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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 Conclusion Frailty in AMI patients aged ≥80 years undergoing PCI was associated with major bleeding, in-hospital death, and mid-term mortality.

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 mm

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.

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.

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.

An 83-year-old man was transferred to our hospital due to worsening effort angina pectoris. Electrocardiogram during chest pain at rest showed ST-segment elevation with hyperacute T waves and negative U waves in leads V2 through V4 ([Figure 1A][1]). Sublingual administration of nitroglycerin

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.

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-1β) and coronary endothelial dysfunction in patients with mTOR-inhibitor DES implantation and to investigate the association between the mTOR pathway and IL-1β. 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-1β levels. Coronary endothelial dysfunction was evaluated by intracoronary infusion of incremental doses of acetylcholine. Serum IL-1β levels were significantly associated with the magnitude of vasoconstriction to acetylcholine at the segment distal (P

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. .

ObjectivesThis study sought to evaluate the relationship between coronary endothelial function and neointimal coverage after drug-eluting stent (DES) implantation.BackgroundThe mechanisms of endothelial dysfunction after DES implantation remain to be fully elucidated. We hypothesized that poor neointimal coverage after DES implantation may be associated with endothelial dysfunction distal to the stent site.MethodsSixty-six stable angina patients treated with a first-generation DES were enrolled. At 9-month follow-up, coronary endothelial function was evaluated with intracoronary infusion of incremental doses of acetylcholine (10−8, 10−7, and 10−6 mol/l) and nitroglycerin (200 μg). Vascular responses at the segments proximal and distal to the stent site were angiographically and quantitatively measured. At the same time, the degree of neointimal coverage was evaluated using coronary angioscopy and classified into 4 grades: 0 (no coverage) to 3 (full coverage).ResultsWe divided the subjects into poor-coverage (grades 0 to 1, n = 33) and good-coverage (grades 2 to 3, n = 33) groups. Acetylcholine induced dose-dependent coronary vasoconstrictions in both groups. At the segment distal to the stent, the magnitude of vasoconstriction to acetylcholine in the poor-coverage group was significantly greater than in the good-coverage group (p < 0.001), whereas vasomotor responses proximal to the stent and vasodilation by nitroglycerine were similar between the 2 groups.ConclusionsCoronary endothelial dysfunction distal to the stent was associated with poor neointimal coverage after DES implantation.

article i nfo Augmenting neovascularization with the use of endothelial progenitor cells (EPCs) is a therapeutic option to rescue critical limb ischemia (CLI). However, the outcomes have been not so satisfactory. The detectable number of injected EPCs at the ischemic site is rather small. If EPCs accumulate more and stay longer there, neovascularization will be augmented. In this study, we tested whether external magnetic forces (EMFs) accumulated magnetized EPCs (Mag-EPCs) at the ischemic site and thereby augmented neovascularization. We cultured peripheral blood-derived mononuclear cells to obtain EPCs and generated Mag-EPCs by a magnetofection method with nanoparticles. Prussian-blue staining revealed magnetic nanoparticles incorporated into the cytoplasms and nuclei of Mag-EPCs. The survival rate of Mag-EPCs at day 9 of culture was 98.7%, indicating no cell toxicity of magnetic nanoparticles. EMFs augmented adhesion capacity of Mag- EPCs not only in the static but also in the flow condition in vitro, compared to without EMFs. The migration capacity of Mag-EPCs with EMFs was 160% more than EPCs or Mag-EPCs without them. After an intravenous injection of Mag-EPCs into the rat with hind-limb ischemia, the recovery of blood flow and capillary density in the ischemic limb were significantly more (p b 0.01) with EMFs than without them. EMFs augmented neovascularization capacity of Mag-EPCs compared to EPCs alone. This method could be a new therapeutic strategy for patients with CLI.

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Hyperlactatemia has been known as a simple marker of poor prognosis in various acutely ill patients. Little is known regarding the prognostic implication of blood lactate level at coronary care unit in patients with acute myocardial infarction (AMI). We investigated the relationship among blood

Mitral regurgitation (MR) is frequently seen in patients with atrial fibrillation (AF) despite no apparent degenerative changes in the leaflet. Annular dilation secondary to left atrial dilation is a possible mechanism of MR associated with AF. We sought to investigate whether successful radio

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.

