Journal of Cardiovascular Pharmacology and Therapeutics最新文献

Background: Neurohormonal blocking drugs, like beta-blockers, angiotensin-converting enzyme inhibitors (ACEIs), and angiotensin receptor blockers (ARBs), are recommended for treating anthracycline-induced left ventricular dysfunction (AILVD). However, there is limited evidence supporting their benefit. Therefore, this study evaluated associations of neurohormonal blockers and other clinical factors with recovery of left ventricular ejection fraction (LVEF) in patients with AILVD.

Methods: This retrospective chart review assessed patients treated with at least one dose of anthracycline, then had ≥10% LVEF reduction or post-anthracycline LVEF value <50%, and then had a follow-up LVEF measurement ≥90 days later. The primary endpoint was LVEF recovery (highest follow-up LVEF-lowest LVEF post-anthracycline). Variables from univariable tests with P < .1 were incorporated in a multiple linear regression model for independent factors significantly associated with LVEF recovery (P < .05).

Results: Out of 104 patients, 83% were female, 86% self-reported white race, 53% had breast cancer, median (IQR) age was 52 (22) years, and LVEF recovery was 14% (16%). The final multivariable model included 2 significant variables: beta-blocker dose after anthracycline exposure (every 25 mg increase in beta-blocker dose was associated with 5.0% increase in LVEF recovery; P = .0005) and the time between the start of the anthracycline and the lowest LVEF post-anthracycline (every 5-year increase in time was associated with 1.8% decrease in LVEF recovery; P = .0379).

Conclusions: In patients with AILVD, a higher beta-blocker dose and earlier detection of LVEF reduction post-anthracycline were significantly and independently associated with improved LVEF recovery. These findings need to be validated in a larger, independent cohort.

Objective: Annexin-A1 (ANXA1) participates in regulating ferroptosis. Ferroptosis is involved in myocardial ischemia-reperfusion injury (MIRI). However, effect and mechanism of ANXA1 in ferroptosis after MIRI remain unclear. Materials and Methods: Gene expression omnibus database was used to screen differentially expressed genes (DEGs), and R package was used to visualize the volcano map and heat map of DEGs in MIRI. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes analyses were used to analyze the related signaling pathways and functions of DEGs. FerrDb database was used to find genes related to ferroptosis. H9c2 cells were cultured under hypoxia/reoxygenation (H/R). Quantitative real-time polymerase chain reaction and western blot detected mRNA and protein expression of relevant genes. Mitochondrial membrane potential was determined by JC-1. Cell viability was assessed using CCK-8. Levels of Fe²⁺, glutathione, malondialdehyde, and reactive oxygen species (ROS) were detected by kits. Results: Genes such as ANXA1 were highly expressed in MIRI compared to normal tissues. Hypoxic cardiomyocytes had enhanced viability after knocking down ANXA1. ANXA1 depletion improved ferroptosis and altered mitochondrial functioning in cardiomyocytes under H/R condition. Ferroptosis inducer Erastin reversed this phenomenon. Phosphorylation levels of c-Jun N-terminal kinase, P38, and Raf in H9c2 cells after ANXA1 silencing were increased. With treatment of RAF inhibitor Sorafenib, above results were reversed. ANXA1 depletion alleviated ferroptosis and mitochondrial damage by activating RAS/Raf/mitogen-activated protein kinase (MAPK) pathway in H/R-induced cardiomyocytes. Conclusions: ANXA1 knockdown reduces cardiomyocyte ferroptosis after MIRI by regulating RAS/Raf/MAPK signaling pathway, which provides new therapeutic targets for MIRI treatment.

Background: Vitamin K antagonists (VKA) continue to be the principal anticoagulants for both the treatment and prevention of venous thromboembolism. The use of VKA often requires regular monitoring to avoid over-anticoagulation and prevent thromboembolic complications. The aim was to determine the indication for VKA use and factors associated with suboptimal anticoagulation control among patients in northern Tanzania.

Methods: This was a retrospective cohort study that examined the anticoagulation data of patients on long-term VKA from 1^st January 2020 to 31^st December 2022. Eligible participants were those on VKAs for at least 7 days and with at least 3 international normalized ratio (INR) results. The level of anticoagulation control was determined through the calculation of the time-in-therapeutic range (TiTR) using the Rosendaal and the percent of INR in therapeutic range methods.

Results: TiTR was found to be 17% using the direct method and 16% using the Rosendaal formula. 102 tests out of 365 were within the target range (28%). Absence of health insurance (aRR: 1.24, 95% CI: 1.06-1.44, P = .007), alcohol consumption (aRR: 1.37, 95% CI: 1.15-1.62, P < .001), and prolonged intervals between tests of 14 to 28 days (aRR: 1.34, 95% CI: 1.05-1.74, P = .018) showed association with INR being out of range.

