Journal of Cardiovascular Pharmacology最新文献

Research objective: This study explored the effects of long-term cold stress (CS) on aortic vascular function in guinea pigs.

Research methods: Hartley guinea pigs (n = 32) were divided into the following groups: atherosclerosis (AS), CS, and menthol-stimulated (M), and control (C). On days 1, 15, 30, 45, and 60, guinea pigs in the AS, CS, and M groups were intraperitoneally injected with bovine serum albumin. The C group was provided with maintenance feed and room temperature water. The AS group was provided with a high-fat diet and room temperature water. The CS group was maintained in a refrigerator at 4°C, while providing a high-fat diet and iced water. The M group was administered menthol solution, and provided with a high-fat diet and room temperature water. The modeling period lasted for 120 days. On day 121, abdominal aortic sera and aortic samples were obtained after intraperitoneal injection of sodium pentobarbital. Blood rheology tests were conducted to assess blood adhesion, biochemical tests to assess lipid levels, and enzyme-linked immunosorbent assays to detect serum nuclear factor-κB, tumor necrosis factor-α, and interleukin-1β, and endothelial nitric oxide synthase, nitric oxide, and endothelin-1 (ET-1) in aortic tissue. Hematoxylin and eosin and oil red O staining were used to examine pathologic changes in the aorta, Western blotting to detect transient receptor potential melastatin 8 and protein kinase G protein expression, quantitative polymerase chain reaction was used to measure VCAM-1 mRNA expression level.

Research findings: Prolonged exposure to CS exacerbated lipid-metabolism disorders in guinea pigs fed a high-fat diet, increased aortic vascular cell adhesion, and exacerbated vascular inflammation, leading to endothelial injury, ultimately worsening pathologic changes associated with aortic atherosclerosis.

Abstract: Cardiac hypertrophy is a crucial risk factor for heart failure when the heart is confronted with physiologic or pathologic stimuli. The ubiquitin-proteasome system plays a critical role in the pathogenesis of cardiac hypertrophy. However, as a key component of the ubiquitin-proteasome system, the role of deubiquitinating enzymes in cardiac hypertrophy is not well understood. In this study, we observed that the expression level of deubiquitinase USP47 was increased in hypertrophic hearts and angiotensin II (Ang II)-stimulated neonatal rat cardiomyocytes. Adenovirus-mediated gain- and loss-of-function approaches indicated that USP47 overexpression significantly attenuated Ang II-induced cardiac hypertrophy in vitro and in vivo, whereas endogenous USP47 deficiency promoted the prohypertrophic effect of Ang II. Further investigation demonstrated that USP47 inhibited O-GlcNAcylation in cardiomyocytes by controlling the expression of O-GlcNAcase. Mechanistically, USP47 bound, deubiquitinated, and stabilized protein arginine methyltransferase 5 (PRMT5), thus upregulating O-GlcNAcase expression. We found that the restoration of PRMT5 abolished the prohypertrophic effects of USP47 silence in vitro. Therefore, our results provide the first evidence of the involvement of USP47 in cardiac hypertrophy and identify USP47 as a potential target for hypertrophic therapy.

It is unclear whether drugs other than warfarin can cause spontaneous gastrointestinal intraluminal hematomas (SGIH). This study aimed to investigate the drugs that induced SGIH based on the FDA Adverse Event Reporting System (FAERS) data. A retrospective pharmacovigilance study was conducted. The disproportionality analysis was performed to assess the reports of drug-induced SGIH from the first quarter of 2004 to the fourth quarter of 2023. Logistics regression analysis was used to explore drug-related SGIH risk factors. Weibull distribution was applied for the onset time of SGIH. A total of 116 drugs associated with SGIH have been reported in the FAERS database. After removing duplicates, 88 unique drugs involving 210 patients were identified. These drugs can be broadly classified into four categories: (1) anticoagulants, (2) new direct oral anticoagulants, (3) antiplatelet agents, and (4) others. The first group is dominated by warfarin (59/210), while the second group, rivaroxaban, accounts for the most significant proportion (9/210). As for the third group, aspirin is the dominant drug (16/210), and for the fourth group, drugs that cause thrombocytopenia are dominant. The median number of reported cases was 11.5 per year, accounting for a median percentage of 0.0094% of all adverse events related to target drugs. The median time to drug-related SGIH onset was 12.5 days (interquartile range 1-220.25 days). When patients on the related drugs present with corresponding abdominal symptoms, it is crucial to consider the differential diagnosis of SGIH despite its low incidence.

