Direct Oral Anticoagulants Would Be Best Choice for Atrial Fibrillation Patients After Coronary Stenting: Retrospective Study in a Japanese Population.

BACKGROUND: The combination of dual antiplatelet therapy (DAPT) plus warfarin in atrial fibrillation (AF) patients after coronary stenting has been reported to confer a significant risk of bleeding complications. Direct oral anticoagulants (DOAC) reduce the risk of stroke and bleeding complications in AF patients compared to warfarin. The optimal anticoagulation strategy for Japanese non-valvular AF patients after coronary stenting remains unclear. METHODS: A total of 3230 patients who underwent coronary stenting were retrospectively reviewed. Of these, 284 cases (8.8%) were complicated by AF. Following coronary stenting, 222 patients received triple antithrombotic therapy (TAT) by DAPT plus oral anticoagulants; 121 patients received DAPT plus warfarin, and 101 patients received DAPT plus DOAC. We compared the clinical data between the two groups. RESULTS: The median International normalized ratio (INR) in the DAPT plus warfarin group was 1.61. Bleeding complications occurred in both groups. No cerebral infarction occurred in the DAPT plus DOAC group, while 4.1% of the DAPT plus warfarin group experienced cerebral infarction during follow-up (P=0.04). Twelve-month freedom from cerebral infarction, myocardial infarction, and cardiovascular death was significantly higher in the DAPT plus DOAC group than in the DAPT plus warfarin group [100% vs. 93.4%, P=0.009]. CONCLUSIONS: DOAC might be an optimal selection as an oral anticoagulant for Japanese AF patients who are receiving DAPT after PCI. A larger, longitudinal follow-up should be performed to clarify the clinical advantage of DOAC over warfarin, including among patients who receive single antiplatelet after coronary stent implantation.

Vascular healing in high-bleeding-risk patients at 3-month after everolimus-eluting stent versus biolimus A9-coated stent implantation: insights from analysis of optical coherence tomography and coronary angioscopy.

The prevalence of high-bleeding-risk (HBR) patients who undergo coronary stenting has been reported as 20-40%. This study sought to assess vascular healing in HBR patients by coronary angioscopy (CAS) and optical coherence tomography (OCT). We prospectively analyzed 38 HBR patients with coronary artery disease who successfully underwent everolimus-eluting stent (EES) implantation (20 patients, 23 lesions) or drug-coated stent (DCS) implantation (18 patients, 18 lesions). Follow-up coronary angiography, CAS, and OCT were planned at 3 months after the procedure. The clinical characteristics and inclusion criteria of HBR were comparable between groups. CAS analysis showed that mean yellow color grade was significantly higher with EES than with DCS (1.33 [1.0, 1.67] vs. 1.0 [0.67, 1.5]; P = 0.04). In contrast, OCT analysis demonstrated that most struts in both groups were well-apposed struts with neointimal coverage (93.9% each; P = 1.00), and percentages of the mean neointimal area were comparable between EES and DCS (4.4 ± 3.5 mm2 vs. 4.5 ± 4.1 mm2; P = 0.91). The frequency of uncovered struts was significantly lower with EES than with DCS (2.4% vs. 5.3%; P < 0.001), whereas the frequency of malapposed struts was significantly higher with EES than with DCS (3.5% vs. 0.8%; P < 0.001). During follow-up, no stent thrombosis or major bleeding complications were encountered in either group. Among HBR patients, both EES and DCS demonstrated good vascular healing at 3-month follow-up with some different features in CAS and OCT assessments.

Intra- and Postprocedural Management of Coronary Artery Perforation During Percutaneous Coronary Intervention.

