Eicosapentaenoic Acid-Enriched High-Density Lipoproteins Exhibit Anti-Atherogenic Properties.

BACKGROUND: It has previously been reported that oral administration of purified eicosapentaenoic acid (EPA) generates EPA-rich high-density lipoprotein (HDL) particles with a variety of anti-inflammatory properties. In this study, the mechanism underlying the anti-atherogenic effects of EPA-rich HDL using reconstituted HDL (rHDL) was investigated.Methods and Results:rHDL was generated by the sodium cholate dialysis method, using apolipoprotein A-1 protein, cholesterol, and various concentrations of EPA-phosphatidylcholine (PC) or egg-PC. Increased EPA-PC contents in rHDL resulted in decreased particle size. Next, the effects of rHDL containing various amounts (0-100% of total PC) of EPA-PC on vascular cell adhesion molecule-1 (VCAM-1) expression in human umbilical vein endothelial cells (HUVECs) was examined. Cytokine-stimulated VCAM-1 expression was inhibited in a dose-dependent manner based on the amount of EPA-PC in rHDL. Surprisingly, the incubation of HUVECs with EPA-rich rHDL resulted in the production of resolvin E3 (RvE3), an anti-inflammatory metabolite derived from EPA. Incubation with EPA-PC alone did not adequately induce RvE3 production, suggesting that RvE3 production requires an endothelial cell-HDL interaction. The increased anti-inflammatory effects of EPA-rich HDL may be explained by EPA itself and RvE3 production. Furthermore, the increase in EPA-PC content enhanced cholesterol efflux. CONCLUSIONS: The EPA-enriched HDL particles exhibit cardioprotective properties via the production of anti-inflammatory lipid metabolites and the increase in cholesterol efflux.

Effectiveness of directional coronary atherectomy in treating recurrent in-stent restenosis: a case report.

Background: In-stent restenosis (ISR) remains a significant clinical problem. It is estimated that 10-20% of patients who develop a first event of ISR will develop recurrent ISR (R-ISR). However, the pathology of R-ISR remains largely unknown, and recommendations for its optimal management are lacking. In this case report, we discuss the effectiveness of directional coronary atherectomy (DCA) as an atherectomy device and the mechanism of R-ISR based on pathological findings obtained from DCA. Case summary: We report the case of a 62-year-old man with a history of ST-segment elevation myocardial infarction treated with percutaneous coronary intervention (PCI) to the mid left circumflex artery using a bare metal stent. Even after the introduction of adequate secondary prevention therapy for ISR, the patient underwent a total of six PCI sessions over 10 years following primary PCI for R-ISR. Eventually, the decision was made to institute treatment with DCA and a drug-coated balloon. No symptoms of restenosis were observed over the following 4 years. Discussion: In this case report, we demonstrate the effectiveness of DCA treatment for debulking a wide range of collagen-rich plaques and show that DCA treatment should be considered for the treatment of R-ISR.

Usefulness of selective percutaneous transluminal angioplasty using renal echo for a patient with bilateral renal artery stenosis and chronic renal failure.

A man in his 70s visited the hospital for chronic kidney disease with hypertension. He had anuria for several days before visiting the hospital. His creatinine level rose to 8.97 mg/dL (from 3 mg/dL) and his systemic blood pressure increased to 183 mm Hg. Other uraemic symptoms were also observed, and he was therefore admitted to the hospital and started continuous haemodiafiltration. MRI and angiography showed a highly stenotic lesion with calcification at the origin of the renal artery; a CT scan showed atrophy of the left kidney. Renal Doppler ultrasonography was performed and renal resistive indexes were: 0.92 for the left kidney and 0.68 for the right kidney. The viability of the right kidney was thought to be maintained, and percutaneous transluminal renal angioplasty (PTRA) for the right renal artery stenosis was performed; his creatinine level improved (3 mg/dL) and his systolic blood pressure decreased (120 mm Hg). We implanted a stent on the right stenotic lesion and the right renal artery blood flow improved. We experienced an effective PTRA for the right renal artery for bilateral renal artery stenosis. Although the indications of PTRA for renal artery stenosis are limited, the evaluation of renal function using ultrasonography could be a useful index for determining the culprit lesion.