The number of patients living with chronic kidney diseases is increasing, and so are the patients with end-stage renal disease (ESRD) undergoing renal replacement therapy (RRT). While there is a common understanding that these patients face higher risks of fatal or non-fatal cardiovascular and cerebrovascular events, and mineralocorticoid receptor antagonists (MRA) have been an essential pillar in managing heart failure, their use in this subset of patients have been overshadowed due to concerns of hyperkalemia. ESRD patients under RRT have often been excluded from landmark trials. This meta-analysis was conducted based on the PRISMA guideline after registering the protocol with PROSPERO (CRD42024499835). A database search included articles until April 2024 and relevant data extracted from the included studies. Analysis was done using RevMan web (version 5.4). A total of 15 studies among 1086 studies were included in the final analysis. Our meta-analysis revealed MRA significantly reduced all-cause mortality (OR 0.35, CI 0.23- 0.54) and cardio-vascular mortality (OR 0.37, 0.21-0.65). With some possible increase in the risk of hyperkalemia (OR 1.56, CI 1.01-2.42), with no discernible difference in the occurrence of stroke (OR 0.57, CI 0.25-1.28) or MI (OR 0.63, CI 0.08-4.72). The utilization of MRA in patients with ESRD under dialysis is linked to improved mortality outcomes, albeit with slight concerns for hyperkalemia. While current evidence leans towards MRA usage, prospective randomized controlled trials involving a broader patient cohort are essential to establish robust guidance for MRA application in this subset of patients.

Large scale randomized trials have shown that sodium-glucose co-transporter 2 (SGLT2) inhibitors can reduce cardiovascular events in patients with cardiovascular disease or with increased risks of cardiovascular disease. However, the evidence from older patients is limited. To compare the efficacy of SGLT2 inhibitors among non-older and older patients we have searched PubMed, Cochrane Central, and Embase until February 2023 for randomized controlled trials (RCTs) investigating SGLT2 inhibitors in older (age ≥ 65 years) patients with diabetes mellitus, chronic kidney disease, and chronic heart failure. The primary outcome was a composite outcome of cardiovascular death, acute myocardial infarction, and stroke. The secondary outcomes were exacerbation of heart failure, kidney disease progression, and a composite of cardiovascular death and heart failure. Our search identified 11 RCTs with a total of 79,370 patients. SGLT2 inhibitors were associated with a reduced risk of the primary outcome in the total cohort (HR: 0.91; CI [0.84-0.99]) with concordant results in both non-older and older populations (HR: 0.96; CI [0.88-1.05], HR: 0.87; CI [0.75-1.01], respectively) without subgroup differences (p=0.23), and a reduced risk of developing the composite of cardiovascular death and heart failure exacerbation in both non-older and older populations (HR: 0.77; CI [0.67-0.87], HR: 0.76; CI [0.71-0.82], respectively) without subgroup differences (p=0.96). A meta-analysis could not be performed for the other outcomes. These results suggested that SGLT2 inhibitors were similarly associated with a reduced risks of cardiovascular events across the spectrum of non-older and older patients with risk factors for developing cardiovascular disease.

Abstract: Patients with atrial fibrillation (AF) taking antithrombotic (AT) therapy are at an increased risk of gastrointestinal bleeding (GIB). The comparative effect of a combination of anticoagulant (AC) and antiplatelet (AP) versus AC monotherapy on clinical outcomes in patients with AF presenting with GIB is not well characterized. This study compares outcomes in AF patients with GIB on AC alone with those on combination AP and AC therapy, as part of a larger prospective study from 2013 to 2023. One hundred and thirty-seven patients diagnosed with AF who presented with overt GIB were evaluated during their hospitalization, at 1 month and 1 year postdischarge and then annually. The median follow-up of patients was 57 months. Patients in the combination AP + AC therapy group had a higher prevalence of coronary artery disease, myocardial infarction, and coronary/vascular stent placement compared with the AC monotherapy group. No statistically significant differences were noted between the 2 groups in terms of end-of-follow-up mortality, in-hospital mortality, major bleeding, rebleeding, and length of hospital stay. Cox regression analysis revealed chronic kidney disease [hazard ratio (HR) 2.05, 95% confidence interval (1.04-4.05) ( P = 0.038)] and warfarin use [HR 4.94, 95% confidence interval (1.11-22.09) ( P = 0.037)] to be independent predictors of mortality at 12 months. Antithrombotic therapy in patients with AF who experience GIB should be mainly directed by their cardiovascular needs. Health care providers may explore non-vitamin K antagonist oral anticoagulants as alternatives to warfarin for AF patients at risk of GIB, and efforts must be maximized to prevent bleeding in patients with chronic kidney disease.

