Journal of Cardiovascular Pharmacology and Therapeutics最新文献

Background: Major atrial fibrillation (AF) guidelines recommend non-vitamin K antagonist oral anticoagulants (NOACs) over warfarin, except in rare clinical circumstances based on 4 randomized controlled trials comparing each NOAC with warfarin. We aimed to investigate the current NOAC prescription behaviors in alignment with the recent clinical evidence available.

Method: We conducted a cross-sectional analysis of NOAC-using patients with non-valvular atrial fibrillation (NVAF) who were aged ≥65 years on the index date (July 1, 2018) based on nationwide claims data. The types of NOACs being taken were analyzed using chi-squared tests, and factors influencing NOAC selection were identified using multinomial logistic regression analysis.

Results: A total of 6,061 patients were included. Among the 4 NOACs, rivaroxaban was the most used NOAC. Patients aged ≥75 years (odds ratio [OR] = 1.270, confidence interval [CI] = 1.089-1.450) and women (OR = 1.148, CI = 1.011-1.284) were more likely to use apixaban relative to rivaroxaban. Patients with prior stroke/transient ischemic attack/thromboembolism had higher odds of using dabigatran (OR = 1.508, CI = 1.312-1.704) and apixaban (OR = 1.186, CI = 1.026-1.346). Patients with renal disease had higher odds of using apixaban (OR = 1.466, 95% CI = 1.238-1.693). These findings are consistent with the efficacy and safety profiles reported in pivotal trials and observational studies comparing individual NOACs.

Conclusion: Among the 4 NOACs, rivaroxaban was the most commonly used NOAC. Apixaban was preferred for patients aged ≥75 years, females, and patients with renal disease.

Pulmonary veno-occlusive disease (PVOD) is a fatal disease of pulmonary vascular lesions leading to right heart failure. Heritable PVOD (hPVOD) is related to biallelic mutation of EIF2AK4 (encoding GCN2), but its molecular mechanism remains unclear. In this study, we aimed to investigate the pathogenesis of PVOD and to find potential drug targets for PVOD. GCN2 dysfunction led to an enhanced transcription of collagen I gene (col1a1 and col1a2) through decreasing ATF3-dependent p38 phosphorylation inhibition in PVOD, which promotes the collagen I synthesis in pulmonary arterial smooth muscle cells (PASMCs) and eventually leads to increased collagen deposition in pulmonary artery. Four GCN2 knockout (KO) cell lines (exon 15 or 33 mutation) were successfully constructed by epiCRISPR system. Two induced pluripotent stem cells (iPSCs) were generated by reprogramming peripheral blood mononuclear cells (PBMCs) of PVOD patient. It was also comfirmed that GCN2 dysfunction could lead to increased expression of collagen I in lateral plate mesoderm lineage-smooth muscle cells (LM-SMCs) differentiated from both GCN2 KO cell lines and iPSCs. SB203580 (a specific inhibitor of p38) improved hemodynamics and pulmonary vascular remodeling in mitomycin C (MMC)-induced PVOD rats by right ventricle echocardiography. On the whole, we proposed that GCN2 deficiency decreased ATF3-dependent p38 phosphorylation inhibition in PVOD development and suggested a potential therapeutic reagent of SB203580 for the treatment of the disease.

Introduction: Angiotensin-converting enzyme inhibitor (ACE-I) and angiotensin receptor blocker (ARB) discontinuation during acute heart failure (AHF) is associated with increased mortality following hospitalization. Although the etiology of acute kidney injury (AKI) in type 1 cardiorenal syndrome (CRS) has been linked to renal venous congestion, ACE-I/ARB withdrawal (AW) theoretically promotes renal function recovery. ACE-I/ARBs are dose-reduced or withheld in approximately half of patients with CRS, but the subsequent impact on renal function remains largely uninvestigated. This study compared AW to ACE-I/ARB continuation (AC) during CRS.

Methods: This was a retrospective, single-center chart review. Patients aged 18-89 years admitted from April 2018 to August 2019 with AHF and AKI were identified using discharge ICD-10 codes. All patients were treated with an ACE-I/ARB before admission. Key exclusion criteria included shock, pregnancy, and end-stage renal disease. The primary endpoint was change in serum creatinine (SCr) from admission through 72 hours. Data were analyzed utilizing chi-square and Mann-Whitney U tests with SPSS software.

Results: A total of 111 admissions were included. AW occurred in 68 patients upon admission. AW patients presented with a higher blood urea nitrogen (P = 0.034), higher SCr (P = 0.021), and lower ejection fraction (P = 0.04). Median SCr change from admission to 72 hours did not differ between groups (AW -0.1 mg/dL vs AC 0.0 mg/dL, P = 0.05). There was no difference in SCr reduction ≥0.3 mg/dL at 72 hours, 30-day readmissions, or ACE-I/ARB prescription at discharge.

Conclusions: In patients with type 1 CRS, AW was not associated with improved renal function at 72 hours. A larger sample size is necessary to confirm these results.

