Pub Date : 2024-10-01DOI: 10.1097/FJC.0000000000001607
Alessandro Sciahbasi, Salvatore De Rosa, Giuseppe Gargiulo, Daniele Giacoppo, Paolo Calabrò, Giovanni Paolo Talarico, Filippo Zilio, Giuseppe Talanas, Matteo Tebaldi, Giuseppe Andò, Stefano Rigattieri, Leonardo Misuraca, Bernardo Cortese, Gerardo Musuraca, Valerio Lucci, Vincenzo Guiducci, Giulia Renda, Luigi Zezza, Francesco Versaci, Maria Benedetta Giannico, Marco Caruso, Dionigi Fischetti, Mauro Colletta, Andrea Santarelli, Claudio Larosa, Alessandro Iannone, Giovanni Esposito, Giuseppe Tarantini, Giuseppe Musumeci, Andrea Rubboli
Abstract: In patients on oral anticoagulant (OAC) therapy undergoing percutaneous coronary intervention (PCI) with stent, international guidelines endorse the use of direct oral anticoagulants (DOAC) rather than vitamin K antagonists (VKA) and dual antithrombotic therapy (DAT) rather than triple antithrombotic therapy (TAT). The aim of this study was to evaluate contemporary real-world data on antithrombotic regimens and outcome in patients on OAC undergoing PCI with stent. Consecutive patients on OAC undergoing PCI were enrolled in the multicenter, prospective, observational PERSEO registry (NCT03392948). Primary end point was net adverse clinical events (NACE) with VKA versus DOAC, whereas a secondary prespecified end point was NACE with DAT versus TAT both at 1-year follow-up. From February 2018 to February 2022; in total, 1234 consecutive patients were included. The main indication for OAC was atrial fibrillation (86%), and the mean CHA 2 DS 2 VASc and HAS-BLED scores were 4 ± 2 and 3.6 ± 1, respectively. Of the 1228 patients discharged alive, 222 (18%) were on VKA and 1006 (82%) on DOAC ( P < 0.01). DAT was employed in 197 patients whereas TAT in 1028. At follow-up, NACE rate was significantly higher than VKA compared with DOAC (23% vs. 16%, P = 0.013) and confirmed after propensity score adjustment. TAT and DAT did not differ as regards NACE rate (17% vs. 19%, P = 0.864) although, compared with TAT, DAT was associated with less major bleedings (2% vs. 5%, P = 0.014), confirmed after propensity score adjustment. In conclusion, in patients on OAC undergoing PCI, DOAC, compared with VKA, was associated with a significantly lower occurrence of NACE and DAT reduced bleedings compared with TAT.
{"title":"Management of Patients Treated With Oral Anticoagulant Therapy Undergoing Percutaneous Coronary Intervention With Stent Implantation: The PERSEO Registry.","authors":"Alessandro Sciahbasi, Salvatore De Rosa, Giuseppe Gargiulo, Daniele Giacoppo, Paolo Calabrò, Giovanni Paolo Talarico, Filippo Zilio, Giuseppe Talanas, Matteo Tebaldi, Giuseppe Andò, Stefano Rigattieri, Leonardo Misuraca, Bernardo Cortese, Gerardo Musuraca, Valerio Lucci, Vincenzo Guiducci, Giulia Renda, Luigi Zezza, Francesco Versaci, Maria Benedetta Giannico, Marco Caruso, Dionigi Fischetti, Mauro Colletta, Andrea Santarelli, Claudio Larosa, Alessandro Iannone, Giovanni Esposito, Giuseppe Tarantini, Giuseppe Musumeci, Andrea Rubboli","doi":"10.1097/FJC.0000000000001607","DOIUrl":"10.1097/FJC.0000000000001607","url":null,"abstract":"<p><strong>Abstract: </strong>In patients on oral anticoagulant (OAC) therapy undergoing percutaneous coronary intervention (PCI) with stent, international guidelines endorse the use of direct oral anticoagulants (DOAC) rather than vitamin K antagonists (VKA) and dual antithrombotic therapy (DAT) rather than triple antithrombotic therapy (TAT). The aim of this study was to evaluate contemporary real-world data on antithrombotic regimens and outcome in patients on OAC undergoing PCI with stent. Consecutive patients on OAC undergoing PCI were enrolled in the multicenter, prospective, observational PERSEO registry (NCT03392948). Primary end point was net adverse clinical events (NACE) with VKA versus DOAC, whereas a secondary prespecified end point was NACE with DAT versus TAT both at 1-year follow-up. From February 2018 to February 2022; in total, 1234 consecutive patients were included. The main indication for OAC was atrial fibrillation (86%), and the mean CHA 2 DS 2 VASc and HAS-BLED scores were 4 ± 2 and 3.6 ± 1, respectively. Of the 1228 patients discharged alive, 222 (18%) were on VKA and 1006 (82%) on DOAC ( P < 0.01). DAT was employed in 197 patients whereas TAT in 1028. At follow-up, NACE rate was significantly higher than VKA compared with DOAC (23% vs. 16%, P = 0.013) and confirmed after propensity score adjustment. TAT and DAT did not differ as regards NACE rate (17% vs. 19%, P = 0.864) although, compared with TAT, DAT was associated with less major bleedings (2% vs. 5%, P = 0.014), confirmed after propensity score adjustment. In conclusion, in patients on OAC undergoing PCI, DOAC, compared with VKA, was associated with a significantly lower occurrence of NACE and DAT reduced bleedings compared with TAT.</p>","PeriodicalId":15212,"journal":{"name":"Journal of Cardiovascular Pharmacology","volume":" ","pages":"457-467"},"PeriodicalIF":2.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141727294","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1097/FJC.0000000000001617
Alexander Burashnikov, Charles Antzelevitch