Background: Little is known regarding the postprocedural management of coronary artery perforation (CAP). Methods and Results: The characteristics, outcomes, and management of 115 CAP cases among 13,453 patients undergoing percutaneous coronary intervention (PCI) between 2001 and 2017 at Miyazaki Medical Association Hospital were analyzed retrospectively. The incidence of CAP was 0.85% (25 [0.19%] coronary ruptures [CRs], 90 [0.67%] wire perforations [WPs]). The most prevalent causes of CRs and WPs were rotational atherectomy (36.0%) and polymer-jacketed wires (41.1%), respectively. Fifty-two percent of CRs were treated using prolonged balloon inflation, whereas 50% of WPs were treated through embolization. Immediate and delayed cardiac tamponade (CT) occurred in 20% and 24% of CRs, respectively, and in 2.2% and 10% of WPs, respectively. The mean (±SD) right atrial pressure (RAP) during delayed CT in the CR and WP groups was 16.0±1.2 and 14.0±3.0 mmHg, respectively. New-onset atrial fibrillation developed in 24.0% and 11.1% of patients in the CR and WP groups, respectively, whereas late-onset coronary artery aneurysm (CAA) occurred in 24.0% and 0% of patients, respectively. One-year mortality rates in patients with immediate and delayed CT were 28.6% and 20.0%, respectively. Conclusions: Special attention should be paid to delayed CT, new-onset atrial fibrillation, and late-onset CAA after CAP treatment. Continuous monitoring of RAP after CAP during PCI may be useful for the early detection of delayed CT.

Outcomes of Elderly Patients With Acute Myocardial Infarction and Heart Failure Who Undergo Percutaneous Coronary Intervention.

Background: As life expectancy rises, percutaneous coronary intervention (PCI) is being performed more frequently, even in elderly patients with acute myocardial infarction (AMI). This study evaluated outcomes of elderly patients with AMI complicated by heart failure (AMIHF), as defined by Killip Class ≥2 at admission, who undergo PCI. Methods and Results: We retrospectively analyzed 185 patients with AMIHF aged ≥80 years (median age 85 years) who underwent PCI between 2009 and 2019. The median follow-up period was 572 days. The rates of in-hospital major bleeding (Bleeding Academic Research Consortium Type 3 or 5) and in-hospital all-cause mortality were 20.5% and 25.9%, respectively. The proportion of frail patients increased during hospitalization, from 40.6% at admission to 59.2% at discharge (P<0.01). The cumulative incidence of all-cause mortality was 36.3% at 1 year and 44.1% at 2 years. After adjusting for confounders, advanced age, Killip Class 4, final Thrombolysis in Myocardial Infarction flow grade <3, and longer door-to-balloon time were associated with higher mortality, whereas higher left ventricular ejection fraction and cardiac rehabilitation were associated with lower mortality (all P<0.05). Progression of frailty during hospitalization was an independent risk factor for long-term mortality in hospital survivors (P<0.01). Conclusions: The management of patients with AMIHF aged ≥80 years who undergo PCI remains challenging, with high rates of in-hospital major bleeding, frailty progression, and mortality.

Impact of frailty on outcomes in elderly patients with acute myocardial infarction who undergo percutaneous coronary intervention.

AIMS: Frailty is characterized by reduced biological reserves and weakened resistance to stressors, and is common in older adults. This study evaluated the prognostic implications of frailty at hospitalization in elderly patients with acute myocardial infarction (AMI) who undergo percutaneous coronary intervention (PCI). METHODS AND RESULTS: We prospectively analysed 546 AMI patients aged ≥80 years undergoing PCI from 2009 to 2017. Frailty was classified based on impairment in walking (unassisted, assisted, and wheelchair/non-ambulatory), cognition (normal, mildly impaired, moderately to severely impaired), and basic activities of daily living. Impairment in each domain was scored as 0, 1, or 2, and patients were categorized into the following three groups based on total score: no frailty (0), mild frailty (1-2), moderate-to-severe frailty (≥3). The median follow-up period was 589 days. Of the 546 patients, 27.8% were frail (mild or moderate-to-severe), and this proportion significantly increased to 35.5% at discharge (P < 0.001). Compared to non-frail patients, frail patients were older, less likely to be male, and had a higher rate of advanced Killip class. Major bleeding (no frailty, 9.6%; mild frailty, 16.9%; moderate-to-severe frailty, 31.8%; P < 0.001) and in-hospital mortality (no frailty, 8.4%; mild frailty, 15.4%; moderate-to-severe frailty, 27.3%; P < 0.001) increased as frailty worsened. After adjusting for confounders, frailty was independently associated with higher mid-term all-cause mortality (hazard ratio, 1.81; 95% confidence interval, 1.23-2.65; P = 0.002). CONCLUSION: Frailty in AMI patients aged ≥80 years undergoing PCI was associated with major bleeding, in-hospital death, and mid-term mortality.