Conclusion: Patients who achieved target therapeutic anticoagulation control were less than the acceptable 65%. Anticoagulation outcomes were better in patients with frequent INR monitoring and those with health insurance. Alcohol consumption carries a high risk of poor anticoagulation control. Further studies are needed to enforce better INR control.

BackgroundThe therapeutic potential of the human amnion has been known since the early twentieth century. Subsequent study has revealed the further therapeutic potential of all elements of the amnion-membrane, cells, fluid-in the treatment of cardiac disease.Materials and MethodsA systematic review was performed utilizing PubMed/MEDLINE and Embase with search terms including "amniotic fluid," "cardiovascular disease," "cardiac disease," "amnion," "amniotic membrane," and "heart." Results were reviewed by each author to ensure inclusion of all relevant articles. Animal studies were included for evaluation of existing preclinical models, and the few available clinical studies of amniotic products were included.ResultsPreclinical studies addressing organ function, assessment, and enhancement of cardiac performance in response to injury, and regenerative potential are included, as are the few clinical studies utilizing amniotic products for the treatment of cardiac disease. Therapeutic approaches include reduction of inflammation, immunomodulation, and the promotion of myocardial regeneration via cellular therapy to target the most common mechanisms underlying myocardial injury.ConclusionsThe components of the human amnion have anti-inflammatory, immunomodulatory, and pro-differentiation abilities which lend the ability to attenuate myocardial ischemia-reperfusion injury, temper cardiac fibrosis, and promote activation of progenitor cells to induce regeneration. Preclinical studies have focused heavily on cellular therapy, but clinical experience has yielded little success. The acellular components of the amnion have fueled more recent investigation and represent a new source of enthusiasm for clinical translation of amniotic products in the treatment of cardiac disease.

BackgroundCardiovascular disease remains the first major reason for death in global, and hypertension is one very usual risk factor for this disease. Chemokine (CXC motif) ligand 13 (CXCL13) exhibits a crucial role in the development and angiogenesis of a variety of diseases. However, the impacts of CXCL13 in the amelioration of hypertension and the associated regulatory mechanisms have rarely reported.MethodsThe hypertensive rat model was induced by Ang II treatment. The protein and mRNA expressions were measured through western blot and RT-qPCR. The systolic blood pressure was monitored. The ET-1 level was examined through the commercial kit. The thickness of vascular elasticity layer was observed through hematoxylin eosin staining. The levels of angiotensin-converting enzyme (ACE), thiobarbituric acid-reactive substances (TBARS), and brain natriuretic peptide (BNP) were inspected through the commercial kits.ResultsCXCL13 exhibited high protein and mRNA expressions in hypertensive rat model. Knockdown of CXCL13 improved vascular remodeling and elevated blood pressure in hypertensive rat model. Moreover, suppression of CXCL13 protected heart in hypertensive rat model through declining the levels of ACE, TBARS, and serum BNP. Next, it was demonstrated that CXCL13 modulated the PF4V1/NF-κB pathway. Eventually, through rescue assays, it was proved that CXCL13 ameliorated hypertension through affecting PF4V1.ConclusionThis study manifested that knockdown of CXCL13 improved vascular remodeling, reduced blood pressure, and protected the heart by affecting the PF4V1/NF-κB signaling pathway in a hypertensive rat model. This discovery may offer novel opinions in the treatment of hypertension.

BackgroundSodium-glucose co-transporter 2 (SGLT2) inhibitors have demonstrated significant cardiovascular benefits in clinical trial. While their role in reducing heart failure hospitalizations and cardiovascular mortality is well established, the precise mechanisms underlying their direct cardiac effects remain unclear. This literature review aims to synthesize current knowledge on the molecular and physiological pathways by which SGLT2 inhibitors may exert effects on cardiac tissue, independent of glycemic control.MethodsA comprehensive review of peer-reviewed articles, randomized controlled trials, meta-analyses, and mechanistic studies published in PubMed and related databases was conducted. The search focused on studies examining the direct impact of SGLT2 inhibitors on cardiac function, remodeling, metabolism, and intracellular signaling pathways. Only studies evaluating the cardiac effects separate from their glucose-lowering action were included in the analysis.ResultsThis review identified several key mechanisms by which SGLT2 inhibitors may benefit the heart directly, including reductions in oxidative stress, inflammation, and myocardial fibrosis. Emerging evidence suggests that these drugs modulate key pathways such as sodium-hydrogen exchange (NHE) inhibition, improvement of mitochondrial function, and promotion of ketone body utilization in cardiomyocytes.ConclusionsSGLT2 inhibitors appear to confer direct cardioprotective effects. These include anti-inflammatory, anti-fibrotic, and energy efficiency improvements in the myocardium. The findings highlight new potential therapeutic mechanisms and provide a foundation for further research into the non-diabetic use of SGLT2 inhibitors in heart failure and other cardiac conditions. Understanding these direct effects could lead to optimized treatment strategies for patients with and without diabetes.

