Pd/Pa fluctuation with continuous ATP administration indicates inaccurate FFR measurement caused by insufficient hyperemia.

Continuous intravenous adenosine triphosphate (ATP) administration is the standard method for inducing maximal hyperemia in fractional flow reserve (FFR) measurements. Several cases have demonstrated fluctuations in the ratio of mean distal coronary pressure to mean arterial pressure (Pd/Pa) value during ATP infusion, which raised our suspicions of FFR value inaccuracy. This study aimed to investigate our hypothesis that Pd/Pa fluctuations may indicate inaccurate FFR measurements caused by insufficient hyperemia. We examined 57 consecutive patients with angiographically intermediate coronary lesions who underwent fractional flow reverse (FFR) measurements in our hospital between November 2016 and September 2018. Pd/Pa was measured after continuous ATP administration (150 µg/kg/min) via a peripheral forearm vein for 5 min (FFRA); and we analyzed the FFR value variation in the final 20 s of the 5 min, defining 'Fluctuation' as variation range > 0.03. Then, 2 mg of nicorandil was administered into the coronary artery during continued ATP infusion, and the Pd/Pa was remeasured (FFRA+N). Fluctuations were observed in 23 of 57 patients. The cases demonstrating discrepancies of > 0.05 between FFRA and FFRA+N were observed more frequently in the fluctuation group than in the non-fluctuation group (12/23 vs. 1/34; p < 0.0001). The discrepancy between FFRA and FFRA+N values was smaller in the non-fluctuation group (mean difference ± SD; -0.00026 ± 0.04636 vs. 0.02608 ± 0.1316). Pd/Pa fluctuation with continuous ATP administration could indicate inaccurate FFR measurements caused by incomplete hyperemia. Additional vasodilator administration may achieve further hyperemia when Pd/Pa fluctuations are observed.

Long-Term Prognosis of Patients Who Underwent Percutaneous Transvenous Mitral Commissurotomy for Mitral Stenosis.

The long-term prognosis for up to 20 years of patients who have undergone percutaneous transvenous mitral commissurotomy (PTMC) for mitral stenosis (MS) is unknown.We examined 77 of 93 patients (83%) with MS and who underwent PTMC from 1989 to 2002 at our institute, as well as the occurrence of either one of the following clinical endpoints until September 1, 2018: all-cause death or repeat intervention for the mitral valve.The mean follow-up duration was 20.5 ± 7.3 years. The mean age was 51 ± 11 years. Overall, the 20-year survival rate was 71% ± 5%; without any intervention, the 20-year survival rate was 40% ± 6%. In patients who achieved good immediate results (i.e., mitral valve area (MVA) of ≥ 1.5 cm2 without mitral regurgitation (MR) of > 2/4 after PTMC), the 20-year survival rate was 80% ± 6%; without any intervention, the 20-year survival rate was 54% ± 7%.In our 20-year observational study, patients who have undergone PTMC for MS had favorable prognosis, especially in those who achieved good immediate results. In those who had poor immediate results, careful follow-up is needed because they might have more clinical event and any intervention for the mitral valve.

Clinical Predictors of Recurrent Ventricular Arrhythmias in Secondary Prevention Implantable Cardioverter Defibrillator Recipients With Coronary Artery Disease　- Lower Left Ventricular Ejection Fraction and Incomplete Revascularization.

BACKGROUND: The implantable cardioverter defibrillator (ICD) is a standard prevention therapy for patients at high risk for sudden cardiac death (SCD) due to life-threatening ventricular arrhythmia (VA), that is, ventricular fibrillation and ventricular tachycardia. However, clinical predictors of recurrent VA in secondary prevention ICD recipients with coronary artery disease (CAD) remain unknown. Methods and Results: We followed up 96 consecutive patients with CAD undergoing ICD implantation for secondary prevention of SCD. Long-term rates and clinical predictors of appropriate ICD therapy (ICD-Tx) for VA were analyzed. Appropriate ICD-Tx occurred in 41 (42.7%) patients during a median follow-up of 2.4 years (interquartile range, 0.9-6.1). These patients had significantly greater left ventricular end-diastolic diameter (62.3±1.3 vs. 54.6±1.1 mm, P<0.001), lower left ventricular ejection fraction (LVEF; 36.3±2.0% vs. 45.7±1.8%, P<0.001), and more incomplete revascularization (ICR; 70.7% vs. 45.5%, P=0.014) than those without appropriate ICD-Tx. Multivariable analysis showed that LVEF (hazards ratio [HR], 0.950; 95% CI: 0.925-0.975; P<0.001) and ICR (HR, 2.293; 95% CI: 1.133-4.637; P=0.021) were significant predictors of appropriate ICD-Tx for VA. CONCLUSIONS: Lower LVEF and ICR were independent predictors of recurrent VA in secondary prevention ICD recipients with CAD.

