despite the atheroprotective role in established atherosclerosis. IDO1 also had proatherosclerotic functions in the developmental stages of atherosclerosis. Modulation of IDO1 could be a good method for alleviating atherosclerosis.

Clinical Features of Post Cardiac Injury Syndrome Following Catheter Ablation of Arrhythmias: Systematic Review and Additional Cases.

BACKGROUND: Post cardiac injury syndrome (PCIS) is a troublesome but not uncommon complication following catheter ablation of arrhythmias. We aimed to study the clinical features of ablation-associated PCIS. METHODS: For this purpose, we conducted a computerised literature search that identified 19 published cases, and we additionally included another two new cases from our centres. Twenty-one (21) cases of PCIS following ablation were analysed. RESULTS: Among the 21 cases, PCIS most commonly occurred after atrial flutter/fibrillation (AFL/AF) ablation (71.4%), followed by atrioventricular re-entrant tachycardia (AVRT) ablation (9.5%), atrioventricular node (AVN) ablation (9.5%), atrioventricular nodal re-entrant tachycardia (AVNRT) ablation (4.8%) and ventricular tachycardia (VT) ablation (4.8%). Thirty-eight (38) per cent of PCIS was suggested to be secondary to cardiac perforation. Specific symptoms or features include pleuritic chest pain (76.2%), fever (76.2%), elevated markers of inflammation (76.2%), pericardial effusion (90.5%), pleural effusion (71.4%) and pulmonary infiltrates (28.6%). Interestingly, all the six cases with pulmonary infiltrates were following AFL/AF ablation (6/15, 40%). Serious clinical manifestations include cardiac tamponade, massive pleural effusion with hypoalbuminaemia and hyponatraemia, and massive pulmonary infiltrates with hypoxaemia. Notably, empiric antibiotic therapy was used in seven cases including five with pulmonary infiltrates but failed to work. No mortality occurred during a mean follow-up of 4.1±5.3 (1 to 19) months. CONCLUSIONS: Catheter ablation of AFL/AF was most commonly involved in ablation-associated PCIS. Pulmonary infiltrate is an important feature of PCIS following AFL/AF ablation and may be misdiagnosed as pneumonia. Although PCIS is troublesome and even dangerous, it does carry a benign prognosis.

MicroRNA-20a protects human aortic endothelial cells from Ox-LDL-induced inflammation through targeting TLR4 and TXNIP signaling.

MiR-20a has been previously reported to participate in the development of various human diseases. However, the role of miR-20a in the pathology of atherosclerosis remains elusive. The present study aimed to reveal the relationship between miR-20a expression and atherosclerosis using in vitro cell model. The expression level of miR-20a was detected in human aortic endothelial cells (HAECs) under Ox-LDL exposure. Meanwhile, the regulatory effects of miR-20a on predicted targets (TLR4 and TXNIP) were also determined. Moreover, the levels of key proteins and inflammatory mediators in TLR4 and NLRP3 signaling were detected to further confirm the regulatory effects of miR-20a. We found that miR-20a expression was repressed under Ox-LDL condition, and both TLR4 and TXNIP acted as regulatory targets of miR-20a. Overexpressed miR-20a reduced ROS generation under Ox-LDL treatment, and this effect was restored by forced expression of TLR4. Moreover, key molecules (including MyD88, TRIF, phosphorylated NF-κB (p65), NLRP3, ASC, cleaved caspase-1, ICAM-1 and IL-1ß) in TLR4 and NLRP3 signaling were significantly repressed under miR-20a overexpression. In conclusion, miR-20a could negatively regulate TLR4 and NLRP3 signaling to protect HAECs from inflammatory injuries, which provides a new insight into the inhibition of atherosclerotic development.

MicroRNA-145 alleviates high glucose-induced proliferation and migration of vascular smooth muscle cells through targeting ROCK1.