Abstract: There is a need for more efficient pharmacological cardioversion of atrial fibrillation (AF). We tested the hypothesis that inhibition of I K1 significantly enhances the efficacy of I Na block to depress atrial excitability and to cardiovert AF. The study was conducted in canine isolated arterially perfused right atrial preparations with rim of ventricular tissue. AF was induced in the presence of acetylcholine (ACh; 0.5 µM). BaCl 2 (10 µM) was used to inhibit I K1 and flecainide (1.5 µM) to block I Na . Sustained AF (>45 minutes) was recorded in 100% atria (5/5) in the presence of ACh alone. Flecainide cardioverted AF in 50% of atria (4/8), BaCl 2 in 0% (0/5), and their combination in 100% (5/5). AF cardioversion occurred in 15 ± 9 minutes with flecainide alone (n = 4) and in 8 ± 9 minutes with the combination (n = 5). Following drug-induced AF cardioversion, AF was inducible in 4/4 atria with flecainide alone (≤5 minutes duration) and in 2/5 atria with the combination (≤30 seconds duration). Atrial excitability was significantly more depressed by combined versus monotherapies. There was little to no effect on ventricular excitability under any condition tested. Thus, inhibition of I K1 significantly enhances the efficacy of flecainide to depress atrial excitability and to cardiovert AF in our experimental setting. A combination of I Na and I K1 inhibition may be an effective approach for cardioversion of AF.
心房颤动(房颤)需要更有效的药物心脏复律。我们测试了这样一个假设:抑制 IK1 可显著提高 INa 阻滞抑制心房兴奋性和心房颤动药物转复的疗效。研究在犬离体动脉灌注右心房制备模型中进行,该制备模型带有心室组织边缘。在乙酰胆碱(ACh;0.5 µM)存在下诱导房颤。用 BaCl2(10 µM)抑制 IK1,用 flecainide(1.5 µM)阻断 INa。在单用 ACh 的情况下,100% 的心房(5/5)记录到持续房颤(>45 分钟)。50%的心房(4/8)、0%的心房(0/5)和100%的心房(5/5)在使用氟卡尼后发生房颤,使用氯化钡后发生房颤。单独使用氟卡尼(flecainide)在15±9分钟内(n=4),联合使用(n=5)在8±9分钟内(n=9)发生房颤。药物诱导房颤心脏复律后,4/4 的心房在单独使用氟卡尼(持续时间≤ 5 分钟)和 2/5 的心房在联合使用氟卡尼(持续时间≤ 30 秒)时可诱发房颤。与单一疗法相比,联合疗法明显更能抑制心房兴奋性。在任何测试条件下,对心室兴奋性几乎没有影响。因此,在我们的实验环境中,抑制 IK1 能显著提高非卡尼抑制心房兴奋性和心房颤动的疗效。结合 INa 和 IK1 抑制可能是心房颤动心脏复律的有效方法。
{"title":"The Efficacy of I Na Block to Cardiovert Atrial Fibrillation Is Enhanced by Inhibition of I K1.","authors":"Alexander Burashnikov, Charles Antzelevitch","doi":"10.1097/FJC.0000000000001617","DOIUrl":"10.1097/FJC.0000000000001617","url":null,"abstract":"<p><strong>Abstract: </strong>There is a need for more efficient pharmacological cardioversion of atrial fibrillation (AF). We tested the hypothesis that inhibition of I K1 significantly enhances the efficacy of I Na block to depress atrial excitability and to cardiovert AF. The study was conducted in canine isolated arterially perfused right atrial preparations with rim of ventricular tissue. AF was induced in the presence of acetylcholine (ACh; 0.5 µM). BaCl 2 (10 µM) was used to inhibit I K1 and flecainide (1.5 µM) to block I Na . Sustained AF (>45 minutes) was recorded in 100% atria (5/5) in the presence of ACh alone. Flecainide cardioverted AF in 50% of atria (4/8), BaCl 2 in 0% (0/5), and their combination in 100% (5/5). AF cardioversion occurred in 15 ± 9 minutes with flecainide alone (n = 4) and in 8 ± 9 minutes with the combination (n = 5). Following drug-induced AF cardioversion, AF was inducible in 4/4 atria with flecainide alone (≤5 minutes duration) and in 2/5 atria with the combination (≤30 seconds duration). Atrial excitability was significantly more depressed by combined versus monotherapies. There was little to no effect on ventricular excitability under any condition tested. Thus, inhibition of I K1 significantly enhances the efficacy of flecainide to depress atrial excitability and to cardiovert AF in our experimental setting. A combination of I Na and I K1 inhibition may be an effective approach for cardioversion of AF.</p>","PeriodicalId":15212,"journal":{"name":"Journal of Cardiovascular Pharmacology","volume":" ","pages":"434-439"},"PeriodicalIF":2.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141901868","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Abstract: Anticoagulant therapy can significantly reduce the incidence of stroke and peripheral embolism events in patients with atrial fibrillation (AF). Although warfarin is widely used as an anticoagulant drug, a wrong dose can lead to increased risks of bleeding or blood clots. The aim of this study was to assess whether nuclear factor-erythroid-2-related factor 2 (Nrf2) can improve the efficacy of warfarin through the regulation of cytochrome P450 family 2 subfamily C member 9 (CYP2C9) using a rat model of AF. Results showed that AF significantly reduced Nrf2 in myocardial tissue of sham-operated rats. Furthermore, Nrf2 overexpression effectively reduced AF-induced atrial fibrosis by reducing collagen in the left atrium, inhibiting the expression of the fibrosis-related genes collagen I and transforming growth factor-β1 in rats with AF. Nrf2 overexpression can activate CYP2C9, decrease the serum concentration of warfarin, and decrease prothrombin time and international normalized ratio in AF rats. In this article, Nrf2 overexpression protects against fibrosis, increased survival in AF rats, and activated CYP2C9 expression, thus broadening the therapeutic range of warfarin in AF rats.