Dual Antiplatelet Therapy Guided by CYP2C19 Polymorphisms after Implantation of Second-Generation Drug-Eluting Stents for Management of Acute Coronary Syndrome.

Prasugrel, a novel P2Y12 receptor inhibitor, is administered to patients with acute coronary syndrome (ACS) after percutaneous coronary intervention (PCI), but it can increase the risk of bleeding. The Japanese exhibit weaker responses to clopidogrel than other races because of CYP2C19 polymorphisms; thus, it is unclear whether these patients should continue dual antiplatelet therapy (DAPT) using prasugrel or switch to clopidogrel in the chronic phase. Here we evaluated the clinical outcomes of DAPT guided by CYP2C19 polymorphisms after implantation of second-generation drug-eluting stents (DESs) for ACS management. Patients with ACS receiving PCI via DES from November 2011 to March 2015 were divided into two groups: conventional DAPT with clopidogrel (n = 41) and gene-guided DAPT (n = 24). In the gene-guided DAPT group, all patients with ACS were given DAPT using prasugrel as soon as possible; extensive and intermediate metabolizers receiving PCI for the first time were switched to clopidogrel at least 2 weeks after discharge, and intermediate metabolizers with repeated ACS and poor metabolizers continued on DAPT using prasugrel. Notably, gene-guided DAPT significantly reduced major adverse cardiovascular/cerebrovascular events (MACCEs; 22.0% versus 4.2%, hazard ratio [HR]: 0.15, 95% confidence interval [CI]: 0.01-0.81; P = 0.0247). Hemorrhagic complications were observed in 3.1% of patients receiving conventional DAPT and absent in the gene-guided group. Moreover, multivariate analysis showed that gene-guided DAPT significantly decreased MACCE incidence (HR: 0.15, 95% CI: 0.01-0.81; P = 0.033). Collectively, these data suggest that CYP2C19 polymorphism analysis may improve treatment decisions in patients with ACS receiving DES-PCI.

Asialoerythropoietin exerts stronger angiogenic activity than erythropoietin via its binding affinity to tissue.

PURPOSE: Although erythropoietin (EPO) is known to express angiogenic and cardioprotective effects, it also induces hypertension, polycythemia, and platelet activation, which may cause serious adverse effects in patients with cardiovascular diseases. We compared the angiogenic effects of EPO and its nonerythropoietic derivative, asialo-EPO (AEPO). METHODS: Lower limb ischemia was induced in ICR and C57/BL mice. Mice were injected intramuscularly with 2 µg/kg of EPO derivatives for 6 or 7 days. To assess biological differences, the tissue affinity of both EPO derivatives was analyzed in vitro using heparin affinity column chromatography. Tissue affinity was also analyzed in vivo using an intramuscular pharmacokinetic study. RESULTS: The survival of ischemic legs was better in the AEPO group than that in the EPO group (5/13 = 38.5 % vs 1/13 = 7.7 %, p < 0.05), and an increase in regenerated vessels was observed in the AEPO group, but not in the EPO group in ICR mice. Vessel/muscle ratios in control, EPO, and AEPO groups were 0.50 ± 0.34, 0.61 ± 0.32, and 2.83 ± 1.13, respectively (p < 0.0001). On the other hand, regenerated vessels were observed in both EPO and AEPO groups (p < 0.001) in C57/BL mice. AEPO, but not EPO, expressed heparin affinity in vitro. Intramuscularly injected EPO gradually decreased in muscle tissue, while AEPO was maintained at 2.5 ng/muscle for 1 day after several hours of a rapid clearance phase in vivo. CONCLUSIONS: AEPO exerts stronger angiogenic effects than those of EPO presumably via its tissue affinity. Administration of AEPO is a promising option for the treatment of patients with critical limb ischemia.