The excessive proliferation and migration of vascular smooth muscle cells (VSMCs) are important steps in atherosclerosis. The present study aimed to investigate whether the high glucose-induced changes of VSCMs are mediated by miR-145 and the potential molecular mechanism involved. We found that loss of miR-145 accompanied with increased proliferation and migration was observed in cultured human VSMCs exposed to high glucose. Exogenous overexpression of miR-145 effectively suppressed the high glucose-induced excessive proliferation and migration of VSMCs. Furthermore, we identified ROCK1 as a downstream target gene product of miR-145, and ROCK1 partially rescues the effects of miR-145 on high glucose-induced VSMC proliferation and migration. Taken together, our results suggested a protective role of miR-145 in high glucose-treated VSMCs by suppressing ROCK1, which might provide a therapeutic target for diabetic atherosclerosis.

MicroRNA-150 attenuates hypoxia-induced excessive proliferation and migration of pulmonary arterial smooth muscle cells through reducing HIF-1α expression.

Pulmonary arterial hypertension (PAH) is a progressive, fatal disease for which currently there is no curative therapy available. Pathologic changes in this disease involve excessive proliferation and migration of pulmonary artery smooth muscle cells (PASMCs). However, the underlying role of miR-150 in PASMCs remains elusive. Here in this study, miR-150 down-regulation was observed in hypoxia-treated PASMCs. Restoration of miR-150 attenuates hypoxia-treated PASMC proliferation and migration. Luciferase reporter assay showed that miR-150 directly regulated expression of HIF-1α. Moreover, overexpression of HIF-1α impaired the suppressive effect of miR-150 on the proliferative and migratory capacities of PASMCs. Altogether, our findings indicate that miR-150 may exert inhibitory effects on excessive proliferation and migration of PASMCs through down-regulation of HIF-1α, providing new insights into the potential mechanisms of human PAH.

Long -term results of transradial rotational atherectomy for heavily calcified coronary artery lesions.

OBJECTIVE: Percutaneous coronary intervention (PCI) for the heavily calcified coronary lesions remains a challenge, and the periprocedural complication rates of the transfemoral approach are high. This study was conducted to investigate the feasibility and long-term results of the transradial approach for rotational atherectomy (RA) prior to stent implantation via the transradial approach in patients with heavily calcified coronary artery lesions. METHODS: RA followed by stent implantation via the transradial approach was performed in 47 patients with severely calcified coronary artery lesions in this retrospectively case-control study. The success rate of the procedure and the 3-year follow-up (36±7.5 months) results were analyzed. RESULTS: RA with subsequent stent implantation or balloon angioplasty procedures were successfully performed in all cases. 6F guiding catheters were used in 45 cases, and 7F catheters were used in 2 patients. Rotablation was performed with a 1.25-mm burr in 29 cases, a 1.25-mm burr followed by a 1.5-mm burr in 17 patients, and a 1.75-mm burr in 1 patient. Percutaneous transluminal coronary angioplasty after RA was performed, followed by stent implantation in all 47 patients. Restenosis was found in 7 cases (7/38) at 13 months (13±3.6) and in 13 cases (13/28) at 36 months (36±7.5) after the procedure; 3 patients died during the 3-year follow-up. The post-procedure cumulative 3-year event-free survival rate was 78%. CONCLUSION: RA prior to stent implantation via the transradial approach is feasible and safe, the success rate is high, and long-term outcome is satisfactory in patients with heavily calcified lesions of the coronary artery.

Docosahexaenoic Acid Attenuates Doxorubicin-induced Cytotoxicity and Inflammation by Suppressing NF-κB/iNOS/NO Signaling Pathway Activation in H9C2 Cardiac Cells.