Predictive Factors for Limb Salvage and Foot Ulcer Recurrence in Patients with Chronic Limb-Threatening Ischemia After Multidisciplinary Team Treatment: A 6-Year Japanese Single-Center Study.

Chronic limb-threatening ischemia (CLTI) is associated with a short-term risk of limb loss. Multidisciplinary teams are often involved in CLTI treatment; however, in Asian countries, multidisciplinary teams that include podiatrists specializing in foot wounds and vascular surgeons who can perform distal bypass surgery are lacking. We investigated predictive factors for limb salvage and foot ulcer recurrence in patients with CLTI treated by a Japanese single-center intensive multidisciplinary team over 6 years. We retrospectively investigated 84 patients with CLTI and foot ulcers who had undergone revascularization and wound treatment between October 2013 and December 2019. Following postrevascularization treatment, including undertaking minor amputations, the healing rate was 77.8%, and the average wound healing time was 75 ± 68 days. To achieve adequate blood supply, 17.7% of patients were treated using a combination of endovascular revascularization and bypass surgeries. Thirty-three (44%) patients had wound recurrence and there was wound recurrence within 6 months in 58.9% of these patients. Multivariate logistic regression analysis showed that postrevascularization skin perfusion pressure was significantly associated with wound healing (odds ratio [OR] 1.13, 95% confidence interval [CI] 1.033-1.243, P = .0078). Diabetes mellitus (OR 9.72, 95% CI 1.855-50.937, P = .0071), and heart disease (OR 3.51, 95% CI 1.052-11.693, P = .0411) were significantly associated with wound recurrence (P < .05). Treatment within a single-center intensive multidisciplinary team resulted in good patient outcomes. Our study indicates that the revascularization endpoint of CLTI treatment should be marked by attainment of adequate blood supply and wound healing. The timing of revascularization and debridement is of utmost importance for the successful treatment of CLTI wounds.

Treatment of sick sinus syndrome in a patient with cardiac lymphoma via chemotherapy without pacemaker implantation: A case report.

Successful treatment of the acute phase of bradycardia in patients with cardiac lymphoma via medical therapy alone has not been reported. This case report describes the successful treatment of sick sinus syndrome in an 84-year-old man with cardiac lymphoma via chemotherapy without pacemaker implantation.

Endovascular abdominal aortic stenosis treatment alleviates renal failure after kidney transplantation.

A 79-year-old man developed bilateral intermittent claudication. Peritoneal dialysis had been initiated at 55 years of age to manage chronic renal failure. In addition, he underwent kidney transplantation at 61 years of age. His Ankle-Brachial Index (ABI) was 0.82 and 0.71 for the right leg and left leg, respectively. Furthermore, his serum creatinine level had increased from 0.98 mg/dL to 2.38 mg/dL over the past 2 years. CT angiography revealed focal calcified stenosis in the terminal abdominal aorta. However, ultrasound revealed no significant stenotic lesion in the supplied artery bound to the transplanted kidney from the right external iliac artery. We performed endovascular therapy for abdominal aortic stenosis using the pressure gradient. Following the procedure, the patient's symptoms disappeared and the ABI increased to 1.25 and 1.14 in the right leg and left leg, respectively. Furthermore, the serum creatinine level improved to 0.96 mg/dL.

Percutaneous treatment of acute axillary artery occlusion after percutaneous coronary intervention: A case report.

The JR guide catheter is preferred for operability; however, we should pay more attention to the guide catheter in the case of radial artery approach with severe vessel tortuosity especially in patients with hypertension or in older female patients.

De novo recurrent spontaneous coronary artery dissection in nonatherosclerotic elderly woman: A case report.

Spontaneous coronary artery dissection (SCAD) is a rare disease which causes acute myocardial infarction (AMI). In this case, we show the recurrence of SCAD and pathological findings of an intimal tear that lead to SCAD of the proximal left anterior descending branch which could contribute to the onset of AMI.

Effect of rosuvastatin and eicosapentaenoic acid on neoatherosclerosis: the LINK-IT Trial.