Revisit of aneurysm clip closing forces: comparison of titanium versus cobalt alloy clip.

Although closing force of cobalt alloy clip is well studied, there is only little information of titanium alloy clip available in the literature. In the present study, we examined and compared closing forces of various types and points of cerebral titanium and cobalt aneurysm clips for cerebral aneurysms. Straight, temporary, bayonet, angled, and fenestrated titanium or cobalt alloy clips were tested by measuring the closing forces at various points along their blade length. Closing forces of all the tested clips linearly increased from tip to base of clip blades. Sugita Titanium II clips had bigger closing forces than Elgiloy clips in all type clips except for the temporary clips. The closing forces of Sugita Titanium II and Yasargil titanium clips were similar in straight permanent type clip although there were some differences in closing forces between other types of Sugita and Yasargil clips. Our data showed that the closing forces differed depending not only on manufacturers but also on materials and shapes.

Emergency EC-IC bypass for symptomatic atherosclerotic ischemic stroke.

Previous studies have shown that extracranial-intracranial (EC-IC) bypass surgery has no preventive effect on subsequent ipsilateral ischemic stroke in patients with symptomatic atherosclerotic internal carotid occlusion and hemodynamic cerebral ischemia. A few studies have assessed whether an urgent EC-IC bypass surgery is an effective treatment for main trunk stenosis or occlusion in acute stage. The authors retrospectively reviewed 58 consecutive patients who underwent urgent EC-IC bypass for symptomatic internal carotid artery or the middle cerebral artery stenosis or occlusion between January 2003 and December 2011. Clinical characteristics and neuroimagings were evaluated and analyzed. Based on preoperative angiogram, responsible lesions were the internal carotid artery in 19 (32.8%) patients and the middle cerebral artery in 39 (67.2%). No hemorrhagic complication occurred. Sixty-nine percent of patients showed improvement of neurological function after surgery, and 74.1% of patients had favorable outcome. Unfavorable outcome was associated with insufficient collateral flow and new infarction after bypass surgery.

Efficacy of Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitor Treatment for Repeated In-stent Restenosis in a Coronary Artery.

A 57-year-old woman experienced chest pain. A coronary angiogram revealed middle left anterior descending artery stenosis. Despite receiving adequate anti-hyperlipidemia treatment and undergoing percutaneous coronary intervention (PCI), she experienced angina and required PCI six more times for in-stent restenosis. As she had high lipoprotein (a) [LP-(a)] levels at the seventh PCI procedure, proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i) was administered, and a reduction in the LP-(a) and low-density lipoprotein cholesterol (LDL-C) values was observed. She experienced no recurrence of angina for five years with PCSK9i treatment. PCSK9i can reduce not only LDL-C but also LP-(a) levels, resulting in cardiac event risk reduction.

Hypocellularity and insufficient expression of angiogenic factors in implanted autologous bone marrow in patients with chronic critical limb ischemia.

The aim of this study was to identify the clinical parameters of absolutely poor-prognosis patients with chronic critical limb ischemia (AP-CLI). Sixteen no-option CLI patients with arteriosclerosis obliterans: ASO (nine) and non-ASO patients (seven) treated with bone marrow-mononuclear cell implantation (BMI) were analyzed. There were three AP-CLI patients (all ASO). The mRNA expression of several angiogenic factors in the implanted cells was analyzed in comparison with normal donor bone marrow. To observe the response of bone marrow components to hypoxia, normal bone marrow cells were cultured for 24 h in 2.5% O(2), and mRNA expression of angiogenic factors were measured. AP-CLI patients exhibited extraordinary low bone marrow cellularity as well as the percentage of CD34-positive cells. Among angiogenic factors, only VEGF expression was maintained in response to HIF-1, while other factors such as HGF, Ang-1, PLGF, and SDF-1 decreased in the implanted bone marrow cells of the patients with CLI compared to normal bone marrow cells. HIF-1 and all of the five angiogenic factors increased in vitro in response to hypoxia. Thus it is highly likely that angiogenic factors except VEGF do not respond to chronic ischemia in bone marrow in vivo. An organ-protection system against tissue ischemia may be applied for acute hypoxia, but it may be insufficient for chronic ischemia.