{"title":"Nrf2 Ameliorates Atrial Fibrosis During Antithrombotic Therapy for Atrial Fibrillation by Modulating CYP2C9 Activity.","authors":"Liting Wu, Zhumeng Li, Lijuan Xu, Yingchao Fan, Delong Mao, Hanxiao Sun, Wenfang Zhuang","doi":"10.1097/FJC.0000000000001618","DOIUrl":"10.1097/FJC.0000000000001618","url":null,"abstract":"<p><strong>Abstract: </strong>Anticoagulant therapy can significantly reduce the incidence of stroke and peripheral embolism events in patients with atrial fibrillation (AF). Although warfarin is widely used as an anticoagulant drug, a wrong dose can lead to increased risks of bleeding or blood clots. The aim of this study was to assess whether nuclear factor-erythroid-2-related factor 2 (Nrf2) can improve the efficacy of warfarin through the regulation of cytochrome P450 family 2 subfamily C member 9 (CYP2C9) using a rat model of AF. Results showed that AF significantly reduced Nrf2 in myocardial tissue of sham-operated rats. Furthermore, Nrf2 overexpression effectively reduced AF-induced atrial fibrosis by reducing collagen in the left atrium, inhibiting the expression of the fibrosis-related genes collagen I and transforming growth factor-β1 in rats with AF. Nrf2 overexpression can activate CYP2C9, decrease the serum concentration of warfarin, and decrease prothrombin time and international normalized ratio in AF rats. In this article, Nrf2 overexpression protects against fibrosis, increased survival in AF rats, and activated CYP2C9 expression, thus broadening the therapeutic range of warfarin in AF rats.</p>","PeriodicalId":15212,"journal":{"name":"Journal of Cardiovascular Pharmacology","volume":" ","pages":"440-450"},"PeriodicalIF":2.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11446533/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141988075","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Abstract: Despite its high prevalence, effective treatment for degenerative mitral regurgitation (MR) remains elusive. Although the mineralocorticoid-receptor antagonist spironolactone, in conjunction with renin-angiotensin-aldosterone system inhibitors, has been shown to reduce mortality in patients with heart failure with reduced ejection fraction, its efficacy in managing degenerative MR is uncertain. In this study, we aimed to compare the effectiveness of valsartan (a renin-angiotensin system inhibitor), spironolactone, and combination therapy in mitigating MR-induced myocardial dysfunction. Using a mini-invasive model of degenerative MR, we administered valsartan (31 mg/kg/d), spironolactone (80 mg/kg/d), or a combination of both to rats over a 4-week period. Serial echocardiography and pressure-volume loops were utilized to assess cardiac function and hemodynamics. Rats with degenerative MR treated with valsartan or spironolactone alone did not show significant improvement in myocardial dysfunction. In contrast, combination therapy resulted in significant improvement. Similarly, the pressure-volume relationship was significantly improved in rats treated with the combination therapy compared with that in rats treated with a single therapy. Mechanistically, combination therapy effectively suppressed circulating and cardiac expression of aldosterone- and apoptosis-associated proteins. Overall, combination treatment with valsartan and spironolactone significantly attenuated the degenerative MR-induced myocardial stress and dysfunction, suggesting a potential therapeutic avenue for managing degenerative MR-induced heart failure.