Abstract: In a randomized double-blinded clinical trial of patients with ST segment elevation myocardial infarction (STEMI), goflikicept, an interleukin-1 blocker, significantly reduced systemic inflammation, measured as the area under the curve (AUC) for high-sensitivity C reactive protein at 14 days. We report secondary analyses of biomarkers at 28 days, and cardiac function and clinical end points at 1 year. Patients received a single administration of goflikicept 80 mg (n = 34), goflikicept 160 mg (n = 34), or placebo (n = 34). Both doses of goflikicept significantly reduced the AUC for high-sensitivity C reactive protein at 28 days compared with placebo, without statistically significant differences between the doses. There were no statistically significant differences between groups in the AUC for natriuretic peptides at 28 days. There were no significant differences between placebo, goflikicept 80 mg, and 160 mg groups in deaths (2.9%, 2.9%, and 0%), hospitalization for cardiovascular reasons (9.1%, 5.9%, and 0%), new-onset or progression of heart failure (9.1%, 5.9%, and 5.9%), and new or increased use of loop diuretics (24.2%, 14.7%, and 17.6%), nor in the number of patients with treatment emergent adverse events, with no treatment-related serious adverse events in any group. In conclusion, in patients with STEMI, interleukin-1 blockade with goflikicept 80 mg or 160 mg was well tolerated and associated with significant reduction of systemic inflammation. Further adequately powered studies are warranted to determine whether the reduction in systemic inflammation with goflikicept translates into a clinical benefit in patients with STEMI.

Abstract: Extracorporeal membrane oxygenation (ECMO) is a mechanical support treatment modality used in patients with refractory cardiac and/or pulmonary failure. Bleeding and thrombotic complications associated with ECMO are inherent concerns that require careful management. Anticoagulation optimization may help mitigate these risks by providing more adequate therapeutic anticoagulation and lessen the bleed risk. Heparin, the most used anticoagulant, carries concerns for heparin-induced thrombocytopenia and possible resistance given its dependence on cofactors and circulating proteins to exert its pharmacologic effect. In contrast, bivalirudin, a direct thrombin inhibitor, exerts its effect independent of cofactors or plasma proteins, and possesses thrombin-binding and metabolism features that may confer advantages in ECMO management. This review of the evidence for bivalirudin utilization in ECMO suggests favorable outcomes in circuit-related thrombosis, bleeding, and dosing reliability. In addition, blood product utilization, circuit interventions, and success in ECMO decannulation and survival were positive findings associated with bivalirudin that merit consideration. Common questions and concerns relative to bivalirudin utilization, including laboratory monitoring, utilization in low-flow states, dosing considerations in renal replacement therapy, reversibility, and cost are also discussed in this review. Moreover, this review suggests that bivalirudin utilization presents the opportunity for ECMO management simplification.

Abstract: Malnutrition is known to worsen the prognosis of chronic heart failure (HF). To gain information that may be helpful in establishing appropriate nutritional interventions for chronic HF, this study was performed to investigate the efficacy of nutritional management with 2 enteral formulas, EH, with a standard nutritional composition, and ER, fortified with omega-3 fatty acids, vitamin D, and carnitine. Experiments were performed in a Dahl rat HF model. After being fed a standard rodent feed (MF) containing 8% NaCl (high salt-MF [HS-MF]) from 6 to 11 weeks of age, rats were assigned to freeze-dried EH or ER diets with an NaCl concentration of 8% (HS-ER or HS-EH) until 18 weeks of age. Serum albumin was significantly higher at 14 and 17 weeks of age in rats fed the HS-ER and HS-EH diets compared with those remaining on the HS-MF diet. Body weight was also significantly higher at 14 and 17 weeks of age in animals fed the HS-ER diet, showing that nutritional deterioration was prevented. In addition, heart weight was significantly lower at 18 weeks of age in the HS-ER group than that in the HS-MF group, suggesting that cardiac hypertrophy was prevented. This study demonstrated improved nutritional status in a HF model in Dahl rats presumably owing to differences in nutritional composition in the diets. Future studies are needed to explore optimal nutritional management with enteral formulas in patients with chronic HF.