Erythropoietin, but not asialoerythropoietin or carbamyl-erythropoietin, attenuates monocrotaline-induced pulmonary hypertension in rats.

Erythropoietin (EPO) has long been utilized for the treatment of renal anemia. The erythropoietin receptor (EPOR) is also expressed in the cardiovascular and central nervous systems in addition to an erythroid lineage, to provide an organoprotective role against several types of cellular stress. Pulmonary hypertension (PH) is a poor prognostic disease caused by primary and secondary pulmonary vascular injury. We observed the effects of EPO derivatives on monocrotaline-induced PH in rats on the supposition that EPO may protect small arteries from injury. Asialoerythropoietin (AEPO) lacks sialic acids in the termini of carbohydrate chains that results in rapid clearance from blood. Carbamyl-erythropoietin (CEPO) interacts with EPOR/ßc heterodimers, but not with EPOR homodimers expressed in erythroid cells. Monocrotaline-injected rats were treated with continuous intravenous injection of 2500 ng/kg/day of EPO, AEPO, or CEPO for 21 days, and lung histology, cardiac function, and mRNA expression in the lungs were examined. Wall thickening of small arteries in the lungs and PH were improved by administration of EPO, but not by its non-hematopoietic derivatives, AEPO, or CEPO. Erythropoietin administration increased mRNA expression of the anti-apoptotic molecule, Bcl-xL, and maintained expression of the CD31 antigen. We conclude that lungs may express EPOR homoreceptors, but not heteroreceptors. Adequate serum erythropoietin levels may be essential for pulmonary protective effects.

Improvement of Mass Lesions around Coronary Arteries and Fractional Flow Reserve after Steroid Therapy in Immunoglobulin-G4-related Coronary Periarteritis.

Immunoglobulin-G4-related disease (IgG4-RD) is a multi-organ systemic inflammatory disorder. The ideal treatment of coronary artery involvement in IgG4-RD remains uncertain due to its rarity. We herein report a case of coronary artery involvement with IgG4-RD, wherein mass lesions surrounded the coronary arteries with a moderate stenosis lesion in the right coronary artery (RCA). The fractional flow reserve (FFR) of the RCA was 0.76. After steroid therapy, the mass lesions around the coronary arteries improved. The FFR of the RCA also improved from 0.76 to 0.86. These findings suggest the efficacy of using steroid therapy for coronary artery involvement with IgG4-RD.

Correlation Between the Japanese Version of the High Bleeding Risk (J-HBR) Criteria and the PRECISE-DAPT Score, and Optimal J-HBR Cut-Off Score to Predict Major Bleeding.

Background: The correlation between the Japanese version of high bleeding risk (J-HBR) criteria and the Predicting Bleeding Complications in Patients Undergoing Stent Implantation and Subsequent Dual Antiplatelet Therapy (PRECISE-DAPT) score is unknown, as is the relationship of both risk scores with ischemic events. Methods and Results: This study enrolled 842 patients who underwent percutaneous coronary intervention (PCI) between January 2016 and December 2020. The 2 bleeding risk scores at the time of PCI and the subsequent risk of bleeding and ischemic events over a 1-year follow-up were examined. The J-HBR score was significantly correlated with the PRECISE-DAPT score (r=0.731, P<0.001). However, 1 year after PCI, the J-HBR was not significantly associated with the incidence of major bleeding and ischemic events (log-rank, P=0.058 and P=0.351, respectively), whereas the PRECISE-DAPT score predicted both the incidence of major bleeding and ischemic events (log-rank, P=0.006 and P=0.019, respectively). According to receiver operating characteristic curve analysis, a J-HBR score ≥1.5 was significantly associated with a higher cumulative incidence of major bleeding, but not ischemic events (log-rank, P=0.004 and P=0.513, respectively). Conclusions: The J-HBR score is highly correlated with the PRECISE-DAPT score. A J-HBR score ≥1.5 can identify high bleeding risk patients without an increased risk of ischemic events.