{"title":"The Combination of Valsartan and Spironolactone Mitigated Mitral Regurgitation-Induced Cardiac Dysfunction in a Novel Rat Model.","authors":"Wei-Ting Chang, Yu-Wen Lin, Chin-Yu Chen, Chon-Seng Hong, Zhih-Cherng Chen, You-Cheng Lin, Jhih-Yuan Shih","doi":"10.1097/FJC.0000000000001614","DOIUrl":"10.1097/FJC.0000000000001614","url":null,"abstract":"<p><strong>Abstract: </strong>Despite its high prevalence, effective treatment for degenerative mitral regurgitation (MR) remains elusive. Although the mineralocorticoid-receptor antagonist spironolactone, in conjunction with renin-angiotensin-aldosterone system inhibitors, has been shown to reduce mortality in patients with heart failure with reduced ejection fraction, its efficacy in managing degenerative MR is uncertain. In this study, we aimed to compare the effectiveness of valsartan (a renin-angiotensin system inhibitor), spironolactone, and combination therapy in mitigating MR-induced myocardial dysfunction. Using a mini-invasive model of degenerative MR, we administered valsartan (31 mg/kg/d), spironolactone (80 mg/kg/d), or a combination of both to rats over a 4-week period. Serial echocardiography and pressure-volume loops were utilized to assess cardiac function and hemodynamics. Rats with degenerative MR treated with valsartan or spironolactone alone did not show significant improvement in myocardial dysfunction. In contrast, combination therapy resulted in significant improvement. Similarly, the pressure-volume relationship was significantly improved in rats treated with the combination therapy compared with that in rats treated with a single therapy. Mechanistically, combination therapy effectively suppressed circulating and cardiac expression of aldosterone- and apoptosis-associated proteins. Overall, combination treatment with valsartan and spironolactone significantly attenuated the degenerative MR-induced myocardial stress and dysfunction, suggesting a potential therapeutic avenue for managing degenerative MR-induced heart failure.</p>","PeriodicalId":15212,"journal":{"name":"Journal of Cardiovascular Pharmacology","volume":" ","pages":"410-417"},"PeriodicalIF":2.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141901867","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1097/FJC.0000000000001623
Caitlin M Gibson, Meghan M Beard, Alisa K Escano, Brittany L Good, Teresa G Potter, Albert M Truong, Benjamin Van Tassell
Abstract: Guidelines recommend intravenous loop diuretics as first-line therapy for patients hospitalized with acute heart failure (AHF) and volume overload. Additional agents can be used for augmentation, but there is limited guidance on agent selection. The study objective was to determine if chlorothiazide or metolazone is associated with differences in diuretic efficacy or safety in loop diuretic-resistant patients with AHF and renal dysfunction (eGFR <45 mL/min/1.73 m²). We conducted a multicenter, retrospective cohort study of patients hospitalized with AHF and renal dysfunction who received metolazone or chlorothiazide in addition to intravenous loop diuretics. The primary end point was a comparison of 24-hour urine output (UOP) between the 24 hours before and after thiazide administration. Secondary and safety end points included weight change, requirement for vasopressors or inotropes, electrolyte abnormalities, and changes in renal function. A total of 221 patients were included. The mean daily diuretic doses were chlorothiazide 632 mg and metolazone 7 mg. The mean 24-hour UOP increased more among chlorothiazide-treated (from 1668 mL to 3826 mL) versus metolazone-treated patients (from 1672 mL to 2834 mL) ( P < 0.001) after the addition of the second diuretic. Statistically significant reductions in serum creatinine were observed in the chlorothiazide group following 72 hours of treatment ( P = 0.016). More hypomagnesemia was observed in the chlorothiazide group; no differences in other electrolytes or changes in weight were observed. Overall, chlorothiazide was associated with a greater increase in 24-hour UOP than metolazone without an excess of potassium or serum creatinine derangements. However, weight changes did not differ significantly between groups. Future prospective studies are needed to confirm potential differences in diuretic response and safety.