Combined Angiotensin Receptor-Neprilysin Inhibitors Improve Cardiac and Vascular Function Via Increased NO Bioavailability in Heart Failure.

BACKGROUND: There is a paucity of data about the mechanisms by which sacubitril/valsartan (also known as LCZ696) improves outcomes in patients with heart failure. Specifically, the effects of sacubitril/valsartan on vascular function and NO bioavailability have not been investigated. We hypothesized that sacubitril/valsartan therapy increases circulating NO levels and improves vascular function in the setting of heart failure. METHODS AND RESULTS: Male spontaneously hypertensive rats underwent myocardial ischemia/reperfusion surgery to induce heart failure and were followed for up to 12 weeks with serial echocardiography. Rats received sacubitril/valsartan (68 mg/kg), valsartan (31 mg/kg), or vehicle starting at 4 weeks after reperfusion. At 8 or 12 weeks of reperfusion, animals were euthanized and tissues were collected for ex vivo analyses of NO bioavailability, aortic vascular reactivity, myocardial and vascular histology, and cardiac molecular assays. Left ventricular structure and function were improved by both valsartan and sacubitril/valsartan compared with vehicle. Sacubitril/valsartan resulted in superior cardiovascular benefits, as evidenced by sustained improvements in left ventricular ejection fraction and end-diastolic pressure. Ex vivo vascular function, as measured by aortic vasorelaxation responses to acetylcholine and sodium nitroprusside, was significantly improved by valsartan and sacubitril/valsartan, with more sustained improvements afforded by sacubitril/valsartan. Furthermore, myocardial NO bioavailability was significantly enhanced in animals receiving sacubitril/valsartan therapy. CONCLUSIONS: Sacubitril/valsartan offers superior cardiovascular protection in heart failure and improves vascular function to a greater extent than valsartan alone. Sacubitril/valsartan-mediated improvements in cardiac and vascular function are likely related to increases in NO bioavailability and explain, in part, the benefits beyond angiotensin receptor blockade.

Predictors of Recurrent In-Stent Restenosis After Paclitaxel-Coated Balloon Angioplasty.

BACKGROUND: Although paclitaxel-coated balloon (PCB) angioplasty is an effective procedure for in-stent restenosis (ISR) after coronary stenting, recurrent ISR after PCB angioplasty still occurs. The aim of this study was to evaluate the predictors of recurrent ISR after PCB angioplasty for ISR.Methods and Results:A total of 157 ISR lesions treated with PCB angioplasty from January 2014 to May 2015 were retrospectively examined. Recurrent ISR was judged on 6-month follow-up angiography. Clinical, angiographic and procedural parameters were evaluated as possible predictors of recurrent ISR. Recurrent ISR occurred in 13.9% of lesions after PCB angioplasty. On multivariate analysis the following independent predictors of recurrent ISR were identified: (1) smaller acute gain after initial ballooning (OR, 3.06; 95% CI: 1.08-8.71; P=0.04); (2) geographic mismatch between PCB position and initial ballooning (OR, 5.59; 95% CI: 1.64-19.1; P=0.006); and (3) use of percutaneous transluminal coronary rotational atherectomy (PTCRA) at primary percutaneous coronary intervention (PCI; OR, 5.53; 95% CI: 1.89-16.2; P=0.002). CONCLUSIONS: Optimal expansion at initial ballooning before PCB angioplasty and careful positioning of PCB are important technical tips to prevent recurrent ISR after PCB angioplasty. Recurrent ISR occurred more frequently in severely calcified lesions that required PTCRA at primary PCI.

