Journal of Cardiovascular Pharmacology and Therapeutics最新文献

Over the past decade, soluble guanylate cyclase (sGC) activators and stimulators have been developed and studied to improve outcomes in patients with heart failure with reduced ejection fraction (HFrEF). The sGC enzyme plays an important role in the nitric oxide (NO)-sGC-cyclic guanosine monophosphate (cGMP) pathway, that has been largely untargeted by current guideline directed medical therapy (GDMT) for HFrEF. Disruption of the NO-sCG-cGMP pathway can be widely observed in patients with HFrEF leading to endothelial dysfunction. The disruption is caused by an oxidized state resulting in low bioavailability of NO and cGMP. The increase in reactive oxygen species can also result in an oxidized, and subsequently heme free, sGC enzyme that NO is unable to activate, furthering the endothelial dysfunction. The novel sGC stimulators enhance the sensitivity of sGC to NO, and independently stimulate sGC, while the sGC activators target the oxidized and heme free sGC to stimulate cGMP production. This review will discuss the pathophysiologic basis for sGC stimulator and activator use in HFrEF, review the pre-clinical and clinical data, and propose a place in the HFrEF armamentarium for this novel pharmacotherapeutic class.

Excessive myocardial oxygen consumption (MVO₂) is considered a limitation for catecholamines, termed oxygen cost of contractility. We hypothesize that increased MVO₂ induced by dobutamine is not directly related to contractility but linked to intermediary myocardial metabolism. Furthermore, we hypothesize that selective β₃ adrenergic receptor (β₃AR) antagonism using L-748,337 prevents this. In an open-chest pig model, using general anesthesia, we assessed cardiac energetics, hemodynamics and arterial metabolic substrate levels at baseline, ½ hour and 6 hours after onset of drug infusion. Cardiac efficiency was assessed by relating MVO₂ to left ventricular work (PVA; pressure-volume area). Three groups received dobutamine (5 μg/kg/min), dobutamine + L-748,337 (bolus 50 μg/kg), or saline for time-matched controls. Cardiac efficiency was impaired over time with dobutamine infusion, displayed by persistently increased unloaded MVO₂ from ½ hour and 47% increase in the slope of the PVA-MVO₂ relation after 6 hours. Contractility increased immediately with dobutamine infusion (dP/dt_max; 1636 ± 478 vs 2888 ± 818 mmHg/s, P < 0.05) and persisted throughout the protocol (2864 ± 1055 mmHg/s, P < 0.05). Arterial free fatty acid increased gradually (0.22 ± 0.13 vs 0.39 ± 0.30 mM, P < 0.05) with peak levels after 6 hours (1.1 ± 0.4 mM, P < 0.05). By combining dobutamine with L-748,337 the progressive impairment in cardiac efficiency was attenuated. Interestingly, this combined treatment effect occurred despite similar alterations in cardiac inotropy and substrate supply. We conclude that the extent of cardiac inefficiency following adrenergic stimulation is dependent on the duration of drug infusion, and β₃AR blockade may attenuate this effect.

Background: Only limited data are available that address the association between body mass index (BMI) and clinical outcomes in patients with heart failure with reduced ejection fraction who are receiving sacubitril/valsartan.

Methods: We performed a retrospective multi-center cohort study in which we compared 3 body mass index groups (normal, overweight and obese groups) in patients with heart failure with reduced ejection fraction receiving sacubitril/valsartan. The follow-up period was at least 1 year. Propensity score weighting was performed. The primary outcomes were hospitalization for heart failure and all-cause mortality.

Results: Of the 721 patients in the original cohort, propensity score weighting generated a cohort of 540 patients in 3 groups: normal weight (n = 78), overweight (n = 181), and obese (n = 281). All baseline characteristics were well-balanced between 3 groups after propensity score weighting. Among our results, we found no significant differences in hospitalization for heart failure (normal weight versus overweight: average hazard ratio [AHR] 1.29, 95% confidence interval [CI] = 0.76-2.20, P = 0.35; normal weight versus obese: AHR 1.04, 95% CI = 0.63-1.70, P = 0.88; overweight versus obese groups: AHR 0.81, 95% CI = 0.54-1.20, P = 0.29) or all-cause mortality (normal weight versus overweight: AHR 0.99, 95% CI = 0.59-1.67, P = 0.97; normal weight versus obese: AHR 0.87, 95% CI = 0.53-1.42, P = 0.57; overweight versus obese: AHR 0.87, 95% CI = 0.58-1.32, P = 0.52).

Conclusion: We identified no significant associations between BMI and clinical outcomes in patients diagnosed with heart failure with a reduced ejection fraction who were treated with sacubitril/valsartan. A large-scale study should be performed to verify these results.

Cardiac reperfusion injury is a well-established outcome following treatment of acute myocardial infarction and other types of ischemic heart conditions. Numerous cardioprotection protocols and therapies have been pursued with success in pre-clinical models. Unfortunately, there has been lack of successful large-scale clinical translation, perhaps in part due to the multiple pathways that reperfusion can contribute to cell death. The search continues for new cardioprotection protocols based on what has been learned from past results. One class of cardioprotection protocols that remain under active investigation is that of controlled reperfusion. This class consists of those approaches that modify, in a controlled manner, the content of the reperfusate or the mechanical properties of the reperfusate (e.g., pressure and flow). This review article first provides a basic overview of the primary pathways to cell death that have the potential to be addressed by various forms of controlled reperfusion, including no-reflow phenomenon, ion imbalances (particularly calcium overload), and oxidative stress. Descriptions of various controlled reperfusion approaches are described, along with summaries of both mechanistic and outcome-oriented studies at the pre-clinical and clinical phases. This review will constrain itself to approaches that modify endogenously-occurring blood components. These approaches include ischemic postconditioning, gentle reperfusion, controlled hypoxic reperfusion, controlled hyperoxic reperfusion, controlled acidotic reperfusion, and controlled ionic reperfusion. This review concludes with a discussion of the limitations of past approaches and how they point to potential directions of investigation for the future.

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.