Stress-induced stenotic vascular remodeling via reduction of plasma omega-3 fatty acid metabolite 4-oxoDHA by noradrenaline.

Stress has garnered significant attention as a prominent risk factor for inflammation-related diseases, particularly cardiovascular diseases (CVDs). However, the precise mechanisms underlying stress-driven CVDs remain elusive, thereby impeding the development of preventive and therapeutic strategies. To explore the correlation between plasma lipid metabolites and human depressive states, liquid chromatography-mass spectrometry (LC/MS) based analysis of plasma and the self-rating depression (SDS) scale questionnaire were employed. We also used a mouse model with restraint stress to study its effects on plasma lipid metabolites and stenotic vascular remodeling following carotid ligation. In vitro functional and mechanistic studies were performed using macrophages, endothelial cells, and neutrophil cells. We revealed a significant association between depressive state and reduced plasma levels of 4-oxoDHA, a specific omega-3 fatty acid metabolite biosynthesized by 5-lipoxygenase (LO), mainly in neutrophils. In mice, restraint stress decreased plasma 4-oxoDHA levels and exacerbated stenotic vascular remodeling, ameliorated by 4-oxoDHA supplementation. 4-oxoDHA enhanced Nrf2-HO-1 pathways, exerting anti-inflammatory effects on endothelial cells and macrophages. One of the stress hormones, noradrenaline, reduced 4-oxoDHA and the degraded 5-LO in neutrophils through the proteasome system, facilitated by dopamine D2-like receptor activation. Our study proposed circulating 4-oxoDHA levels as a stress biomarker and supplementation of 4-oxoDHA as a novel therapeutic approach for controlling stress-related vascular inflammation.

Novel UV-B Phototherapy With a Light-Emitting Diode Device Prevents Atherosclerosis by Augmenting Regulatory T-Cell Responses in Mice.

BACKGROUND: Ultraviolet B (UV-B) irradiation is an effective treatment for human cutaneous disorders and was shown to reduce experimental atherosclerosis by attenuating immunoinflammatory responses. The aim of this study was to clarify the effect of specific wavelengths of UV-B on atherosclerosis and the underlying mechanisms focusing on immunoinflammatory responses. METHODS AND RESULTS: Based on light-emitting diode technology, we developed novel devices that can emit 282 nm UV-B, which we do not receive from natural sunlight, 301 nm UV-B, and clinically available 312 nm UV-B. We irradiated 6-week-old male atherosclerosis-prone Apoe-/- (apolipoprotein E-deficient) mice with specific wavelengths of UV-B and evaluated atherosclerosis and immunoinflammatory responses by performing histological analysis, flow cytometry, biochemical assays, and liquid chromatography/mass spectrometry-based lipidomics. Irradiation of 282 nm UV-B but not 301 or 312 nm UV-B significantly reduced the development of aortic root atherosclerotic plaques and plaque inflammation. This atheroprotection was associated with specifically augmented immune responses of anti-inflammatory CD4+ Foxp3 (forkhead box P3)+ regulatory T cells in lymphoid tissues, whereas responses of other immune cells were not substantially affected. Analysis of various lipid mediators revealed that 282 nm UV-B markedly increased the ratio of proresolving to proinflammatory lipid mediators in the skin. CONCLUSIONS: We demonstrated that 282 nm UV-B irradiation effectively reduces aortic inflammation and the development of atherosclerosis by systemically augmenting regulatory T-cell responses and modulating the balance between proresolving and proinflammatory lipid mediators in the skin. Our findings indicate that a novel 282 nm UV-B phototherapy could be an attractive approach to treat atherosclerosis.

Electrophysiological and Pathological Impact of Medium-Dose External Carbon Ion and Proton Beam Radiation on the Left Ventricle in an Animal Model.

Background Medium-dose (25 gray) x-ray radiation therapy has recently been performed on patients with refractory ventricular tachyarrhythmias. Unlike x-ray, carbon ion and proton beam radiation can deliver most of their energy to the target tissues. This study investigated the electrophysiological and pathological changes caused by medium-dose carbon ion and proton beam radiation in the left ventricle (LV). Methods and Results External beam radiation in the whole LV was performed in 32 rabbits. A total of 9 rabbits were not irradiated (control). At the 3-month or 6-month follow-up, the animals underwent an open-chest electrophysiological study and were euthanized for histological analyses. No acute death occurred. Significant LV dysfunction was not seen. The surface ECG revealed a significant reduction in the P and QRS wave voltages in the radiation groups. The electrophysiological study showed that the local conduction times in each LV site were significantly longer and that the local LV bipolar voltages were significantly lower in the radiation groups than in the control rabbits. Histologically, apoptosis, fibrotic changes, and a decrease in the expression of the connexin 43 protein were seen in the LV myocardium. These changes were obvious at 3 months, and the effects were sustained 6 months after radiation. No histological changes were seen in the coronary artery and esophagus, but partial radiation pneumonitis was observed. Conclusions Medium-dose carbon ion and proton beam radiation in the whole LV resulted in a significant electrophysiological disturbance and pathological changes in the myocardium. Radiation of the arrhythmogenic substrate would modify the electrical status and potentially induce the antiarrhythmic effect.