Interleukin-1ß is associated with coronary endothelial dysfunction in patients with mTOR-inhibitor-eluting stent implantation.

Implantation of mammalian target of rapamycin (mTOR)-inhibitor drug-eluting stents (DESs) impairs coronary endothelial function. There are no known non-invasive biomarkers of coronary endothelial dysfunction. We aimed to assess the association between serum interleukin-1beta (IL-1ß) and coronary endothelial dysfunction in patients with mTOR-inhibitor DES implantation and to investigate the association between the mTOR pathway and IL-1ß. We enrolled 35 patients who had implanted DESs for coronary artery disease. At a 10-month follow-up, peripheral venous blood samples were collected to measure IL-1ß levels. Coronary endothelial dysfunction was evaluated by intracoronary infusion of incremental doses of acetylcholine. Serum IL-1ß levels were significantly associated with the magnitude of vasoconstriction to acetylcholine at the segment distal (P < 0.05) but not proximal to the stent. Serum IL-1ß levels were positively correlated with stent length (P < 0.05). To examine the direct effects of mTOR inhibition on IL-1ß release, sirolimus was incubated in cultured human umbilical vein endothelial cells (HUVECs) or coronary artery smooth muscle cells (CASMCs). Sirolimus directly increased IL-1ß mRNA expression (P < 0.01) and enhanced IL-1ß release into the culture media (P < 0.01) in CASMCs, but not in HUVECs. Inhibition of mTOR triggers IL-1ß release through transcriptional activation in CASMCs. Serum IL-1ß levels are a potential biomarker for mTOR-inhibitor DES-associated coronary endothelial dysfunction.

Changes in P2Y12 reaction units after switching treatments from prasugrel to clopidogrel in Japanese patients with acute coronary syndrome followed by elective coronary stenting.

Patients with ischemic heart disease are administered a dual antiplatelet therapy after percutaneous coronary intervention. This consists of aspirin and thienopyridine, which can be switched from prasugrel to clopidogrel. However, the impact of switching is unknown. This study aimed to determine the efficacy and safety of switching from prasugrel to clopidogrel in Japanese patients. One-hundred and thirty-six patients with acute coronary syndrome scheduled to undergo percutaneous coronary intervention and patients with coronary artery disease requiring elective coronary stenting were enrolled. Patients were randomly assigned into the following groups: prasugrel for 6 weeks at loading/maintenance doses of 20/3.75 mg (Continued Group; n = 68) or prasugrel at 20/3.75 mg for 2 weeks followed by clopidogrel at 75 mg for 4 weeks (Switched Group; n = 68). Aspirin (loading dose/maintenance dose 324/81-100 mg/day) was coadministered in both groups. The primary endpoint was the mean P2Y12 reaction unit (PRU) at week 6 and the secondary endpoint was the PRU in groups subdivided based on the presence of CYP2C19 gene polymorphisms. At week 6, the PRU was significantly lower in the Continued Group relative to the Switched Group (140.7 and 183.0, respectively; P < 0.001), which was also evident after correction with the baseline values (144.1 vs. 176.6, respectively; P = 0.005). Extensive and poor metabolizers in the Switched Group, based on CYP2C19 gene polymorphisms, had significantly higher PRU values than those in the Continued Group. Thus, switching treatments from prasugrel to clopidogrel significantly increased the PRU in patients receiving antiplatelet therapy subsequent to percutaneous coronary intervention. Clinical Trial Registration UMIN ID, UMIN000015122.

