Abstract Background: Prostaglandin-E1 (PGE1) is a potent vasodilator with anti-inflammatory and antiplatelet effects. However, the mechanism by which PGE1 contributes to the amelioration of cardiac injury remains unclear. Methods: The present study was designed to investigate how PGE1 protects against hypoxia/reoxygenation (H/R)-induced injuries by regulating microRNA-21-5p (miR-21-5p) and fas ligand (FASLG). Rat H9C2 cells and isolated primary cardiomyocytes were cultured under hypoxic conditions for 6 h (6H, hypoxia for 6 h), and reoxygenated for periods of 6 (6R, reoxygenation for 6 h), 12, and 24 h, respectively. Cells from the 6H/6R group were treated with various doses of PGE1; after which, their levels of viability and apoptosis were detected. Results: The 6H/6R treatment regimen induced the maximum level of H9C2 cell apoptosis, which was accompanied by the highest levels of Bcl-2-associated X protein (Bax) and cleaved-caspase-3 expression and the lowest level of B-cell lymphoma 2 (Bcl-2) expression. Treatment with PGE1 significantly diminished the cell cytotoxicity and apoptosis induced by the 6H/6R regimen, and also decreased expression of IL-2, IL-6, P-p65, TNF-α, and cleaved-caspase-3. In addition, we proved that PGE1 up-regulated miR-21-5p expression in rat cardiomyocytes exposed to conditions that produce H/R injury. FASLG was a direct target of miR-21-5p, and PGE1 reduced the ability of H/R-injured rat cardiomyocytes to undergo apoptosis by affecting the miR-21-5p/FASLG axis. In addition, we proved that PGE1 could protect primary cardiomyocytes against H/R-induced injuries. Conclusions: These results indicate that PGE1 exerts cardioprotective effects in H9C2 cells during H/R by regulating the miR-21-5p/FASLG axis.

Vascular depression (VaDep), which was proposed over two decades ago, is a distinct subtype of depression primarily observed in patients with stroke and cerebral small-vessel disease and is characterized by white matter hyperintensities; however, the lack of standardized diagnostic criteria and consensus limits its clinical application. This review explores the pathological conditions and vascular risk factors that may precipitate VaDep, particularly in relation to stroke and cerebral small-vessel disease. VaDep is distinguished by unique pathophysiological mechanisms and treatment responses. We categorize these mechanisms into three groups: 1) macroscopic mechanisms, including vascular aging, cerebral hypoperfusion, blood-brain barrier disruption, and neural circuit dysfunction; 2) microscopic mechanisms, involving the inflammatory response, hypothalamic-pituitary-adrenal axis dysregulation, impaired monoamine synthesis, and mitochondrial dysfunction; and 3) undetermined mechanisms, such as microbiota-gut-brain axis dysbiosis. These insights support VaDep as a distinct depression subtype, differentiating it from late-life depression and major depressive disorder. Treatment is challenging, as patients with VaDep often exhibit resistance to conventional antidepressants. Addressing vascular risk factors and protecting vascular integrity are essential for effective management. Future research should validate these mechanisms and develop novel diagnostic and therapeutic approaches to improve VaDep outcomes.