PurposeDemonstration of the role of autocrine motility factor receptor (AMFR) in atrial fibrillation (AF) mice.MethodsThe AF model was established by administering Ang II to mice and transfected with AMFR knockdown or AMFR overexpression plasmids by tail vein injection of the AAV vector. Atrial fibrosis was examined by Masson staining. The mRNA expression of inflammatory factors TNF-α, IL-1β, and IL-6 in atrial tissue was detected by PCR. Reactive oxygen species (ROS) production in atrial tissue was examined by dihydroethidium staining. Apoptotic cells of atrial tissue were examined by TUNEL staining. The expression levels of fibrosis-related genes (COL1A1 and α-SMA), apoptosis-related genes (cleaved-caspase3 and cleaved-PARP), and SOD1 were detected by western blot. The ubiquitination level of superoxide dismutase 1 (SOD1) was detected by ubiquitination assay.ResultsAng II resulted in increased AMFR expression in mouse atrial tissue, and knockdown of AMFR inhibited atrial fibrosis, inflammatory factors, and ROS production, as well as apoptosis in mice. In addition, the knockdown of AMFR inhibited the ubiquitination level of SOD1 and increased the protein expression level of SOD1, whereas overexpression of AMFR exerted the opposite effect and aggravated Ang II-induced AF.ConclusionKnockdown of AMFR promotes SOD1 expression by inhibiting SOD1 ubiquitination levels and attenuates atrial fibrosis in AF mice by regulating SOD1.

Hypopituitarism, resulting from a partial or complete deficiency of anterior or posterior pituitary hormones, is associated with increased cardiovascular (CV) morbidity and mortality. This heterogeneous endocrinological disorder may arise from various etiologies, including genetic mutations, pituitary tumors, traumatic brain injury, and autoimmune diseases. Hypopituitarism often results in multiple endocrine deficits that contribute to metabolic dysregulation characterized by insulin resistance, dyslipidemia, and increased visceral adiposity, all known risk factors for CV disease (CVD). Additionally, the presence of chronic inflammation and endothelial dysfunction further increases the risk of CVD in these patients. While standard hormone replacement therapy (HRT) is crucial for restoring hormonal balance, it can sometimes have adverse metabolic effects that can exacerbate atherosclerosis and CVD. Emerging evidence suggests that optimizing HRT regimens and addressing specific hormone deficiencies, such as growth hormone and cortisol, may reduce these risks and improve CV outcomes. This review comprehensively analyzes the etiology, pathophysiological mechanisms underlying CV risk in anterior pituitary dysfunction, and treatment strategies to mitigate CV morbidity and mortality in patients with hypopituitarism.

BackgroundClopidogrel is a pro-drug that requires metabolic activation by hepatic cytochrome P450 (CYP) enzymes in two steps. Previous studies have shown that the administration of continuous nitrate significantly affects the activity of hepatic CYP. In this pilot study, we assess the impact of intravenous nitrate treatment on the antiplatelet effects of clopidogrel in patients with non-ST-elevation myocardial infarction (NSTEMI).MethodWe included 20 NSTEMI patients: 15 in the nitrate group and five in the control group. All patients received a 300 mg acetylsalicylic acid and a 600 mg clopidogrel loading dose. The nitrate group was administered an intravenous glyceryl trinitrate infusion at 10 µg/min for 48 h. After the drugs were initiated, blood samples were collected from patients at intervals of 30th minutes, 60th minutes, 120th minutes, fourth hour, sixth hour, and 48th hour to assess platelet function. The antiplatelet effect of clopidogrel was evaluated using the platelet reactivity unit (PRU) from the Verify-Now P2Y12 assay.ResultThe PRU values at baseline and the 30th, 60th, 120th minutes, and 48th hour were similar between the two groups (P > .05). However, PRU values at the fourth and sixth hours were significantly higher in the nitrate group than in the control group (274.1 ± 53.9 vs 162.4 ± 39.9; P = .002 and 272.0 ± 67.0 vs 185.6 ± 18.1; P = .03, respectively).ConclusionIntravenous nitrate therapy in patients with NSTEMI delayed the onset of the antiplatelet effect of orally loaded clopidogrel by at least 4 h. This point should be kept in mind in patients using clopidogrel and nitrate therapy together. (NCT06878638).