The Course of Ischemic Mitral Regurgitation in Acute Myocardial Infarction After Primary Percutaneous Coronary Intervention: From Emergency Room to Long-Term Follow-Up.

BACKGROUND: Previously published evidence on ischemic mitral regurgitation (IMR) and its adverse prognosis after myocardial infarction has been based on the severity of IMR in the subacute or chronic period of myocardial infarction. However, the state of IMR can vary from the early stage to the chronic stage as a result of various responses of myocardium after primary percutaneous coronary intervention (PCI). METHODS AND RESULTS: Standard echocardiography was serially performed in 546 consecutive patients with first-onset acute myocardial infarction (1) immediately after their arrival (pre-PCI), (2) before discharge (early post-PCI), and (3) 6 to 8 months after PCI (late post-PCI). The course of IMR after primary PCI and the prognostic impact of the IMR in each phase were investigated. IMR was found in 193/546 (35%) patients at the emergency room. In the acute phase after PCI, IMR improved in 63 patients. IMR worsened in 78 patients despite successful PCI. Shorter onset-to-reperfusion time and nontotal occlusion before PCI were the independent predictors of early improvement of IMR. In the chronic phase, IMR improved in 79 patients and worsened in 36 patients. Lower peak creatine kinase-myocardial band was an independent predictor of late improvement of IMR. IMR before PCI worsened 30-day prognosis (P=0.02), and persistent IMR in the chronic phase worsened long-term prognosis (P=0.04) after primary PCI. CONCLUSIONS: Degrees of IMR changed in the early and chronic phase after primary PCI for acute myocardial infarction. IMR on arrival and persistent IMR in the chronic phase worsened short-term and long-term prognosis after acute myocardial infarction, respectively.

Clinical Implications of Additional Pedal Artery Angioplasty in Critical Limb Ischemia Patients With Infrapopliteal and Pedal Artery Disease.

PURPOSE: To evaluate the clinical implications of additional pedal artery angioplasty (PAA) for patients with critical limb ischemia (CLI). METHODS: Twenty-nine patients (mean age 77.8±8.6 years; 21 men) with CLI (32 limbs) presenting with de novo infrapopliteal and pedal artery (Kawarada type 2/3) disease were reviewed. The need for PAA was based on the existence of sufficient wound blush (WB) around the target wounds after conventional above-the-ankle revascularization. Fourteen patients with insufficient WB in 14 limbs received additional PAA, while 15 patients with sufficient WB in 18 limbs did not. The groups were compared for overall survival, limb salvage, and amputation-free survival within 1 year after the procedure. The wound healing rate, time to wound healing, and freedom from reintervention rate were also evaluated. RESULT: The success rate of additional PAA was 93% (13/14). All limbs with successful PAA achieved sufficient WB (13/13). Despite insufficient WB before the additional PAA, overall survival (86% vs 73%, p=0.350), limb salvage (93% vs 83%, p=0.400), amputation-free survival (79% vs 53%, p=0.102), and freedom from reintervention (64% vs 73%, p=0.668) rates were similar in both groups. Furthermore, the wound healing rate (93% vs 60%, p=0.05) was higher and time to wound healing (86.0±18.7 vs 152.0±60.2 days, p=0.05) was shorter in the patients who received PAA. CONCLUSION: Additional PAA might improve the WB and clinical outcomes (especially speed and extent of wound healing) in patients with CLI attributed to infrapopliteal and pedal artery disease.

The impact of three-dimensional optical coherence tomography and kissing-balloon inflation for stent implantation to bifurcation lesions.