Blood pressure dipping patterns have long been considered to be associated with adverse events. We aimed to investigate whether dipping patterns of postoperative MAP were related to 90-day and hospital mortality in patients undergoing CABG. Four thousand three hundred ninety-one patients were classified into extreme dippers (night-to-day ratio of MAP ≤ 0.8), dippers (0.8 < night-to-day ratio of MAP ≤ 0.9), non-dippers (0.9 < night-to-day ratio of MAP ≤ 1), and reverse dippers (> 1). Compared with non-dippers, reverse dippers were at a higher risk of 90-day mortality (aHR = 1.58; 95

Endothelial-to-mesenchymal transition (EndoMT) is associated with neointimal hyperplasia and vein graft failure, and heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) has emerged as a major modulator of EMT. We aimed to investigate the functional consequence of EndoMT in neointimal hyperplasia and the precise role of hnRNPA1 in the regulation of EndoMT and neointimal hyperplasia. We investigated the spatial and temporal distribution characteristics of EndoMT cells in a mouse model of vein graft transplantation. In vitro, we studied the interaction between EndoMT cells and VSMCs, and the underlying mechanism was investigated by cytokine antibody assays. In cultured HUVECs, we studied the effect of hnRNPA1 on EndoMT and the cellular interactions by using siRNA-mediated knockdown and adenovirus-mediated overexpression. We further investigated the role of hnRNPA1 in EndoMT and neointimal hyperplasia in vivo with an AAV-mediated EC-specific hnRNPA1 overexpression murine model. We demonstrated the presence of EndoMT cells during the initial stage of neointimal formation, and that EndoMT cells promoted the proliferation and migration of VSMCs in vitro. Mechanistic studies revealed that EndoMT cells express and secrete a higher level of PDGF-B. Furthermore, we found a regulatory role for hnRNPA1 in EndoMT in vitro and in vivo. Similarly, we found that hnRNPA1 overexpression in ECs reduced the expression and secretion of PDGF-B during EndoMT, effectively inhibiting EndoMT cell-mediated activation of VSMCs in vitro and neointimal formation in vivo. Taken together, these findings indicate that EndoMT cells can activate VSMCs through a paracrine mechanism mediated by hnRNPA1 and lead to neointimal hyperplasia.

HomeCirculationVol. 145, No. 10Rare Case of Wide QRS Tachycardia After Sintilimab Treatment for Lung Cancer Free AccessCase ReportPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessCase ReportPDF/EPUBRare Case of Wide QRS Tachycardia After Sintilimab Treatment for Lung Cancer Yi Tang, PhD, Yi Zhang, PhD and Xiao-Yan Yang, MD Yi TangYi Tang https://orcid.org/0000-0002-3785-1947 Department of Cardiology, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Clinical Medicine Research Center of Heart Failure of Hunan Province, Hunan Normal University, Changsha, China. , Yi ZhangYi Zhang Department of Cardiology, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Clinical Medicine Research Center of Heart Failure of Hunan Province, Hunan Normal University, Changsha, China. and Xiao-Yan YangXiao-Yan Yang Correspondence to: Xiao-Yan Yang, MD, Hunan Provincial People's Hospital, No.61, Jiefang West Road, Furong District, Changsha 410005, China. Email E-mail Address: [email protected] https://orcid.org/0000-0002-5553-3408 Department of Cardiology, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Clinical Medicine Research Center of Heart Failure of Hunan Province, Hunan Normal University, Changsha, China. Originally published7 Mar 2022https://doi.org/10.1161/CIRCULATIONAHA.121.058936Circulation. 2022;145:783–786ECG ChallengeA 66-year-old man with normal baseline ECG taking 4 cycles of sintilimab for left lung squamous cell lung cancer presented with chest tightness and dyspnea. He was previously healthy and had been diagnosed with lung cancer 4 months earlier. His vital signs were as follows: blood pressure, 143/95 mm Hg; heart rate, 128 beats/min; respiratory rate, 31 breaths/min; and oxygen saturation, 95% at 50% oxygen concentration. In addition, his serum troponin I was 4.1 ng/mL (normal value < 0.10 ng/mL) and NT-proBNP (N-terminal pro–B-type natriuretic peptide) was 1050 ng/L (normal value < 300 pg/mL).Transthoracic echocardiogram demonstrated global left ventricular systolic impairment with a left ventricular ejection fraction of 45%. In contrast, a baseline echocardiogram conducted before managing the malignancy of the patient demonstrated normal left ventricular function. His ECG is shown in Figure 1A and 1B with a wide QRS complex tachycardia. Emergency coronary angiography did not reveal any significant stenosis.Download figureDownload PowerPointFigure 1. ECG on admission.What is the diagnosis of the wide QRS complex tachycardia? What is its most likely cause and how would you treat the patient?Please turn the page to read the diagnosis.Response to ECG ChallengeThe ECG of the