Journal of Cardiovascular Pharmacology最新文献

Intravenous (IV) digoxin loading dose recommendations for rate control of atrial arrhythmias in critically ill patients are not well studied. When using digoxin in the setting of atrial fibrillation/atrial flutter (AF/AFL), a loading dose (LD) in either a fixed-dose regimen, weight-based dose, or pharmacokinetic-based calculation to target a serum digoxin concentration (SDC) of 0.8-1.5 ng/mL is recommended. The objective of this study was to assess the safety and effectiveness of digoxin LD used in critically ill patients for rate control of AF/AFL and to assess the SDC achieved. This single center retrospective cohort study included patients who received IV digoxin and had a SDC drawn. The primary endpoint was the median SDC achieved after a digoxin LD. Secondary outcomes included the frequency of SDCs ≥1.5 ng/mL and heart rate (HR) control. A total of 92 patients were included. The median total LD of digoxin for the entire cohort was 11mcg/kg (750 mcg). For 61% of the cohort, the LD was distributed over six-hour intervals. The median SDC after completion of the IV digoxin LD was 1.3 ng/mL (0.9, 1.7). The incidence of supratherapeutic SDC was 36% for the total cohort. A target HR < 110 beats per minute within 24 hours from digoxin LD was achieved in 60% of the cohort. In conclusion, a median total digoxin LD of 750 mcg in critically ill patients with AF/AFL, targeting a SDC < 1.5ng/mL may be considered for acute rate control, taking into account drug-drug interactions in the cardiac intensive care unit. Future studies are necessary to confirm our findings.

The clinical effect of drug-drug interactions (DDIs) between antiplatelets and antiretrovirals (ART) on bleeding, thrombosis, and other major adverse cardiovascular events (MACE) is unknown. The objective of this retrospective study was to assess the incidence of DDI at P2Y12 inhibitor (P2Y12inh) initiation and the effect of DDI on patient outcomes. Adult people living with human immunodeficiency virus (PLWH; HIV) receiving ART newly initiated on an oral P2Y12inh were included. The primary outcome was the incidence of DDI between ART and P2Y12inh at P2Y12inh initiation. Secondary outcomes included bleeding events, MACE, and switches in P2Y12inh. There were 149 PLWH included, of these, 119 (80%) were initiated on clopidogrel, 23 (15%) on ticagrelor, and 7 (5%) on prasugrel. 93 PLWH (60%) had a DDI at time of P2Y12inh initiation, with highest incidence in the clopidogrel group (n=84, 71%), followed by ticagrelor (n=9, 39%) and none with prasugrel. Within 1 year, MACE occurred in 12 PLWH, with DDI present at the time of 4 events. There were 29 bleeding events occurring within 1 year, including 17 events with DDI at time of event. However, 88% of DDI in patients with bleeding events were expected to decrease the efficacy of P2Y12inh. Though we observed high incidence of DDI between P2Y12inh and ART in PLWH, MACE and bleeding events at 1 year did not correlate with DDI. It remains unknown if DDI presence at P2Y12inh initiation with ART causes clinical outcomes of concern, or if underlying platelet reactivity in PLWH is associated with these events.

Patients with ST-segment elevation myocardial infarction (STEMI) and complex coronary artery disease (CAD) face a poor prognosis, including increased heart failure (HF) risk. Phase 2 clinical trials of anakinra have shown inhibition of the acute inflammatory response and prevention of HF after STEMI, but data on its effects based on CAD complexity are lacking. We performed a pooled secondary analysis of 139 patients with STEMI. The SYNTAX (Synergy Between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery), SYNTAX II and Gensini scores were calculated, and patients were divided into two groups below and above the median. We evaluated the effect of anakinra on the area-under-the-curve of high-sensitivity C-reactive protein (hsCRP-AUC) at 14 days, and the composite endpoint of new-onset HF, HF hospitalization, or all-cause death at 1-year follow-up using Kaplan-Meier survival curves, Cox regression analysis for Hazard Ratios (HR), and tested interactions between subgroups. All three CAD complexity scores (SYNTAX, SYNTAX II and Gensini) were associated with an increased risk of adverse events (HR 1.02 to 1.06, all p-values ≤0.025). We found no statistically significant interactions between CAD extent, measured as single-vessel or multi-vessel CAD, SYNTAX score ≤9 or >9, SYNTAX II score ≤24 or >24, Gensini score ≤32 or >32, and treatment effect of anakinra on hsCRP-AUC or the composite clinical endpoint (all p-values for interaction >0.05). In conclusion, among patients with STEMI, IL-1 blockade with anakinra significantly attenuated the acute inflammatory response and reduced the risk of HF-related events regardless of the spectrum of CAD complexity.