{"title":"Metolazone Versus Chlorothiazide in Acute Heart Failure Patients With Diuretic Resistance and Renal Dysfunction: A Retrospective Cohort Study.","authors":"Caitlin M Gibson, Meghan M Beard, Alisa K Escano, Brittany L Good, Teresa G Potter, Albert M Truong, Benjamin Van Tassell","doi":"10.1097/FJC.0000000000001623","DOIUrl":"10.1097/FJC.0000000000001623","url":null,"abstract":"<p><strong>Abstract: </strong>Guidelines recommend intravenous loop diuretics as first-line therapy for patients hospitalized with acute heart failure (AHF) and volume overload. Additional agents can be used for augmentation, but there is limited guidance on agent selection. The study objective was to determine if chlorothiazide or metolazone is associated with differences in diuretic efficacy or safety in loop diuretic-resistant patients with AHF and renal dysfunction (eGFR <45 mL/min/1.73 m²). We conducted a multicenter, retrospective cohort study of patients hospitalized with AHF and renal dysfunction who received metolazone or chlorothiazide in addition to intravenous loop diuretics. The primary end point was a comparison of 24-hour urine output (UOP) between the 24 hours before and after thiazide administration. Secondary and safety end points included weight change, requirement for vasopressors or inotropes, electrolyte abnormalities, and changes in renal function. A total of 221 patients were included. The mean daily diuretic doses were chlorothiazide 632 mg and metolazone 7 mg. The mean 24-hour UOP increased more among chlorothiazide-treated (from 1668 mL to 3826 mL) versus metolazone-treated patients (from 1672 mL to 2834 mL) ( P < 0.001) after the addition of the second diuretic. Statistically significant reductions in serum creatinine were observed in the chlorothiazide group following 72 hours of treatment ( P = 0.016). More hypomagnesemia was observed in the chlorothiazide group; no differences in other electrolytes or changes in weight were observed. Overall, chlorothiazide was associated with a greater increase in 24-hour UOP than metolazone without an excess of potassium or serum creatinine derangements. However, weight changes did not differ significantly between groups. Future prospective studies are needed to confirm potential differences in diuretic response and safety.</p>","PeriodicalId":15212,"journal":{"name":"Journal of Cardiovascular Pharmacology","volume":" ","pages":"451-456"},"PeriodicalIF":2.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141901865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1097/FJC.0000000000001613
Jing Zhang, Xiaoqi Xiong, Jun Li, Changjun Luo, Qiang Su, Xin Hao, Qiang Wu, Wanzhong Huang
Abstract: Myocardial ischemia-reperfusion (MIR)-induced arrhythmia remains a major cause of death in patients with cardiovascular diseases. The reduction of Cx43 has been known as a major inducer of arrhythmias after MIR, but the reason for the reduction of Cx43 remains largely unknown. The aim of this study was to find the key mechanism underlying the reduction of Cx43 after MIR and to screen out an herbal extract to attenuate arrhythmia after MIR. The differentially expressed genes in the peripheral blood mononuclear cell (PBMCs) after MIR were analyzed using the data from several gene expression omnibus data sets, followed by the identification in PBMCs and the serum of patients with myocardial infarction. Tumor necrosis factor superfamily protein 14 (TNFSF14) was increased in PBMCs and the serum of patients, which might be associated with the injury after MIR. The toxic effects of TNFSF14 on cardiomyocytes were investigated in vitro . Valtrate was screened out from several herbal extracts. Its protection against TNFSF14-induced injury was evaluated in cardiomyocytes and animal models with MIR. Recombinant TNFSF14 protein not only suppressed the viability of cardiomyocytes but also decreased Cx43 by stimulating the receptor LTβR. LTβR induces the competitive binding of MAX to MGA rather than the transcriptional factor c-Myc, thereby suppressing c-Myc-mediated transcription of Cx43. Valtrate promoted the N-linked glycosylation modification of LTβR, which reversed TNFSF14-induced reduction of Cx43 and attenuated arrhythmia after MIR. In all, valtrate suppresses TNFSF14-induced reduction of Cx43, thereby attenuating arrhythmia after MIR.
心肌缺血再灌注(MIR)诱发的心律失常仍然是心血管疾病患者死亡的主要原因。众所周知,Cx43的减少是心肌缺血再灌注后心律失常的主要诱因,但Cx43减少的原因在很大程度上仍不清楚。本研究旨在找到 MIR 后 Cx43 减少的关键机制,并筛选出一种草药提取物来减轻 MIR 后的心律失常。研究利用多个 GEO 数据集的数据分析了心肌梗死后外周血单核细胞(PBMC)中的差异表达基因,并对心肌梗死患者的外周血单核细胞和血清中的差异表达基因进行了鉴定。研究发现,心肌梗死患者的血浆细胞和血清中肿瘤坏死因子超家族蛋白14(TNFSF14)的含量增加,这可能与心肌梗死后的损伤有关。体外研究了 TNFSF14 对心肌细胞的毒性作用。从几种草药提取物中筛选出了戊酸盐。在心肌细胞和 MIR 动物模型中评估了其对 TNFSF14 诱导的损伤的保护作用。重组 TNFSF14 蛋白不仅抑制了心肌细胞的活力,还通过刺激受体 LTβR 降低了 Cx43。LTβR可诱导MAX与MGA而非转录因子c-Myc竞争性结合,从而抑制c-Myc介导的Cx43转录。戊酸盐促进了LTβR的N-连接糖基化修饰,从而逆转了TNFSF14诱导的Cx43减少,并减轻了MIR后的心律失常。总之,缬氨酸盐抑制了 TNFSF14 诱导的 Cx43 减少,从而减轻了 MIR 后的心律失常。
{"title":"Valtrate Suppresses TNFSF14-Mediated Arrhythmia After Myocardial Ischemia-Reperfusion by Inducing N-linked Glycosylation of LTβR to Regulate MGA/MAX/c-Myc/Cx43.","authors":"Jing Zhang, Xiaoqi Xiong, Jun Li, Changjun Luo, Qiang Su, Xin Hao, Qiang Wu, Wanzhong Huang","doi":"10.1097/FJC.0000000000001613","DOIUrl":"10.1097/FJC.0000000000001613","url":null,"abstract":"<p><strong>Abstract: </strong>Myocardial ischemia-reperfusion (MIR)-induced arrhythmia remains a major cause of death in patients with cardiovascular diseases. The reduction of Cx43 has been known as a major inducer of arrhythmias after MIR, but the reason for the reduction of Cx43 remains largely unknown. The aim of this study was to find the key mechanism underlying the reduction of Cx43 after MIR and to screen out an herbal extract