Doxorubicin (DOX) is a widely used antineoplastic agent for a variety of carcinomas. However, it is cardiotoxic and leads to cardiomyopathy. Previous studies have indicated that omega-3 polyunsaturated acids (ω-3 PUFAs) have therapeutic effects on dilated and diabetic cardiomyopathies. However, whether ω-3 PUFAs exert therapeutic effects on DOX-induced cardiomyopathy remains unclear. In this study, we explored the effect and underlying mechanisms of docosahexaenoic acid (DHA), an important type of ω-3 PUFA, on DOX-induced cardiotoxicity and inflammation. H9C2 cardiac cells were exposed to DOX (5 µM) and interfered with by DHA (10 µM) for 4 hours. The effect of DHA on H9C2 cell viability was measured by Cell Counting Kit-8 assay. The levels of mRNA and protein expression of inflammatory cytokines were determined by real-time polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. Reactive oxygen species and nitric oxide (NO) levels were determined by corresponding kits. The protein expression of key molecules in the nuclear factor-kappa B/inducible isoform of nitric oxide synthase/nitric oxide (NF-κB/iNOS/NO) signaling pathway was determined by western blotting. DOX-induced significant cytotoxicity and reactive oxygen species production in H9C2 cardiac cells. It also induced cardiac inflammation as evidenced by significantly increased expressions of inflammatory cytokines, including tumor necrosis factor-α, interleukin-6, interleukin-1ß, monocyte chemoattractant protein-1, and inducible isoform of NO synthase. However, DHA effectively attenuated DOX-induced cytotoxicity and inflammation. A further mechanistic study revealed that DHA suppressed DOX-induced activation of the NF-κB/iNOS/NO signaling pathway in H9C2 cells. Our results indicate that DHA may protect against DOX-induced cardiotoxicity by inhibiting NF-κB/iNOS/NO signaling pathway activation.

Digoxin Is Associated With Increased All-cause Mortality in Patients With Atrial Fibrillation Regardless of Concomitant Heart Failure: A Meta-analysis.

For decades, digoxin has been widely used to control ventricular rate in atrial fibrillation (AF). However, it remains controversial as to whether digoxin is associated with increased mortality in AF. In this study, we searched relevant studies that were published before December 1, 2014, in PubMed, EMBASE, and the Cochrane central databases. We systematically reviewed the references and performed a meta-analysis of 8 carefully selected studies with 302,738 patients who were included for the final analysis. It was shown that digoxin use was associated with increased risk of all-cause mortality in AF overall [hazard ratio (HR) = 1.375, 95% confidence intervals (CI), 1.201-1.574, P = 0.0001]. Subgroup analysis further revealed that digoxin was associated with increased all-cause mortality in patients with AF, which was complicated by heart failure (HF) (HR = 1.201, CI, 1.074- 1.344, P = 0.001), and in those subjects without HF (HR = 1.172, CI, 1.148-1.198, P = 0.0001). Sensitivity analyses found results to be robust. Our findings indicated that digoxin use was associated with significantly increased all-cause mortality in patients with AF regardless of concomitant HF. We suggest that digoxin should not be preferentially used over other rate control medications in AF.

Serum lipoprotein(a) positively correlates with coronary artery calcification in low-risk chinese han patients: a study from a single center.

BACKGROUND: Elevated plasma levels of lipoprotein(a) (Lp(a)) and a higher degree of coronary artery calcification (CAC) are both considered to be risk factors for atherosclerosis. However, previous studies have demonstrated that the relationship between Lp(a) levels and the degree of CAC indicates significant heterogeneity that may be due to varying ethnicities. The purpose of this study was to examine the predictive power of Lp(a) for CAC as measured by multidetector computed tomography (MDCT) in the Han ethnic group of China. METHODS: A total of 1082 subjects were recruited in this study. The patients were divided into four groups: patients without hypertension or diabetes were group 1, patients with hypertension were group 2, patients with diabetes were group 3 and patients with both hypertension and diabetes were group 4. CAC score (CACs), lipid profiles (Lp(a), LDL, HDL, TG, TC), HbA1C, glucose, personal health history and body morphology were measured in all participants. The predictive power of Lp(a) for calcified atherosclerotic plaque was determined by correlations and ordinal logistic regression. RESULTS: There was no significant difference in the CACs between group 2 and group 3 (z = 1.790, p = 0.736), and there were significant differences among the other groups. However, there was no significant difference in the total Lp(a) among the 4 groups (χ(2) = 0.649, p = 0.885). Only In group 1, Lp(a) was a statistically significant predictor of the presence of calcified coronary plaque using ordinal logistic regression. CONCLUSIONS: Levels of Lp(a) positively correlate with CACs among Chinese Han people who are without diabetes and hypertension, suggesting that Lp(a) may be an important risk factor for the presence of calcified atheromas.