Melatonin is a neuroendocrine hormone that exerts protective effects on the heart. Increasing evidence suggests that macrophage M2-type polarization improves myocardial regeneration and repair. Therefore, this study investigated whether melatonin ameliorates dilated cardiomyopathy (DCM) by modulating M2-type polarization. DCM mice were established by induction with doxorubicin and then treated with melatonin. Cardiac dysfunction was determined by measuring left ventricular ejection fraction (LVEF) and left ventricular internal dimensions at end-diastole and end-systole. Heart injury and fibrosis were determined by hematoxylin and eosin staining and Sirius Red staining, respectively. Serum concentrations of melatonin, tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6) were measured through enzyme-linked immunosorbent assays. M2-type macrophages were analyzed by flow cytometry. Relative mRNA and protein levels were determined by reverse transcription quantitative polymerase chain reaction and western blotting, respectively. Circulating melatonin levels were significantly decreased in DCM mice and were associated with LVEF. Treatment with melatonin markedly ameliorated cardiac dysfunction, improved survival, and alleviated pathological changes and collagen deposition in DCM mice. Furthermore, melatonin-treated DCM mice displayed lower serum and cardiac levels of IL-1β, IL-6, and TNF-α, as well as higher numbers of M2-type macrophages in cardiac tissue, indicating that melatonin treatment could decrease inflammatory responses and facilitate M2 macrophage polarization in DCM mice. Thus, melatonin treatment alleviated cardiac dysfunction and inflammatory responses by promoting M2 macrophage polarization in the DCM mouse model.

Glucagon-like peptide-1 (GLP-1) receptor agonists exhibit beneficial cardiovascular effects. However, the renal effects of different doses of liraglutide in an essential hypertension model have not yet been investigated. SHR female rats were treated for 30 days, twice a day, with saline (control) or liraglutide at low (0.06 mg/kg, LL) and high (0.6 mg/kg, LH) doses. Volume intake and excretion were monitored for a period of 24h. In renal tissue, nitrite-NO2-, nitrate-NO3-, advanced protein oxidation products-AOPP, collagen deposition, creatinine (Cr), urea (U), sodium, and potassium were analyzed. liraglutide reduced body weight gain in both groups. However, in the high dose, it increased urinary volume excretion and sodium/potassium ratio. Both doses reduced the urinary U/Cr ratio and LH increased the serum U/Cr ratio. AOPP was reduced only in LL. LH augmented collagen and early markers of kidney injury (blood urea nitrogen-BUN, BUN/Cr). LH increased NO3-, reduced NO2-, and caused an aberrant increase in GFR. Both doses' effects were independent of blood pressure and glycemic control. liraglutide appears to have distinct effects on the hypertensive female kidney depending on the dose, with higher doses impairing kidney function.

HECT-type E3 ubiquitin ligases (HECT E3s) participate in the progression of cardiovascular diseases. HERC2 has been reported to play critical roles in many pathological processes, but its role in cardiac hypertrophy remains unclear. In this study, we observed that the expression and activity of HERC2 was significantly upregulated in hypertrophic hearts and angiotensin II (Ang II)-stimulated primary cardiomyocytes. Knockdown of HERC2 in cardiomyocytes significantly alleviated the myocardial hypertrophy induced by Ang II. Conversely, cardiac specific overexpression of HERC2 aggravated Ang II-induced cardiac hypertrophy in vitro and in vivo. Furthermore, we demonstrated that HERC2 promoted cardiac hypertrophy via increasing the expression of lin-28 homologue A (Lin28a), an RNA-binding protein that regulates pathological cardiac hypertrophic. Knocking down Lin28a attenuated Ang II-induced myocardial hypertrophy and abolished the increase in myocardial hypertrophy by overexpression of HERC2. Further investigation indicated that HERC2 promoted the expression level of Lin28a by reducing MeCP2, a transcriptional suppressor of Lin28a. We also showed that the pro-hypertrophic effect of HERC2 was partially dependent on MeCP2 inhibition. Mechanistically, HERC2 directly bound with MeCP2, and promoting its K48-linked polyubiquitination and degradation. Combined, these findings demonstrate HERC2 plays a crucial role in pathological cardiac hypertrophy, thereby indicating that targeting the HERC2/MeCP2/Lin28a axis is a potential strategy for heart failure therapy.