patient reveals a wide complex tachycardia with a rate of 111 beats/min and 2 distinct QRS complexes. The 2 QRS morphologies were alternating beat-to-beat in the same limb lead, showing an alternating R-R interval. In Figure 2A, the QRS morphologies regularly alternates up and down. In Figure 2B, clear atrioventricular dissociation can be seen. These findings are consistent with the typical ECG manifestations of bidirectional ventricular tachycardia (BVT). BVT is most commonly seen as a consequence of digitalis toxicity, aconitine poisoning, or familial catecholaminergic polymorphic ventricular tachycardia. This patient was not taking digitalis and did not have a history of aconite ingestion. Furthermore, this does not meet the characteristics of catecholaminergic polymorphic ventricular tachycardia. Elevated troponin, BVT, and depressed ventricular wall motion after sintilimab use support the diagnosis of myocarditis associated with an immune checkpoint inhibitor (ICI).Download figureDownload PowerPointFigure 2. Annotated ECG at admission.ECG showed 2 morphologies of QRS complex tachycardia (red and blue arrows) with a rate of 111 bpm and 2 R-R intervals alternating in a regular way, consistent with bidirectional ventricular tachycardia. A, QRS pattern with regular upward and downward alternating. B, P waves (P) unrelated to the QRS complex can be seen, which supports the atrioventricular dissociation finding.The mechanism of BVT is believed to be related to delayed afterdepolarizations. Delayed afterdepolarizations play an important role in triggering and maintaining BVT through a "ping pong" mechanism.1 Triggered activity from delayed afterdepolarizations are attributed to elevated intracellular calcium, leading to transient inward current, activation of inward sodium current, and subsequent triggered action potential. A common mechanism between the etiologies of BVT is elevated intracellular calcium via spontaneous release or increased ryanodine receptor sensitivity.1 There are various proposed mechanisms attempting to explain ICI-mediated arrythmias. Some of these theories include inflammation of the His-Purkinje conduction system and ventricular myocarditis with inflammation and fibrosis, both of which lead to triggered activity, automaticity, and reentry. Spontaneous release of sarcoplasmic reticulum calcium from inflammation is thought to explain BVT in myocarditis.2The mechanism of ICI-associated myocarditis appears to be T-cell–mediated. Endomyocardial biopsy results from multiple series identified lymphocyte infiltration of CD4+, CD8+, and PD1 (programmed cell death protein 1). ICIs may affect various structural components of the cardiovascular system, leading to a wide range of cardiovascular adverse events, including myocarditis, heart failure, cardiogenic shock, and Takotsubo cardiomyopathy in the myocardium, as well as atrial fibrillation, supraventricular tachycardia, ventricular tachycardia, and heart block, all of which affect the electric conduction system.2BVT caused by ICI-associated myocarditis is rarely reported.3 Management of this condition typically includes immunosuppression with glucocorticoids. We discontinued sintilimab and administered 200 mg of methylprednisolone daily and intravenous immunoglobulin. The patient's troponin level gradually decreased to 0.66 ng/mL; however, his NT-proBNP gradually increased from 1050 to 13 100 pg/mL. He received temporary pacing therapy for a high atrioventricular block on day 6, but the dyspnea worsened and hemodynamic instability appeared. The patient did not receive extracorporeal membrane oxygenation treatment for personal reasons, required discharge from the hospital, and died on day 4 after discharge. Elevated troponin usually indicates damage to cardiomyocytes, and it is inexpensive and widely available. Some authors proposed that checking the baseline serum troponin level of the patient and checking the serum troponin level in each cycle after the second dose of ICI (2- or 3-week infusions) may be valuable for clinicians to identify ICI-related myocarditis in time.Article InformationAcknowledgmentsThe authors thank Professor Hong-Guang Wu from The University of Hong Kong Shenzhen Hospital for his valuable comments on the ECG analysis.Sources of FundingThis work was supported by grants from the Key Research and Development Program of Hunan Province (2019SK2021), National Natural Science Foundation of China (81800056), and Hunan Provincial University Reform and Development Fund (2018-82).Nonstandard Abbreviations and AcronymsBVTbidirectional ventricular tachycardiaICIimmune checkpoint inhibitorNT-proBNPN-terminal pro–B-type natriuretic peptideDisclosures None.FootnotesFor Sources of Funding and Disclosures, see page 786.Circulation is available at www.ahajournals.org/journal/circCorrespondence to: Xiao-Yan Yang, MD, Hunan Provincial People's Hospital, No.61, Jiefang West Road, Furong District, Changsha 410005, China. Email [email protected]comReferences1. Baher AA, Uy M, Xie F, Garfinkel A, Qu Z, Weiss JN. Bidirectional ventricular tachycardia: ping pong in the His-Purkinje system.Heart Rhythm. 