Background: Vascular stiffness and endothelial dysfunction are accelerated by acute myocardial infarction (AMI) and subsequently increase the risk for recurrent coronary events.

Aim: To explore whether remote ischemic perconditioning (RIPerc) protects against coronary and aorta endothelial dysfunction as well as aortic stiffness following AMI.

Methods: Male OFA-1 rats were subjected to 30 min of occlusion of the left anterior descending artery (LAD) followed by reperfusion either 3 or 28 days with or without RIPerc. Three groups: (1) sham operated (Sham, without LAD occlusion); (2) myocardial ischemia and reperfusion (MIR) and (3) MIR + RIPerc group with 3 cycles of 5 minutes of IR on hindlimb performed during myocardial ischemia were used. Assessment of vascular reactivity in isolated septal coronary arteries (non-occluded) and aortic rings as well as aortic stiffness was assessed by wire myography either 3 or 28 days after AMI, respectively. Markers of pro-inflammatory cytokines, adhesion molecules were assessed by RT-qPCR and ELISA.

Results: MIR promotes impaired endothelial-dependent relaxation in septal coronary artery segments, increased aortic stiffness and adverse left ventricular remodeling. These changes were markedly attenuated in rats treated with RIPerc and associated with a significant decline in P-selectin, IL-6 and TNF-α expression either in infarcted or non-infarcted myocardial tissue samples.

Conclusions: Our study for the first time demonstrated that RIPerc alleviates MIR-induced coronary artery endothelial dysfunction in non-occluded artery segments and attenuates aortic stiffness in rats. The vascular protective effects of RIPerc are associated with ameliorated inflammation and might therefore be caused by reduced inflammatory signaling.

Chloride channel 3 (ClC-3), a Cl^-/H⁺ antiporter, has been well established as a member of volume-regulated chloride channels (VRCCs). ClC-3 may be a crucial mediator for activating inflammation-associated signaling pathways by regulating protein phosphorylation. A growing number of studies have indicated that ClC-3 overexpression plays a crucial role in mediating increased plasma low-density lipoprotein levels, vascular endothelium dysfunction, pro-inflammatory activation of macrophages, hyper-proliferation and hyper-migration of vascular smooth muscle cells (VSMCs), as well as oxidative stress and foam cell formation, which are the main factors responsible for atherosclerotic plaque formation in the arterial wall. In the present review, we summarize the molecular structures and classical functions of ClC-3. We further discuss its emerging role in the atherosclerotic process. In conclusion, we explore the potential role of ClC-3 as a therapeutic target for atherosclerosis.

Background: Atherosclerotic cardiovascular disease is a significant cause of morbidity and mortality worldwide. While use of statin therapy has improved management of lipids, an unmet need in reducing residual atherosclerotic cardiovascular disease risk and ischemic events persists. We provide an overview of the pharmacology of omega-3 fatty acids, omega-3 fatty acid cardiovascular outcomes trials, landmark clinical data and pharmacology of icosapent ethyl (a stable and highly purified ethyl ester of eicosapentaenoic acid), and the critical differences between fish oil supplements and prescription omega-3 fatty acids.

Method: A PubMed literature review was conducted in April 2020 to identify articles discussing omega-3 fatty acid cardiovascular outcomes trials, pharmacology of icosapent ethyl, and the evaluation of fish oil dietary supplements and prescription omega-3 fatty acids.

Results: Both eicosapentaenoic acid and docosahexaenoic acid have been widely associated with positive health benefits; however, data are inconsistent regarding the benefit of combination eicosapentaenoic acid and docosahexaenoic acid in patients with cardiovascular disease. Eicosapentaenoic acid, and specifically icosapent ethyl, has demonstrated atherosclerotic cardiovascular disease risk reduction among statin-treated patients. Important clinical differences exist between dietary supplement and prescription omega-3 fatty acid products.

Conclusions: As research regarding the optimal management of dyslipidemia continues, additional therapy beyond statins is necessary to reduce atherosclerotic cardiovascular disease risk. In large cardiovascular outcomes trials, eicosapentaenoic acid has demonstrated cardiovascular benefit. Icosapent ethyl possesses a favorable efficacy and safety profile and should be considered as an adjunct to statin therapy to reduce ischemic event risk.

Neonatal megakaryopoiesis and platelet turnover form a developmentally unique pattern by generating a pool of newly released reticulated platelets from the bone marrow into the circulation. Reticulated platelets are more reactive and hyperaggregable compared to mature platelets, due to their high residual mRNA content, large size, increased expression of platelet surface receptors, and degranulation. The proportion of reticulated platelets in neonates is higher compared to that in adults. Due to the emergence of an uninhibited platelet subpopulation, the newly formed reticulated platelet pool is inherently hyporesponsive to antiplatelets. An elevated population of reticulated platelets is often associated with increased platelet reactivity and is inversely related to high on-treatment platelet reactivity, which can contribute to ischemia. Measurements of the reticulated platelet subpopulation could be a useful indicator of increased tendency for platelet aggregation. Future research is anticipated to define the distinct functional properties of newly formed reticulated or immature platelets in neonates, as well as determine the impact of enhanced platelet turnover and high residual platelet reactivity on the response to antiplatelet agents.