Fosinopril attenuates the doxorubicin-induced cardiomyopathy by restoring the function of sarcoplasmic reticulum.

Fosinopril, an angiotensin-converting enzyme inhibitor, is known to attenuate cardiomyopathy induced by doxorubicin (DOX); however, the mechanisms of this cardioprotection are not fully elucidated yet. In the present study, experimental cardiomyopathy was induced in rats by administration of DOX with or without co-treatment with fosinopril. Fosinopril was utilized on day 1 or 14 of the treatment with DOX to compare efficacies of early versus late co-treatments. We observed that fosinopril attenuated changes induced by DOX (e.g., less increased heart and left ventricular weights, diminished lung congestion and ascites, attenuated LVEDP and LVSP, and less decreased +dP/dt and -dP/dt). Further, fosinopril diminished the levels of markers of cardiac toxicity (i.e., plasma levels and activities of cardiac enzymes and proteins AST, LDH, CPK, cTnI, and BNP). Fosinopril also prevented DOX-induced decreases in Ca(2+) uptake and restored activity of Ca(2+)-stimulated ATPase in left ventricular sarcoplasmic reticulum. We next tested whether the improved Ca(2+) transport activity in sarcoplasmic reticulum was due to modulation of SERCA2 and phospholamban expressions by fosinopril. Fosinopril attenuated the decrease in SERCA2 and phospholamban expressions caused by DOX. In conclusion, cardioprotective effects of fosinopril in the DOX-induced cardiomyopathy appear to be due to its ability to prevent remodeling of the cardiac sarcoplasmic reticulum membrane.

Elevated levels of oxidized low-density lipoprotein correlate positively with C-reactive protein in patients with acute coronary syndrome.

The relationship between oxidized low-density lipoprotein (Ox-LDL) and C-reactive protein (CRP) in patients with acute coronary syndrome (ACS) is unknown. We, therefore, measured serum levels of Ox-LDL and high-sensitivity (hs)-CRP in 90 ACS patients, 45 stable angina pectoris (SAP) patients, and 66 healthy controls using sandwich ELISA. ACS patients were subdivided into: (1) acute myocardial infarction (AMI; n = 45); (2) unstable angina pectoris (UAP; n = 45) groups. In AMI patients, Ox-LDL (177.5 mmol/l) and hs-CRP (25.40 mg/l) levels were significantly higher (P < 0.01) than in UAP (Ox-LDL:107.5 mmol/l, hs-CRP:10.7 mg/l) and SAP (Ox-LDL:82.3 mmol/l, hs-CRP:2.10 mg/l) patients as well as controls (Ox-LDL:41.4 mmol/l, hs-CRP:1.76 mg/l). Ox-LDL/hs-CRP levels in UAP patients were significantly higher (P < 0.01) than in SAP patients and controls. Importantly, a positive correlation was found between Ox-LDL and CRP (r = 0.622; P < 0.01) levels. Serum levels of total, HDL, and LDL cholesterol did not differ among these patient groups. In conclusion, our data show that Ox-LDL and hs-CRP levels correlate positively in ACS patients, supporting the hypothesis that Ox-LDL and CRP may play a direct role in promoting the inflammatory component of atherosclerosis in these individuals. We suggest that Ox-LDL/CRP elevated levels may serve as markers of the severity of the disease in evaluation and management of ACS patients.