2011; 8:599–605. doi: 10.1016/j.hrthm.2010.11.038CrossrefMedlineGoogle Scholar2. Salem JE, Manouchehri A, Moey M, Lebrun-Vignes B, Bastarache L, Pariente A, Gobert A, Spano JP, Balko JM, Bonaca MP, et al.. Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study.Lancet Oncol. 2018; 19:1579–1589. doi: 10.1016/S1470-2045(18)30608-9CrossrefMedlineGoogle Scholar3. Alhumaid W, Yogasundaram H, Senaratne JM. Slow bidirectional ventricular tachycardia as a manifestation of immune checkpoint inhibitor myocarditis. Eur Heart J. 2021; 42(29):2868. doi: 10.1093/eurheartj/ehab219CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By (2022) Sintilimab, Reactions Weekly, 10.1007/s40278-022-14843-7, 1905:1, (453-453), Online publication date: 1-May-2022. March 8, 2022Vol 145, Issue 10Article InformationMetrics © 2022 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.121.058936PMID: 35254921 Originally publishedMarch 7, 2022 PDF download Advertisement SubjectsArrhythmias

Abstract Background Dapagliflozin, a selective inhibitor of sodium-glucose cotransporter 2 (SGLT2), can reduce cardiovascular events and mortality in patients with heart failure. A number of mechanisms have been proposed to explain the beneficial effects of SGLT2 inhibitors. The purpose of this study was to determine whether dapagliflozin can improve pulmonary vascular remodelling and the efficacy of dapagliflozin as an add-on therapy to sildenafil in rats with pulmonary arterial hypertension (PAH). Methods A monocrotaline (MCT)-induced PAH rat model was used in our study. MCT-injected rats were randomly divided into four groups and treated for 3 weeks with daily per os treatment with vehicle, dapagliflozin (1 mg/kg/day), sildenafil (25 mg/kg/day), or a combination of dapagliflozin (1 mg/kg/day) and sildenafil (25 mg/kg/day). Haemodynamic measurements, histological analysis, enzyme-linked immunosorbent assay and western blotting analysis were employed to detect the changes in PAH rats after treatments. Results Dapagliflozin significantly attenuated MCT-induced increases in right ventricular systolic pressure (RVSP) and right ventricular hypertrophy (RVH) in PAH rats. Dapagliflozin effectively decreased the thickening of pulmonary artery media and decreased the muscularization of pulmonary arterioles in PAH rats. Moreover, dapagliflozin attenuated nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome activation in lung tissues and the levels of interleukin-1β (IL-1β) and interleukin-18 (IL-18) in plasma. However, dapagliflozin as an add-on therapy to sildenafil in rats with PAH did not show a more pronounced beneficial effect on right ventricular systolic pressure and pulmonary vascular remodelling in MCT rats than sildenafil alone. Conclusions Dapagliflozin reduces right ventricular systolic pressure and pulmonary vascular remodelling in a rat model of PAH. However, combination therapy with dapagliflozin and sildenafil was not more effective than monotherapy with sildenafil in PAH rats.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors, a novel class of hypoglycemic drugs, show excellent cardiovascular benefits, and have further improved heart failure outcomes, significantly reducing cardiovascular and all-cause mortality irrespective of diabetes status. However, the efficacy of SGLT2 inhibitors in pulmonary arterial hypertension (PAH) and right ventricular (RV) dysfunction remains unknown. This study aimed to evaluate the effects of dapagliflozin in rats with PAH and RV dysfunction. PAH was induced in rats by monocrotaline (MCT) subcutaneous injection (60 mg/kg). Isolated RV dysfunction was induced in another group of rats by pulmonary trunk banding (PTB). Dapagliflozin (1.5 mg/kg) was administered daily via oral gavage one day (prevention groups) or two weeks (reversal groups) after modeling. Echocardiography and hemodynamic assessments were used to observe pulmonary vascular resistance and RV function. Histological staining was used to observe pulmonary vascular and RV remodeling. As compared with MCT group, dapagliflozin treatment did not significantly improve the survival of rats. Pulmonary arterial media wall thickness in MCT group was significantly increased, but dapagliflozin did not significantly improved vascular remodeling both in the prevention group and reversal group. In MCT group, RV hypertrophy index, RV area, the fibrosis of RV increased significantly, and RV function decreased significantly. Consistently, dapagliflozin did not show protective effect on the RV remodeling and function. In the PTB model, we also did not find the direct effect of dapagliflozin on the RV. This is a negative therapeutic experiment, suggesting human trials with dapagliflozin for PAH or RV failure should be cautious.