Background: Flecainide is a useful antiarrhythmic for atrial fibrillation (AF). However, because of ventricular proarrhythmia risk, a history of myocardial infarction (MI) or coronary artery disease (CAD) is a flecainide exclusion, and stress testing is used to exclude ischemia. We assessed whether absent/mild coronary artery calcium (CAC) can supplement or avoid the need for stress testing.

Methods: We assessed ischemic burden using regadenoson Rb-82 PET/CT in 1372 AF patients ≥50 years old without symptoms or signs of clinical CAD. CAC was determined qualitatively by low dose attenuation computed tomography (CT) (n = 816) or by quantitative CT (n = 556). Ischemic burden and clinical outcomes were compared by CAC burden.

Results: Patients with CAC absent or mild (n = 766, 57.2%) were younger, more frequently female, and had higher BMI but lower rates of diabetes, hypertension, and dyslipidemia. Average ischemic burden was lower in CAC-absent/mild patients, and CAC-absent/mild patients showed greater coronary flow reserve, had fewer referrals for coronary angiography, and less often had obstructive CAD. Revascularization at 90 days was lower, and the rate of longer-term major adverse cardiovascular events was favorable.

Conclusions: An easily administered, inexpensive, low radiation CAC scan can identify a subset of flecainide candidates with a low ischemic burden on PET stress testing that rarely needs coronary angiography/intervention and has favorable outcomes. Absent or mild CAC-burden combined with other clinical information may avoid or complement routine stress testing. However, additional, ideally randomized and multicenter trials are indicated to confirm these findings before replacing stress testing with CAC screening in selecting patients for flecainide therapy in clinical practice.

In the era of the coronavirus disease 2019 (COVID-19) pandemic, acute cardiac injury (ACI), as reflected by elevated cardiac troponin above the 99th percentile, has been observed in 8%-62% of patients with COVID-19 infection with highest incidence and mortality recorded in patients with severe infection. Apart from the clinically and electrocardiographically discernible causes of ACI, such as acute myocardial infarction (MI), other cardiac causes need to be considered such as myocarditis, Takotsubo syndrome, and direct injury from COVID-19, together with noncardiac conditions, such as pulmonary embolism, critical illness, and sepsis. Acute coronary syndromes (ACS) with normal or near-normal coronary arteries (ACS-NNOCA) appear to have a higher prevalence in both COVID-19 positive and negative patients in the pandemic compared to the pre-pandemic era. Echocardiography, coronary angiography, chest computed tomography and/or cardiac magnetic resonance imaging may render a correct diagnosis, obviating the need for endomyocardial biopsy. Importantly, a significant delay has been recorded in patients with ACS seeking advice for their symptoms, while their routine care has been sharply disrupted with fewer urgent coronary angiographies and/or primary percutaneous coronary interventions performed in the case of ST-elevation MI (STEMI) with an inappropriate shift toward thrombolysis, all contributing to a higher complication rate in these patients. Thus, new challenges have emerged in rendering a diagnosis and delivering treatment in patients with ACI/ACS in the pandemic era. These issues, the various mechanisms involved in the development of ACI/ACS, and relevant current guidelines are herein reviewed.

Arterial perivascular adipose tissue (PVAT) can elicit vasodilator signals complementary to those elicited by the endothelium in SHRSP.Z-Lepr^fa/IzmDmcr (SHRSP.ZF) rats, an animal model of metabolic syndrome (MetS). Here, we tested whether a glucose cotransporter 2 inhibitor (SGLT2-i; tofogliflozin) increased this PVAT effect to prevent the deterioration of cardiac function in aging SHRSP.ZF rats. Tofogliflozin treatments (1 or 10 mg/kg/day) or vehicle (control) were administered for 10 weeks by oral gavage to SHRSP.ZF rats, starting at 13 weeks of age. At 23 weeks of age, glucose levels in the serum and urine (24 h after the last administration) were determined using commercial kits. Vasodilator responsiveness of PVAT-surrounded or PVAT-free superior mesenteric arteries was determined using acetylcholine with organ-bath methods. Cardiac ventricular function and coronary flow were determined using Langendorff heart preparations. Serum and urine glucose levels in SGLT2-i treatment groups did not differ from those in the controls, but the ratios of glycated to non-glycated albumin were lower than those in the controls. Tofogliflozin treatments did not alter relaxations in the presence of PVAT or affect relaxations of PVAT-free arteries. Left ventricular systolic pressures, maximum rate of pressure decline, and coronary flow in ex vivo hearts did not differ among the treatment groups. PVAT effects and cardiac dysfunction were not altered by tofogliflozin treatment in SHRSP.ZF rats with MetS. These results do not provide strong evidence to support the use of SGLT2-i as a cardiovascular protective therapy in MetS, which occurs prior to the onset of type 2 diabetes.