The role of balloon pulmonary angioplasty and pulmonary endarterectomy: Is chronic thromboembolic pulmonary hypertension still a life-threatening disease?

BACKGROUND: The management of non-operable chronic thromboembolic pulmonary hypertension (CTEPH) has evolved with the availability of balloon pulmonary angioplasty (BPA) and pulmonary vasodilators. We launched the BPA program in 2011. The aim was to analyze the survival and treatment efficacy of our CTEPH treatment program in the modern management era. METHODS AND RESULTS: We retrospectively reviewed data from 143 consecutive CTEPH patients diagnosed from January 2011 (i.e. after the availability of BPA) to December 2019. Of forty-one patients who underwent pulmonary endarterectomy (PEA), 25 underwent additional BPA (Combination group) and the others were treated with only PEA (PEA group). Ninety patients underwent BPA (BPA group). The remaining 12 patients did not undergo any interventional treatments. The 1- and 5-year survival rates of operated patients (n = 41) were 97.4% and 90.0%, compared to 96.9% and 86.9% in not-operated patients (n = 102), respectively (p = 0.579). There was no mortality in the Combination group. Mean pulmonary artery pressure after treatments in the PEA only, Combination, and BPA only groups was 20.5 ± 6.7, 17.9 ± 4.9, and 20.7 ± 4.6 mmHg, respectively (p = 0.067, one-way ANOVA). Percent decrease of pulmonary vascular resistance in each treatment groups was -73.7 ± 11.3%, -74.3 ± 11.8%, and - 54.9 ± 22.5%, respectively (p < 0.01, one-way ANOVA). CONCLUSION: There was no significant difference in long-term survival between operated and not-operated CTEPH. Moreover, the Combination approach might have the potential to introduce notable improvements in the prognosis of CTEPH. BPA and PEA appear to be mutually complementary therapies in the modern management era.

Efficacy of preoperative amino acid supplements on postoperative physical function and complications in open heart surgery patients: A study protocol for a randomized controlled trial.

BACKGROUND: Elderly patients undergoing cardiac surgery often show poor nutritional status, muscle wasting, and sarcopenia, which are reported to affect postoperative functional recovery and incidence of complications. Amino acids are essential in maintaining nutritional status, synthesizing muscle protein, and promoting beneficial energy balance of the heart muscle. ß-Hydroxy ß-methylbutyric acid (HMB) is a leucine metabolite known to increase muscle protein synthesis and inhibit protein catabolism; it has been used to more effectively support patients with muscle wasting due to wearing diseases. However, the efficacy of amino acid administration comprising HMB in patients undergoing open heart surgery remains unclear. This study aims to examine whether preoperative short-term aggressive amino acid administration helps support postoperative recovery of physical function and prevent complications. METHODS: This is a single-center prospective randomized controlled trial (UMIN000030490). Patients aged ≥65 years who will be hospitalized for medical examination before cardiac surgery will be recruited. The participants will be randomly assigned to the experimental or control group. The experimental group will be administered with an amino acid supplement with HMB 1200mg, l-glutamine 7000mg, and l-arginine 7000mg once or twice per day depending on the degree of renal dysfunction, for 14-28 days preoperatively. The control group will not receive any nutritional intervention. The main outcome will be a change in the 6-min walking test distance pre- and postoperatively as a sign of functional recovery. Secondary outcomes such as the incidence of complications; physical, nutritional, and psychological states; mortality; and length of hospital stay will also be evaluated. CONCLUSION: This clinical study will determine the effects of preoperative short-term oral amino acid supplementation with HMB, l-glutamine, and l-arginine on postoperative physical function in elderly patients undergoing cardiac surgery.

Characteristics of Residual Atrial Posterior Wall and Roof-Dependent Atrial Tachycardias after Pulmonary Vein Isolation.

BACKGROUND: Roof-dependent atrial tachycardia (roof AT) sometimes occurs after pulmonary vein isolation (PVI) of atrial fibrillation (AF). This study aimed to investigate the relationship between the anatomy of the residual left atrial posterior wall and occurrence of roof AT. METHODS: A total of 265 patients with AF who underwent PVI were enrolled. After the PVI, induced or recurrent roof AT was confirmed by an entrainment maneuver or activation mapping using a three-dimensional (3D) mapping system. To identify the predictors of roof AT, the minimum distance between both PVI lines (d-PVI) was measured by a 3D mapping system and the anatomical parameters, including the left atrial (LA) diameter, left atrial volume index (LAVi), and shape of the left atrial roof, were analyzed by 3D computed tomography. RESULTS: Roof AT was documented in 11 (4.2%) of 265 patients. A multivariable analysis demonstrated that the d-PVI, Deep V shape of the LA roof, and LAVi were associated with roof AT occurrences (d-PVI: odds ratio: 0.72, confidence interval [CI]: 0.61-0.86, P < 0.001; Deep V shape: odds ratio: 0.19, CI: 0.04-0.82, P = 0.03; LAVi: odds ratio: 1.05, CI: 1.02-1.07, P = 0.001). A receiver-operating characteristic curve analysis yielded an optimal cut-off value of 15.5 mm and 55.7 mL/m2 for the d-PVI and LAVi, respectively. CONCLUSION: The shorter d-PVI at the LA roof, greater LAVi, and Deep V shape were associated with the occurrence of a roof AT.