Background: This study aimed to investigate the prognostic value of glucose variability (GV) in predicting postoperative major adverse events (MAEs) in patients with infective endocarditis (IE) who underwent surgical treatment. Methods: This retrospective observational study included a total of 381 consecutive patients who underwent surgical treatment in our institution from October 2007 to August 2019. The MAEs included all-cause death, stroke, myocardial infarction, acute heart failure, IE recurrence, acute renal failure and sepsis. Postoperative GV in the first 24 hours was measured by the mean 24-hour glucose, standard deviation, coefficient of variation (CV) and mean amplitude of glycemic excursions. Univariate and multivariate logistic regression analyses were performed to identify the independent association of GV with MAEs. Results: Of the 381 patients, 79 (20.7%) developed MAEs. The 30-day mortality of the overall study cohort was 5.23%. The multivariate logistic regression analysis indicated that 24-hour GV, measured as the CV [odds ratio (OR) =1.49, 95% CI, 1.23–3.57, P=0.012], was significantly associated with MAEs in IE patients. For every 10% increase in 24‐hour CV, there was a 49% increase in the risk of MAEs. Furthermore, compared to patients in the low tertile of GV, patients in the top tertile of 24-hour GV had a higher 30-day mortality and an increased incidence of heart failure and hemodialysis as well as longer ventilation support. Conclusions: The results of this retrospective investigation demonstrated that increased GV measured by CV is an independent predictor of postoperative MAEs in patients undergoing surgical treatment for IE.

Thrombophilia refers to a group of conditions where the blood clots more easily than normal. These blood clots can cause problems such as deep vein thrombosis or pulmonary embolism. Most kinds of mutated coagulation factors II (F2) exhibit lower procoagulant activity, but in some cases, a higher coagulation rate has been observed. The underlying mechanism is that those variations can prevent F2s from being inhibited by antithrombin, leading to a contiguous activation of procoagulation, and causing recurrent thromboembolism. In this study, a patient was admitted to our hospital due to repeated chest pain for 2 days and aggravated for 4 h. A medical history investigation showed that he had three deep venous thromboses in the lower limbs and one portal vein thrombosis events during the past 10 years. The electrocardiogram showed Q wave elevation and slight ST segment elevation in lead V2, and coronary angiogram showed a total occlusion of the left anterior descending artery. Laboratory testing found that troponin I was obviously elevated. Family history also indicated that both his father (II-3) and grandfather (I-1) died from pulmonary thromboembolism. Whole-exome sequencing was performed to detect the genetic lesion of the patient, and a novel mutation (c.1621 C>T/p.R541W) of F2 was identified in the patient. This novel mutation resulted in a substitution of arginine by tryptophan, leading to antithrombin resistance (ATR). Our study is consistent with previously published papers. In conclusion, this study not only identifies a novel mutation of F2 and will contribute to the genetic diagnosis and counseling of families with thrombosis but also suggests that the site p.R541 of F2 may play a crucial role in thrombosis.