AIMS: We aimed to assess the effect of 10 mg/day of rosuvastatin plus eicosapentaenoic acid (EPA) versus 2.5 mg/day of rosuvastatin on the extent of neoatherosclerosis using optical coherence tomography (OCT). METHODS AND RESULTS: We randomly assigned 50 patients with non-obstructive neoatherosclerotic plaques detected on OCT to receive either rosuvastatin 10 mg/day and EPA 1,800 mg/day (intensive therapy group) or rosuvastatin 2.5 mg (standard therapy group). Follow-up OCT was performed one year later to evaluate serial changes in neoatherosclerosis. The serum low-density lipoprotein cholesterol (LDL-C) level decreased significantly from baseline to 12-month follow-up in the intensive therapy group (89 mg/dL to 70 mg/dL; p<0.001), while no change occurred in the standard therapy group. Lipid index change and percent changes in macrophage grade were significantly lower in the intensive therapy group than in the standard therapy group (-53.6 vs 310.1, p=0.001; -37.0% vs 35.3%, p<0.001; respectively). Percent changes in lipid index and macrophage grade were positively correlated with the changes in serum LDL-C and C-reactive protein levels, and negatively correlated with the change in serum EPA/arachidonic acid and 18-hydroxyeicosapentaenoic acid (EPA bioactive metabolite) level. CONCLUSIONS: Compared with rosuvastatin 2.5 mg/day, rosuvastatin 10 mg/day and EPA 1,800 mg/day significantly stabilised non-obstructive neoatherosclerotic plaques. CLINICAL TRIAL REGISTRATION: UMIN ID: UMIN000012576. https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000014711.

Efficacy of Complex Fractionated Atrial Electrogram-Guided Extensive Encircling Pulmonary Vein Isolation for Persistent Atrial Fibrillation.

Background: In persistent AF, the effect of adjunctive ablation in addition to PV isolation (PVI) is controversial. We considered a new modified PVI including complex fractionated atrial electrogram (CFAE) area. Methods and Results: In 57 patients with persistent AF undergoing first ablation, CFAE were mapped before ablation and CFAE-guided extensive encircling PVI (CFAE-guided EEPVI) was performed. The PVI line was designed to include the CFAE area near PV or to cross the minimum cycle length points of the CFAE area near PV (CFAE-guided EEPVI group). The outcome was compared with conventional PVI in 34 patients with persistent AF (conventional PVI group). During a mean follow-up of 365±230 days after the first procedure, AF in 13 and atrial tachycardia (AT) in 9 patients recurred in the CFAE-guided EEPVI group, while only AF in 17 patients recurred in the conventional PVI group. Eight of 9 AT in the CFAE-guided EEPVI group were successfully ablated at second procedure. After first and second procedures, the recurrence of atrial tachyarrhythmia in the CFAE-guided EEPVI group was significantly reduced compared with the conventional PVI group (8 patients, 14% vs. 11 patients, 32%, respectively; P<0.01, log-rank test). Conclusions: CFAE-guided EEPVI was more effective for persistent AF compared with conventional PVI after first and second procedures, because recurring AT as well as re-conduction of PV was successfully ablated.

Enhanced Impact of Cholesterol Absorption Marker on New Atherosclerotic Lesion Progression After Coronary Intervention During Statin Therapy.

AIM: Clinical trials suggest that residual risks remain for coronary artery disease (CAD) during low-density lipoprotein cholesterol (LDL-C) lowering therapy. We aimed to investigate the role of exogenous lipids in the prognosis of CAD after percutaneous coronary intervention (PCI). METHODS: A total of 145 patients with CAD, who underwent elective PCI, and 82 non-CAD (control) patients were enrolled in this study. CAD patients underwent follow-up coronary angiography 6-9 months after PCI, and were classified into three groups: 1) patients who showed in-stent restenosis (ISR) in the original stented segment, 2) patients with other non-target coronary atherosclerotic lesions (de novo), and 3) patients with neither ISR nor a de novo lesion. Biochemical analyses were performed on fasting serum samples at the time of follow-up coronary angiography. RESULTS: Despite the controlled serum LDL-C levels, CAD patients with statin showed elevated cholesterol absorption marker campesterol/total cholesterol (TC), synthesis marker lathosterol/TC, campesterol/lathosterol ratio, and apolipoprotein B48 (apoB48) concentration compared with non-CAD patients. The high campesterol/TC, campesterol/lathosterol ratio, and apoB48 concentration were associated with de novo lesion progression after PCI. In stepwise multivariate logistic regression analysis, campesterol/TC and apoB48 concentrations were independent risk factors for de novo lesion progression in statin-treated CAD patients after PCI. CONCLUSION: The increase of cholesterol absorption marker and apoB48 concentration may lead to the progression of de novo lesions, and these markers may represent a residual risk during statin treatment after PCI.