The rates of restenosis and stent thrombosis after the therapeutic stent deployment for bifurcation lesions are still comparably high after the introduction of the new-generation drug-eluting stents (DESs), because of the various factors including their morphology. We experienced a case of a successful percutaneous coronary intervention using three-dimensional optical coherence tomography (3D OCT) with a single stent deployment to a bifurcation lesion of the left anterior descending artery (LAD) and left circumflex artery (LCx) with a following kissing-balloon inflation (KBI). The 3D OCT, after the inflation of the jailed ostium of the LCx following the stent deployment to the LAD crossing the LCx, could clearly demonstrate a stent deformation and incomplete apposition at an opposite site of the LCx, which may cause high rates of restenosis and stent thrombosis. These stent abnormalities were steadily corrected by a subsequent KBI of the LAD and LCx. Furthermore, the 3D OCT images were the same findings as those of the experiments from both an in vitro phantom coronary bifurcation model and macroscopic images of the stent. .

FOXO4-knockdown suppresses oxidative stress-induced apoptosis of early pro-angiogenic cells and augments their neovascularization capacities in ischemic limbs.

The effects of therapeutic angiogenesis by intramuscular injection of early pro-angiogenic cells (EPCs) to ischemic limbs are unsatisfactory. Oxidative stress in the ischemic limbs may accelerate apoptosis of injected EPCs, leading to less neovascularization. Forkhead transcription factor 4 (FOXO4) was reported to play a pivotal role in apoptosis signaling of EPCs in response to oxidative stress. Accordingly, we assessed whether FOXO4-knockdown EPCs (FOXO4KD-EPCs) could suppress the oxidative stress-induced apoptosis and augment the neovascularization capacity in ischemic limbs. We transfected small interfering RNA targeted against FOXO4 of human EPCs to generate FOXO4KD-EPCs and confirmed a successful knockdown. FOXO4KD-EPCs gained resistance to apoptosis in response to hydrogen peroxide in vitro. Oxidative stress stained by dihydroethidium was stronger for the immunodeficient rat ischemic limb tissue than for the rat non-ischemic one. Although the number of apoptotic EPCs injected into the rat ischemic limb was greater than that of apoptotic EPCs injected into the rat non-ischemic limb, FOXO4KD-EPCs injected into the rat ischemic limb brought less apoptosis and more neovascularization than EPCs. Taken together, the use of FOXO4KD-EPCs with resistance to oxidative stress-induced apoptosis may be a new strategy to augment the effects of therapeutic angiogenesis by intramuscular injection of EPCs.

Platelet-derived microparticles augment the adhesion and neovascularization capacities of circulating angiogenic cells obtained from atherosclerotic patients.

OBJECTIVE: The neovascularization-related capacities of circulating angiogenic cells (CACs) are impaired in atherosclerotic patients, which may explain the unsatisfactory effects of therapeutic angiogenesis with atherosclerotic patient-derived CACs. Platelet-derived microparticles (PMPs) were reported to augment the re-endothelialization capacity of CACs. Accordingly, we investigated whether PMPs could augment the neovascularization-related capacities of atherosclerotic patient-derived CACs in vitro and in vivo and if so, the associated mechanisms. METHODS AND RESULTS: We isolated mononuclear cells and PMPs from atherosclerotic patient-derived peripheral blood and generated PMP-pretreated CACs (PMP-CACs) by co-culture of the mononuclear cells and PMPs. Although the migration capacity of PMP-CACs was similar to that of CACs, the adhesion capacity of PMP-CACs was greater. PMPs released RANTES into the culture medium, and the receptors were similarly expressed on the surfaces of CACs and PMP-CACs. Intravenous injection of PMP-CACs to rats with hindlimb ischemia augmented neovascularization of the ischemic limbs more than the injection of CACs. The number of PMP-CACs incorporated into the capillaries of the ischemic limbs was greater than that of incorporated CACs. The augmented adhesion and neovascularization capacities by PMP-CACs were canceled out by a RANTES neutralizing antibody. CONCLUSIONS: PMP-secreted RANTES may play a role in the augmenting adhesion and neovascularization capacities of CACs. Injection of PMP-CACs may be a new strategy to augment the effects of therapeutic angiogenesis for limb ischemia in atherosclerotic patients.