The Relationship Between Cardiac Vulnerability and Restitution Properties of the Ventricular Activation Recovery Interval.

INTRODUCTION: The restitution of the action potential duration (APD) is an important contributor to ventricular fibrillation (VF) initiation by a single critically timed ectopic beat. We hypothesized that a steep slope of the activation recovery interval restitution curve was related to the upper limit of vulnerability (ULV). METHODS AND RESULTS: Fifty-four consecutive patients with implantable cardioverter defibrillators (ICDs) implanted between April 2012 and July 2013 were included. At the implantation, pacing from the right ventricular (RV) coil to an indifferent electrode inserted in the ICD pocket was performed, and the unipolar electrograms from the RV coil were simultaneously recorded. We assessed the standard restitution by introducing extra-stimuli, while measuring the activation recovery interval (ARI). Our protocol for the vulnerability test consisted of delivering three 15 J shocks on the T-peak and within ±20 milliseconds of it. If VF was not induced by that procedure, a ULV of ≤15 J was defined. The relationship between the ULV and maximum slope of the restitution curve was analyzed. A restitution curve could finally be obtained in a total of 40 patients. The background characteristics were similar between the two groups. The maximum slope of the restitution curve was steeper in the ULV > 15 J group than ULV ≤ 15 J group (1.55 ± 0.45 vs. 0.91 ± 0.64, P < 0.05). A maximum slope exceeding 1.0 was the optimal point for discriminating patients with a ULV > 15 J from a ULV ≤ 15 J (sensitivity 61.5% and specificity 96.3%). CONCLUSION: The maximum slope of the restitution curve was significantly related to the ULV. High defibrillation threshold patients could be detected by the ARI dynamics.

Crista Terminalis as the Anterior Pathway of Typical Atrial Flutter: Insights from Entrainment Map with 3D Intracardiac Ultrasound.

BACKGROUND: The precise location of truly active reentry circuits of typical atrial flutter (AFL) has not been well identified. The purpose of this study was to verify our hypothesis that the posterior block line is located along the posteromedial right atrium (PMRA) and the crista terminalis (CT) is the anterior pathway of AFL, with real-time intracardiac echo (ICE). METHODS: The entire right atrium (RA) three-dimensional activation and entrainment mapping were evaluated during AFL in 18 patients using CARTO sound. RESULTS: The CT was clearly visualized by ICE and the local electrograms along the CT were single potentials in all the patients. The CT was recognized as the truly active anterior pathway based on entrainment mapping in all patients. Double potentials were recorded along the PMRA. Entire RA entrainment mapping could be performed in 16 patients. The reentry circuits were separated into three passages. The first was around the tricuspid annulus (TA), the second the anterior superior vena cava (SVC; AFL waves passed between the anterior SVC and RA appendage), and the last the posterior SVC (between the posterior SVC and upper limit of the PMRA). All three of these passages were active in four, around the TA and anterior SVC in eight, around the TA and posterior SVC in three, and around only the anterior SVC in one patient. CONCLUSIONS: The CT functions as the anterior pathway of typical AFL, and the posterior block line was located along the PMRA. Dual or triple circuits were recognized in the majority of AFL patients.

Administration of high dose eicosapentaenoic acid enhances anti-inflammatory properties of high-density lipoprotein in Japanese patients with dyslipidemia.

OBJECTIVE: It has been reported that high-density lipoprotein (HDL) loses anti-inflammatory function and promotes atherosclerosis under pathological conditions. However, no pharmacological therapy to improve HDL function is currently available. We aimed to evaluate the effect of oral administration of eicosapentaenoic acid (EPA) on HDL function. METHODS: Japanese patients with dyslipidemia were treated with EPA (1800 mg/day, 4 weeks), and anti-inflammatory functions of HDL were assessed utilizing in vitro cell-based assays. RESULTS: The EPA treatment did not change serum cholesterol and triglyceride levels, but it significantly increased EPA concentrations in the serum and HDL fraction. The EPA/arachidonic acid ratio in the HDL was in proportion to that in the serum, suggesting that the orally administered EPA was efficiently incorporated into the HDL particles. The HDL after EPA treatment showed significantly increased activity of anti-oxidative enzyme, paraoxonase-1. In addition, the EPA-rich HDL significantly improved endothelial cell migration, and markedly inhibited cytokine-induced expression of vascular cell adhesion molecule-1, in human umbilical vein endothelial cells, compared to HDL before the EPA treatment. Moreover, the EPA-rich HDL augmented cholesterol efflux capacity from macrophages. CONCLUSION: Oral administration of EPA regenerated anti-oxidative and anti-inflammatory functions of HDL, and promoted cholesterol efflux from macrophages. Therefore, EPA may transform "dysfunctional HDL" to "functional", in patients with coronary risk factors.