High-density lipoprotein protects cardiomyocytes from oxidative stress via the PI3K/mTOR signaling pathway.

Low levels of plasma high-density lipoprotein (HDL) cholesterol are associated with an increased risk of heart failure, regardless of the presence or absence of coronary artery disease. However, the direct effects of HDL on failing myocardium have not been fully elucidated. We found that HDL treatment resulted in improved cell viability in H9c2 cardiomyocytes under oxidative stress. This cardioprotective effect of HDL was regulated via the phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway. mTOR signaling promotes cell survival through the inactivation of the BCL2-associated agonist of cell death via phosphorylation of ribosomal protein S6 kinase. Modulation of cardiac PI3K/mTOR signaling by HDL could represent a novel therapeutic strategy for heart failure.

Novel mechanism of regulation of the 5-lipoxygenase/leukotriene B4 pathway by high-density lipoprotein in macrophages.

High-density lipoprotein (HDL) interacts with various cells, particularly macrophages, in functional cell-HDL interactions. Here, we found that HDL protein quality and lipid quality play critical roles in HDL functions. HDL fractions from healthy volunteers (HDLHealthy) and patients with recurrent coronary atherosclerotic disease (HDLCAD) were prepared. To analyse functional HDL-macrophage interactions, macrophages were co-incubated with each HDL, and lipid mediator production was assessed by liquid chromatography/mass spectrometry-based metabololipidomics. HDLHealthy treatment attenuated the pro-inflammatory lipid mediator production, particularly that of leukotriene (LT) B4, and this treatment enhanced lipoxin (LX) B4 and resolvin (Rv) E2 production. HDLHealthy treatment enhanced the proteasome-mediated degradation of the LTB4-producing enzyme 5-lipoxygenase (LO) in activated macrophages; however, HDLCAD did not show these anti-inflammatory effects. HDLHealthy was engulfed by macrophages via clathrin-mediated endocytosis, which was a critical step in 5-LO/LTB4 regulation. We also found that HDLCAD showed higher levels of the LTB4-producing enzymes and thus promoted LTB4 production from HDLCAD. In addition, LTB4 attenuated HDL endocytosis, HDL-mediated 5-LO degradation in macrophages, and HDL-derived augmentation of macrophage phagocytosis. These results indicated that local LTB4 produced de novo from HDLCAD regulates HDL-macrophage functional interactions and plays critical roles in dysfunctional, inflammatory HDL characteristics.

2-Aminobutyric acid modulates glutathione homeostasis in the myocardium.

A previous report showed that the consumption of glutathione through oxidative stress activates the glutathione synthetic pathway, which is accompanied by production of ophthalmic acid from 2-aminobutyric acid (2-AB). We conducted a comprehensive quantification of serum metabolites using gas chromatography-mass spectrometry in patients with atrial septal defect to find clues for understanding myocardial metabolic regulation, and demonstrated that circulating 2-AB levels reflect hemodynamic changes. However, the metabolism and pathophysiological role of 2-AB remains unclear. We revealed that 2-AB is generated by an amino group transfer reaction to 2-oxobutyric acid, a byproduct of cysteine biosynthesis from cystathionine. Because cysteine is a rate-limiting substrate for glutathione synthesis, we hypothesized that 2-AB reflects glutathione compensation against oxidative stress. A murine cardiomyopathy model induced by doxorubicin supported our hypothesis, i.e., increased reactive oxygen species are accompanied by 2-AB accumulation and compensatory maintenance of myocardial glutathione levels. Intriguingly, we also found that 2-AB increases intracellular glutathione levels by activating AMPK and exerts protective effects against oxidative stress. Finally, we demonstrated that oral administration of 2-AB efficiently raises both circulating and myocardial glutathione levels and protects against doxorubicin-induced cardiomyopathy in mice. This is the first study to demonstrate that 2-AB modulates glutathione homeostasis in the myocardium.