Journal of Cardiovascular Pharmacology最新文献

Abstract: Takotsubo syndrome (TTS) is an acute stress-induced cardiomyopathy characterized by transient left ventricular dysfunction, often mimicking acute myocardial infarction but without obstructive coronary artery disease. Although typically reversible, TTS can be complicated by serious adverse events, including life-threatening ventricular arrhythmias. The pathophysiology is complex but strongly linked to sympathetic nervous system hyperactivity and a surge in catecholamines, often termed "neurogenic stunned myocardium." This review discusses the role of arrhythmias in TTS, the influence of the autonomic nervous system, and explores the rationale, mechanisms, and potential applications of stellate ganglion blockade, particularly left stellate ganglion blockade, in the management of TTS-related arrhythmias, illustrated by a clinical case.

Abstract: Atherosclerosis is a chronic progressive disease that occurs in the inner walls of arteries. Endothelial dysfunction is a key component in the early stages of atherosclerosis. Unhealthy lifestyle factors (eg, smoking), hypertension, hyperglycemia, and hyperlipidemia are important risk factors that may induce endothelial cell injury or even lead to cellular death. Hypertension contributes to atherosclerosis by exerting mechanical stress that damages endothelial cells. Current studies have shown that vascular endothelial cells are mainly involved in programmed cell death pathways, including apoptosis, pyroptosis, autophagy, ferroptosis, necroptosis, cuproptosis, parthanatos, and NETosis. This review synthesizes current knowledge on programmed cell death pathways in vascular endothelia during atherogenesis, delineating their triggering factors, molecular underpinnings, and potential regulatory targets.

Abstract: Hypercholesterolemia is associated with atherosclerotic cardiovascular disease (ASCVD), a leading cause of morbidity and mortality. Nonstatin lipid-lowering therapies (LLTs) such as ezetimibe, proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies (mAbs), bempedoic acid, and inclisiran have been recommended in clinical guidelines to treat patients with ASCVD and/or high cardiovascular (CV) risk having elevated low-density lipoprotein cholesterol (LDL-C) despite being treated with maximally tolerated doses (MTD) of statins. Our previously published network meta-analysis (NMA) 1 was updated in this study to evaluate comparative efficacy of nonstatin LLTs in reducing LDL-C among patients with ASCVD and/or high CV risk receiving MTD statins. The systematic literature review previously conducted to inform our NMA was updated through January 2023, wherein more recent clinical trials of nonstatin LLTs (ORION-15, ORION-18, and HUA TUO) and additional data on monthly dosing regimens for PCSK9 mAbs were included. The outcome of interest was percentage change in LDL-C at week 24. Random-effects Bayesian NMA was performed. Comparative efficacy was estimated as mean difference (MD) with 95% credible intervals (CrIs). A total of 20 trials were deemed relevant for the NMA. Consistent with the previous findings from our NMA, this study demonstrated that inclisiran provided superior efficacy in LDL-C lowering compared with ezetimibe and bempedoic acid (MD: -44.24 [95% CrI: -51.84 to -36.70]). This NMA further reaffirmed that inclisiran provided comparable LDL-C reduction versus alirocumab (MD: -1.93% [95% CrI: -8.56 to 4.20]) and evolocumab (MD: 2.00% [95% CrI: -4.58 to 8.60]) among patients with ASCVD and/or high CV risk on MTD statins.

Abstract: Takotsubo syndrome (TTS) is a stress-induced cardiomyopathy that is associated with important morbidity and in-hospital mortality. Microvascular dysfunction, inflammation, and fibrosis may play crucial roles in TTS pathophysiology. In this study, we investigated the effect of methotrexate (MTX), an antiproliferative and immunosuppressive drug, on ventricular function in a rat model of takotsubo syndrome. TTS induction was performed in Wistar male rats with 2 subcutaneous injections of isoproterenol (ISO, 85 mg/kg), with a 24-hour interval. Twenty-seven animals were allocated to 3 groups: sham: controls treated with saline; ISO: TTS-induced with ISO, treated with saline; MTX: TTS-induced with ISO, treated with MTX (1 mg/kg i.p.). Animals were treated once a week, for 4 weeks. After treatments, animals underwent an echocardiographic examination. Histology and protein expression of markers of apoptosis, angiogenesis, and fibrosis were performed. Linear correlation was used to test echocardiographic variables versus protein expression. MTX treatment improved LV systolic and diastolic functions in TTS rats, shown by higher ejection fraction (66% vs. 44%, P < 0.05) and normalized E/A ratio (1.6 ± 0.3 vs. 3.4 ± 0.7, P < 0.05). MTX reduced myocardial fibrosis in subendocardium and interstitium and decreased expression of proapoptotic markers (caspase 3 and BAX/Bcl-2 ratio). In addition, MTX-treated rats exhibited reduced hypoxia, as indicated by lower HIF-2α expression, and increased angiogenesis, evidenced by elevated VEGF. In conclusion, MTX treatment enhances cardiac function and decreases adverse remodeling in this TTS rat model, conceivably through antifibrotic and proangiogenic mechanisms. These findings suggest that MTX may be a promising therapeutic option for TTS, warranting further investigation.