to attenuate arrhythmia after MIR. The differentially expressed genes in the peripheral blood mononuclear cell (PBMCs) after MIR were analyzed using the data from several gene expression omnibus data sets, followed by the identification in PBMCs and the serum of patients with myocardial infarction. Tumor necrosis factor superfamily protein 14 (TNFSF14) was increased in PBMCs and the serum of patients, which might be associated with the injury after MIR. The toxic effects of TNFSF14 on cardiomyocytes were investigated in vitro . Valtrate was screened out from several herbal extracts. Its protection against TNFSF14-induced injury was evaluated in cardiomyocytes and animal models with MIR. Recombinant TNFSF14 protein not only suppressed the viability of cardiomyocytes but also decreased Cx43 by stimulating the receptor LTβR. LTβR induces the competitive binding of MAX to MGA rather than the transcriptional factor c-Myc, thereby suppressing c-Myc-mediated transcription of Cx43. Valtrate promoted the N-linked glycosylation modification of LTβR, which reversed TNFSF14-induced reduction of Cx43 and attenuated arrhythmia after MIR. In all, valtrate suppresses TNFSF14-induced reduction of Cx43, thereby attenuating arrhythmia after MIR.</p>","PeriodicalId":15212,"journal":{"name":"Journal of Cardiovascular Pharmacology","volume":" ","pages":"418-433"},"PeriodicalIF":2.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141727295","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1097/FJC.0000000000001603
Bu-Yuan Hsiao
Abstract: The aim of this study was to evaluate the potential associations between Sjogren syndrome and outcomes of acute myocardial infarction (AMI) hospitalization. This population-based, retrospective observational study extracted data from the US Nationwide Inpatient Sample between 2005 and 2018. Adults aged 20 years or older hospitalized for AMI were eligible for inclusion. Propensity score matching was applied to balance the characteristics between the comparison groups (ie, with and without Sjogren syndrome). Associations between Sjogren syndrome and in-hospital outcomes were determined using univariate and multivariable logistic regression analyses. A total of 1,735,142 patients were included. After propensity score matching, 4740 patients remained for subsequent analyses (948 had Sjogren syndrome and 3792 did not). After adjustment, patients with Sjogren syndrome had significantly lower in-hospital mortality (adjusted OR: 0.52, 95% CI, 0.36-0.73, P < 0.001), prolonged length of stay (aOR: 0.83, 95% CI, 0.69-0.995, P = 0.044), cardiogenic shock (aOR: 0.58, 95% CI, 0.40-0.83, P = 0.004), cardiac dysrhythmias (aOR: 0.77, 95% CI, 0.66-0.90, P < 0.001), acute kidney injury (aOR: 0.56, 95% CI, 0.45-0.70, P < 0.001), or respiratory failure (aOR: 0.63, 95% CI, 0.48-0.81, P < 0.001) than those without Sjogren syndrome. The stratified analysis revealed that Sjogren syndrome was associated with decreased odds of in-hospital mortality in patients with non-ST elevation myocardial infarction or ST-elevation myocardial infarction. In conclusion, among patients admitted to US hospitals for AMI, the patients with Sjogren syndrome have a lowered probability of in-hospital mortality, certain morbidities, and prolonged length of stay. Further investigations should be conducted to establish a robust understanding of the associations observed.
{"title":"Sjogren Syndrome and Outcomes of Acute Myocardial Infarction: A Propensity Score-Matched Analysis of the Nationwide Inpatient Sample 2005-2018.","authors":"Bu-Yuan Hsiao","doi":"10.1097/FJC.0000000000001603","DOIUrl":"10.1097/FJC.0000000000001603","url":null,"abstract":"<p><strong>Abstract: </strong>The aim of this study was to evaluate the potential associations between Sjogren syndrome and outcomes of acute myocardial infarction (AMI) hospitalization. This population-based, retrospective observational study extracted data from the US Nationwide Inpatient Sample between 2005 and 2018. Adults aged 20 years or older hospitalized for AMI were eligible for inclusion. Propensity score matching was applied to balance the characteristics between the comparison groups (ie, with and without Sjogren syndrome). Associations between Sjogren syndrome and in-hospital outcomes were determined using univariate and multivariable logistic regression analyses. A total of 1,735,142 patients were included. After propensity score matching, 4740 patients remained for subsequent analyses (948 had Sjogren syndrome and 3792 did not). After adjustment, patients with Sjogren syndrome had significantly lower in-hospital mortality (adjusted OR: 0.52, 95% CI, 0.36-0.73, P < 0.001), prolonged length of stay (aOR: 0.83, 95% CI, 0.69-0.995, P = 0.044), cardiogenic shock (aOR: 0.58, 95% CI, 0.40-0.83, P = 0.004), cardiac dysrhythmias (aOR: 0.77, 95% CI, 0.66-0.90, P < 0.001), acute kidney injury (aOR: 0.56, 95% CI, 0.45-0.70, P < 0.001), or respiratory failure (aOR: 0.63, 95% CI, 0.48-0.81, P < 0.001) than those without Sjogren syndrome. The stratified analysis revealed that Sjogren syndrome was associated with decreased odds of in-hospital mortality in patients with non-ST elevation myocardial infarction or ST-elevation myocardial infarction. In conclusion, among patients admitted to US hospitals for AMI, the patients with Sjogren syndrome have a lowered probability of in-hospital mortality, certain morbidities, and prolonged length of stay. Further investigations should be conducted to establish a robust understanding of the associations observed.