Abstract: The aim of this study was to explore the relationship between in-stent neoatherosclerosis (ISNA) and the neutrophil-to-lymphocyte ratio (NLR) in patients with in-stent restenosis (ISR) following drug-eluting stent (DES) implantation. We divided 216 patients into 3 groups based on the NLR tertile. We performed a comparative analysis of baseline, angiographic, and features of optical coherence tomography (OCT) between the NLR groups and performed univariate and multivariate logistic regression analyses to assess the association of the NLR with ISNA and in-stent thin-cap fibroatheroma (TCFA). Patients in the third tertile NLR group had a higher incidence of ISNA and in-stent TCFA compared with those in the first tertile. Multivariate logistic regression analysis showed that the hazard ratios and 95% confidence intervals for ISNA and TCFA were 2.673 (1.257-5.684; P = 0.038) and 4.272 (1.740-10.488; P = 0.004), respectively, for patients in the highest tertile compared with those in the lowest tertile. Our study showed that an increased NLR was associated with ISNA and in-stent plaque fragility in patients with ISR following DES implantation.

Abstract: Panax notoginseng has the effect of stimulating circulation to end stasis. Our study was designed to evaluate the anti-thrombotic effect of protoparaxotriol saponins (PTS) from P. notoginseng and the involved mechanisms. A thrombosis model was constructed, and the anti-thrombotic activity of PTS was determined by erythrocyte staining, heart rate, and blood flow velocity. In addition, quantitative real-time polymerase chain reaction was used to identify changes in the expression of genes related to coagulation, inflammation, and apoptosis. PTS alleviated arachidonic acid-induced caudal vein thrombosis, restored blood flow, and increased the area of cardiac erythrocyte staining, heart rate, and blood flow velocity. It reduced the ponatinib-induced cerebral thrombus area and decreased the intensity of erythrocyte staining. The quantitative polymerase chain reaction data showed that the anti-thrombotic effect of PTS was mediated by suppression of genes related to coagulation, inflammation, and apoptosis and also involved inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathways.

Abstract: Heart failure has always been a prevalent, disabling, and potentially life-threatening disease. For the treatment of heart failure, controlling cardiac remodeling is very important. In recent years, clinical trials have shown that sodium-glucose cotransporter-2 (SGLT-2) inhibitors not only excel in lowering glucose levels but also demonstrate favorable cardiovascular protective effects. However, the precise mechanisms behind the cardiovascular benefits of SGLT-2 inhibitors remain elusive. In this research, we assessed the impact of canagliflozin (CANA, an SGLT-2 inhibitor) on cardiac remodeling progression in mice and preliminarily elucidated the possible mechanism of action of the SGLT-2 inhibitor. Our results indicate that the administration of canagliflozin significantly attenuates myocardial hypertrophy and fibrosis and enhances cardiac ejection function in mice with isoprenaline (ISO)-induced cardiac remodeling. Notably, excessive mitophagy, along with mitochondrial structural abnormalities observed in ISO-induced cardiac remodeling, was mitigated by canagliflozin treatment, thereby attenuating cardiac remodeling progression. Furthermore, the differential expression of AMPK/PINK1/Parkin pathway-related proteins in ISO-induced cardiac remodeling was effectively reversed by canagliflozin, suggesting the therapeutic potential of targeting this pathway with the drug. Thus, our study indicates that canagliflozin holds promise in mitigating cardiac injury, enhancing cardiac function, and potentially exerting cardioprotective effects by modulating mitochondrial function and mitophagy through the AMPK/PINK1/Parkin pathway.