Abstract: Postural orthostatic tachycardia syndrome (POTS) is a clinical syndrome of tachycardia on standing leading to palpitations, dizziness, chest pain, and/or fatigue. An exaggerated norepinephrine response with standing is often present in POTS, but it remains unclear whether the tachycardia is compensatory for a reduced stroke volume or whether the tachycardia is itself causing the symptoms of POTS. We herein report the effects of heart rate (HR) lowering with ivabradine, a selective I f channel blocker, on symptom burden in patients with POTS. After ivabradine treatment, there was a significant reduction in the change in HR with standing in all patients from 40 (30-70) to 15 (8-19) bpm ( P = 0.011), without significant changes in blood pressure. The Malmö score was significantly reduced in all patients from 86 (74-92) to 39 (32-66) ( P = 0.005). A correlation between change in HR with standing and the change in Malmö score (R = +0.828; R 2 quadratic = 0.635; P < 0.001) was present. The parallel improvement in HR response and symptoms with ivabradine suggests that the tachycardia response in POTS may not be considered compensatory but rather central to the pathophysiology of POTS symptoms.

Abstract: Flavin adenine dinucleotide (FAD), a cofactor that catalyzes the reaction of flavin protein, participates in fatty acid β-oxidation, which has been shown to inhibit pathological cardiac hypertrophy and fibrosis in spontaneously hypertensive rats. However, the therapeutic advantage of FAD for heart failure (HF) treatment has not been investigated. This study aimed to explore the effects and underlying mechanisms of FAD in a transverse aortic constriction-induced HF mouse model and in vitro tert-butyl hydroperoxide (tBHP)-induced cardiomyocyte apoptosis model experiments. FAD considerably inhibited tBHP-induced cardiomyocyte apoptosis. In addition, FAD significantly increased the activity and expression of the short-chain acyl-CoA dehydrogenase enzyme and adenosine triphosphate (ATP) content while reducing the content of free fatty acids and reactive oxygen species both in vitro and in vivo. Meanwhile, FAD increased the mitochondrial membrane potential, suppressed mitochondrial membrane swelling, and decreased myocardial fibrosis and TUNEL-positive apoptosis cells in the TAC-induced HF mice. In conclusion, our results indicate that FAD plays a positive role in preventing and treating HF, which can be attributed in part to the activation of short-chain acyl-CoA dehydrogenase.

Abstract: Oxytocin (OT) has been shown to provide myocardial protection against ischemia-reperfusion (I/R) injury. This study investigates the involvement of muscarinic receptors in the OT-induced cardioprotection, focusing on its potential mechanisms and effects on myocardial infarction (MI) and ischemic arrhythmias. Male rats anesthetized with pentobarbital sodium were subjected to 25-minute ischemia followed by 120-minute reperfusion after intraperitoneal administration of OT (0.01 μg), atropine (1.5 µg/kg), or saline. Cardioprotection was evaluated by monitoring lactate dehydrogenase, malondialdehyde, and cardiac creatine kinase isoenzyme levels, infarct size, arrhythmia severity, ventricular fibrillation (VF), and mortality. OT markedly reduced infarct size, oxidative stress, and the severity of ischemic arrhythmias, including ventricular tachycardia and VF, compared with saline-treated I/R animals. OT also significantly improved survival rates. Pretreatment with atropine abolished most protective effects of OT but did not significantly alter its suppression of VF, suggesting the involvement of muscarinic receptor-independent mechanisms. These findings highlight that the OT-induced cardioprotection, mediated in part by acetylcholine locally released in the left ventricle, extends beyond infarct limitation to include potent antiarrhythmic effects. The dual impact of OT on MI and arrhythmias provides insights into the mechanisms underlying its preconditioning effect and its potential application in MI management.

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive, fatal disease. Dissociation of tetrameric transthyretin (TTR) is the triggering event in the pathogenic mechanism; destabilizing TTR mutations accelerate the process. The TTR stabilizers, tafamidis and acoramidis, are the only FDA approved treatments for patients with ATTR-CM. By mimicking the stabilizing characteristics of the super-stabilizing, disease-protecting variant T119M, we hypothesize that acoramidis displays differential TTR binding, kinetic stability, and tetramer stabilization compared with other TTR stabilizers, such as tafamidis and diflunisal. The TTR binding affinity and thermodynamic stability of TTR interaction of acoramidis and tafamidis were assessed by surface plasmon resonance (SPR) and microscale thermophoresis (MST). Tetrameric TTR stabilization by acoramidis, tafamidis, and diflunisal in the presence of plasma proteins against acidic denaturation was measured by immune blots. In kinetic studies, SPR demonstrated 4 times longer residence time for acoramidis bound to TTR compared with tafamidis. The dissociation constants were consistent with those determined by equilibrium measurements in MST. The affinity of acoramidis for purified TTR, as measured by MST, was 4 times higher than that of tafamidis. When tested at clinically relevant plasma concentrations, acoramidis stabilized TTR against acidic denaturation to a much higher extent (≥90%) than tafamidis or diflunisal. Of note, both tafamidis and diflunisal demonstrated partial stabilization of tetrameric TTR. Relative to other stabilizers, acoramidis is more potent as independently assessed by TTR binding affinity, kinetic stability, and acid-mediated denaturation. These properties may contribute to the ability of acoramidis to achieve near-complete stabilization of TTR in plasma samples.