Transcatheter coil embolization for large pulmonary arteriovenous fistulae through an artificial tricuspid ball valve.

Pulmonary arteriovenous fistulae (PAFs) occur congenitally or are acquired. A PAF can cause hypoxemia, sudden death from rupture, abscess formation, and embolism. Treatment for PAF is transcatheter embolization or surgery. Transcatheter embolization is the first choice of treatment; however, this treatment is impossible to perform if a patient has had tricuspid or pulmonary valve replacement. In this paper, we describe a case of PAFs complicated with tricuspid valve replacement with a ball valve (which had been performed 40 years earlier) that was treated with transcatheter embolization. .

Conservative treatment with an intra-aortic balloon pump to treat acute myocardial infarction due to spontaneous coronary artery dissection.

Spontaneous coronary artery dissection (SCAD) is a rare cause of acute coronary syndrome. Treatment for SCAD includes conservative approaches, percutaneous coronary intervention (PCI), and coronary artery bypass graft surgery. Although the success rate of PCI is low, conservative treatment often leads to a good clinical course. Three patients with SCAD who were conservatively treated with intra-aortic balloon pumping without coronary intervention are presented. All three patients continue to do well. .

Establishment of culturing system for ex-vivo expansion of angiogenic immature erythroid cells, and its application for treatment of patients with chronic severe lower limb ischemia.

Angiogenesis therapy by bone marrow-mononuclear cell implantation (BMI) has been utilized. We found that erythroid cells played an essential role in angiogenesis by BMI. We then tried to establish a novel cell therapy by implantation of ex vivo expanded immature erythroblasts cultured from hematopoietic stem/precursor cells. Immature to mature erythroblasts were purified from human bone marrow, and mRNA expression were analyzed. Strongly expressed VEGF and PLGF in immature erythroid cells decreased according to erythroid maturation. To expand very immature erythroid cells, we established a two-step culturing system, i.e., bone marrow cells were cultured in the presence of Flt-3L, SCF and TPO for 7 days, and the cells were further cultured in the presence of SCF, IGF-I and EPO for an additional 7 days. The in vivo angiogenic effects of implantation of the ex vivo expanded cells were stronger than that of BMI in mouse limb ischemia model. Three patients with severe chronic lower limb ischemia accompanied by Burger's disease or collagen arteritis were enrolled in a pilot clinical trial of the novel cell therapy by transplantation of ex-vivo expanded immature erythroid cells. In the clinical trial, most clinical symptoms such as rest pain and skin ulcers improved in 4 weeks, and did not recur in the one-year follow-up. No adverse events were observed in any of the patients. Moreover this novel cell therapy required only a small amount of bone marrow collection. Further enrollment of patients with chronic severe lower limb ischemia is necessary to confirm the efficacy and safety of this novel cell therapy, and to estimate the necessary amount of bone marrow aspirate.

[Application of a polyethylene glycol hydrogel sealant system to prevent CSF leakage for lumbar intradural surgery: technical case report].

Postoperative cerebrospinal fluid (CSF) leakage is one of the most important surgical complications in spinal surgery. Particularly in intradural spinal cord tumor surgery, it is very important to prevent CSF leakage postoperatively, as it can lead to postoperative complications such as infection and pseudomeningocele formation. Compared to the intracranial region, as the operative field is narrower and the structure of the dura mater is more fragile in the spinal region, meticulous dural suturing is sometimes impossible after intradural procedures. To prevent CSF leakage, some surgical procedures and materials have been developed in the neurosurgical field, including the recently introduced polyethylene glycol-based hydrogel sealant system. The hydrogel sealant system consists of synthetic absorbable material, which eliminates the risk of viral transmission and reduces the risk of allergic reaction. It proved to have potential for reducing postoperative CSF leakage. We used this material in intradural lumbar lesion surgery, and postoperative CSF leakage did not occur with this surgical procedure. We report our experience with dural plasty using the hydrogel sealant system in the intradural lumbar spinal lesion surgery and discuss the usefulness of this material.