Aims: Unsatisfactory effects of therapeutic angiogenesis in critical limb ischemia may be ascribed to use of circulating angiogenic cells (CACs) with impaired neovascularization-related capacities of atherosclerotic patients. We tested whether ultrasound cell stimulation can restore the impaired capacities. Methods and Results: During four-day-culture of human peripheral blood-derived mononuclear cells to achieve CACs, we stimulated the culture cells daily with low-intensity pulsed ultrasound stimulation (LIPUS). LIPUS to healthy volunteer-derived culture cells augmented generation and migration capacities of CACs, increased concentrations of angiopoietin 2 and nitrogen oxides in the culture medium, and increased expressions of phosphorylated-Akt and endothelial nitric oxide synthetase in CACs on western blotting. LIPUS to atherosclerotic patient-derived culture cells also augmented the generation and migration capacities of CACs. Although neovascularization in the ischemic hindlimb of athymic nude mice was impaired after intramuscular injection of atherosclerotic patient-derived CACs compared with that of healthy volunteer-derived CACs, LIPUS to atherosclerotic patient-derived culture cells restored the impaired neovascularization. Conclusion: Therapeutic angiogenesis with LIPUS-pretreated CACs may be a new strategy to rescue critical limb ischemia in atherosclerotic patients.

Aims Unsatisfactory effects of therapeutic angiogenesis in critical limb ischaemia may be ascribed to use of circulating angiogenic cells (CACs) derived from atherosclerotic patients with impaired neovascularization-related capacities. We tested whether ultrasound cell stimulation can restore the impaired capacities. Methods and results During culture of human peripheral blood-derived mononuclear cells for 4 days to achieve CACs, we stimulated the cells in culture daily with low-intensity pulsed ultrasound stimulation (LIPUS). Application of LIPUS to cells in culture derived from healthy volunteers augmented the generation and migration capacities of CACs, increased concentrations of angiopoietin 2 and nitrogen oxides in the culture medium, and increased the expression of phosphorylated-Akt and endothelial nitric oxide synthase in CACs on western blotting. Application of LIPUS to cells in culture derived from atherosclerotic patients also augmented the generation and migration capacities of CACs. Although neovascularization in the ischaemic hindlimb of athymic nude mice was impaired after intramuscular injection of CACs derived from atherosclerotic patients compared with that using CACs derived from healthy volunteers, LIPUS of the cells in culture derived from atherosclerotic patients restored the neovascularization capacities. Conclusion Therapeutic angiogenesis with LIPUS-pre-treated CACs may be a new strategy to rescue critical limb ischaemia in atherosclerotic patients.

Buerger's disease often shows poor collateral artery generation (i.e. neovascularization) in the ischemic limbs. However, the etiology has not yet been clarified. Circulating endothelial progenitor cells (EPCs) derived from bone marrow contribute to neovascularization in the multi-step process which includes the following capacities; mobilization, differentiation, adhesion, migration, invasion and secretion.We assessed EPCs capacities in vitro and ex vivo in age- and sex-matched controls (n = 12) and patients with Buerger's disease (n = 12), derived from peripheral blood-derived mononuclear cells (PB-MNCs).In the flow cytometry analysis, the numbers of circulating EPC (CD34(+)/KDR(+) or CD133(+)/KDR(+) PB-MNC) were similar between controls and patients with Buerger's disease. Next, we cultured PB-MNC to obtain EPCs. The number of early outgrowth EPCs was significantly decreased in patients with Buerger's disease (p 0.005), indicating the reduced generation of early outgrowth EPCs in Buerger's disease. However, adhesion, migration, invasion and secretion capacities were not impaired in patients with Buerger's disease.The early outgrowth EPCs generation is reduced in patients with Buerger's disease.

To the Editor: Ischemic peripheral neuropathy is a term used to describe the neurological deficits of peripheral nerves in patients with peripheral artery obstructive disease ([1][1]). Although ischemic peripheral neuropathy is a major complication of critical limb ischemia resulting in impaired

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.