</p>","PeriodicalId":15212,"journal":{"name":"Journal of Cardiovascular Pharmacology","volume":" ","pages":"394-399"},"PeriodicalIF":2.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141723715","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1097/FJC.0000000000001615
Catherine X Wright, Attila Feher
{"title":"From Risk to Resilience: Improved Outcomes After Myocardial Infarction in Patients With Sjogren's Syndrome.","authors":"Catherine X Wright, Attila Feher","doi":"10.1097/FJC.0000000000001615","DOIUrl":"10.1097/FJC.0000000000001615","url":null,"abstract":"","PeriodicalId":15212,"journal":{"name":"Journal of Cardiovascular Pharmacology","volume":" ","pages":"389-390"},"PeriodicalIF":2.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141727293","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1097/FJC.0000000000001622
Yan-Feng Liang, Qing-Xin You, Shu-Yue Chen, Lei Ni, Xiang-Lian Meng, Jian-Xiang Gao, Yong-Bo Ren, Han-Jun Song, Jia-Lu Su, Yang Teng, Qing-Yun Gu, Chao Lv, Bo-Yang Yuan, Xuan Wang, Yong-Tai Zheng, Dong-Dong Zhang
Abstract: The hypothalamic paraventricular nucleus (PVN) plays a central role in regulating cardiovascular activity and blood pressure. We administered hydroxylamine hydrochloride (HA), a cystathionine-β-synthase inhibitor, into the PVN to suppress endogenous hydrogen sulfide and investigate its effects on the mitogen-activated protein kinase (MAPK) pathway in high salt (HS)-induced hypertension. We randomly divided 40 male Dahl salt-sensitive rats into 4 groups: the normal salt (NS) + PVN vehicle group, the NS + PVN HA group, the HS + PVN vehicle group, and the HS + PVN HA group, with 10 rats in each group. The rats in the NS groups were fed a NS diet containing 0.3% NaCl, while the HS groups were fed a HS diet containing 8% NaCl. The mean arterial pressure was calculated after noninvasive measurement using an automatic sphygmomanometer to occlude the tail cuff once a week. HA or vehicle was infused into the bilateral PVN using Alzet osmotic mini pumps for 6 weeks after the hypertension model was successfully established. We measured the levels of H 2 S in the PVN and plasma norepinephrine using enzyme linked immunosorbent assay. In addition, we assessed the parameters of the MAPK pathway, inflammation, and oxidative stress through western blotting, immunohistochemical analysis, or real-time polymerase chain reaction. In this study, we discovered that decreased levels of endogenous hydrogen sulfide in the PVN contributed to the onset of HS-induced hypertension. This was linked to the activation of the MAPK signaling pathway, proinflammatory cytokines, and oxidative stress in the PVN, as well as the activation of the sympathetic nervous system.
下丘脑室旁核(PVN)在调节心血管活动和血压(BP)方面起着核心作用。我们将胱硫醚-β-合成酶(CBS)抑制剂盐酸羟胺(HA)注入下丘脑室旁核,以抑制内源性硫化氢(H2S),并研究其对高盐诱导的高血压中丝裂原活化蛋白激酶(MAPK)通路的影响。我们将 40 只雄性 Dahl 盐敏感大鼠随机分为 4 组:NS+PVN 车辆组、NS+PVN HA 组、HS+PVN 车辆组和 HS+PVN HA 组,每组 10 只。NS(正常盐)组大鼠食用含 0.3% NaCl 的正常盐饮食,而 HS(高盐)组大鼠食用含 8% NaCl 的高盐饮食。每周一次使用自动血压计闭合尾部袖带进行无创测量,然后计算平均动脉压(MAP)。高血压模型成功建立后,使用 Alzet 渗透压微型泵将 HA 或药物注入双侧 PVN,持续 6 周。我们用酶联免疫吸附法测定了PVN中的H2S水平和血浆去甲肾上腺素(NE)水平。此外,我们还通过 Western 印迹、免疫组化分析或实时 PCR 评估了 MAPK 通路、炎症和氧化应激的参数。在目前的研究中,我们发现PVN中内源性硫化氢水平的降低是高盐诱导的高血压发病的原因之一。这与 MAPK 信号通路的激活、促炎细胞因子和 PVN 中的氧化应激以及交感神经系统的激活有关。
{"title":"The Impact of Hydrogen Sulfide in the Paraventricular Nucleus on the MAPK Pathway in High Salt-Induced Hypertension.","authors":"Yan-Feng Liang, Qing-Xin You, Shu-Yue Chen, Lei Ni, Xiang-Lian Meng, Jian-Xiang Gao, Yong-Bo Ren, Han-Jun Song, Jia-Lu Su, Yang Teng, Qing-Yun Gu, Chao Lv, Bo-Yang Yuan, Xuan Wang, Yong-Tai Zheng, Dong-Dong Zhang","doi":"10.1097/FJC.0000000000001622","DOIUrl":"10.1097/FJC.0000000000001622","url":null,"abstract":"<p><strong>Abstract: </strong>The hypothalamic paraventricular nucleus (PVN) plays a central role in regulating cardiovascular activity and blood pressure. We administered hydroxylamine hydrochloride (HA), a cystathionine-β-synthase inhibitor, into the PVN to suppress endogenous hydrogen sulfide and investigate its effects on the mitogen-activated protein kinase (MAPK) pathway in high salt (HS)-induced hypertension. We randomly divided 40 male Dahl salt-sensitive rats into 4 groups: the normal salt (NS) + PVN vehicle group, the NS + PVN HA group, the HS + PVN vehicle group, and the HS + PVN HA group, with 10 rats in each group. The rats in the NS groups were fed a NS diet containing 0.3% NaCl, while the HS groups were fed a HS diet containing 8% NaCl. The mean arterial pressure was calculated after noninvasive measurement using an automatic sphygmomanometer to occlude the tail cuff once a week. HA or vehicle was infused into the bilateral PVN using Alzet osmotic mini pumps for 6 weeks after the hypertension model was successfully established. We measured the levels of H 2 S in the PVN and plasma norepinephrine using enzyme linked immunosorbent assay. In addition, we assessed the parameters of the MAPK pathway, inflammation, and oxidative stress through western blotting, immunohistochemical analysis, or real-time polymerase chain reaction. In this study, we discovered that decreased levels of endogenous hydrogen sulfide in the PVN contributed to the onset of HS-induced hypertension. This was linked to the activation of the MAPK signaling pathway, proinflammatory cytokines, and oxidative stress in the PVN, as well as the activation of the sympathetic nervous system.</p>","PeriodicalId":15212,"journal":{"name":"Journal of Cardiovascular Pharmacology","volume":" ","pages":"468-478"},"PeriodicalIF":2.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11446517/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141901869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-13DOI: 10.1097/fjc.0000000000001630
Djemail Ismaili,Johannes Petersen,Carl Schulz,Thomas Eschenhagen,Jussi T Koivumäki,Torsten Christ
Atrial fibrillation (AF) poses a significant therapeutic challenge with drug interventions showing only limited success. Phosphodiesterases (PDE) regulate cardiac electrical stability and may represent an interesting target. Recently, PDE8 inhibition was proposed as an antiarrhythmic intervention by increasing L-type Ca2+ current (ICa,L) and action potential duration (APD). However, the effect size of PDE8 inhibition on ICa,L and APD seems discrepant and effects on force are unknown. We investigated the impact of PDE8 inhibition on force using PF-04957325 in right atrial appendages, obtained from patients in sinus rhythm (SR) and with persistent AF (peAF) undergoing cardiac surgery. A computational model was employed to predict the effects of PDE8 inhibition on APD in SR and peAF. Results showed no increase in force after exposure to increasing concentrations of the PDE8 inhibitor PF-04957325 in either SR or peAF tissues. Furthermore, PDE8 inhibition did not affect the potency or efficacy of norepinephrine-induced inotropic effects in either group. Arrhythmic events triggered by norepinephrine were observed in both SR and peAF, but their frequency remained unaffected by PF-04957325 treatment. Computational modeling predicted that the reported increase in ICa,L induced by PDE8 inhibition would lead to substantial APD prolongation at all repolarization states, particularly in peAF. Our findings indicate that PDE8 inhibition does not significantly impact force or arrhythmogenicity in human atrial tissue.
{"title":"PDE8 Inhibition and Its Impact on ICa,L in Persistent Atrial Fibrillation: Evaluation of PDE8 as a Potential Drug Target.","authors":"Djemail Ismaili,Johannes Petersen,Carl Schulz,Thomas Eschenhagen,Jussi T Koivumäki,Torsten Christ","doi":"10.1097/fjc.0000000000001630","DOIUrl":"https://doi.org/10.1097/fjc.0000000000001630","url":null,"abstract":"Atrial fibrillation (AF) poses a significant therapeutic challenge with drug interventions showing only limited success. Phosphodiesterases (PDE) regulate cardiac electrical stability and may represent an interesting target. Recently, PDE8 inhibition was proposed as an antiarrhythmic intervention by increasing L-type Ca2+ current (ICa,L) and action potential duration (APD). However, the effect size of PDE8 inhibition on ICa,L and APD seems discrepant and effects on force are unknown. We investigated the impact of PDE8 inhibition on force using PF-04957325 in right atrial appendages, obtained from patients in sinus rhythm (SR) and with persistent AF (peAF) undergoing cardiac surgery. A computational model was employed to predict the effects of PDE8 inhibition on APD in SR and peAF. Results showed no increase in force after exposure to increasing concentrations of the PDE8 inhibitor PF-04957325 in either SR or peAF tissues. Furthermore, PDE8 inhibition did not affect the potency or efficacy of norepinephrine-induced inotropic effects in either group. Arrhythmic events triggered by norepinephrine were observed in both SR and peAF, but their frequency remained unaffected by PF-04957325 treatment. Computational modeling predicted that the reported increase in ICa,L induced by PDE8 inhibition would lead to substantial APD prolongation at all repolarization states, particularly in peAF. Our findings indicate that PDE8 inhibition does not significantly impact force or arrhythmogenicity in human atrial tissue.","PeriodicalId":15212,"journal":{"name":"Journal of Cardiovascular Pharmacology","volume":"42 1","pages":""},"PeriodicalIF":3.0,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142252396","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}